13.1: Normal Flora of the Human Body - Biology

The importance of the normal bacterial flora (a.k.a. More recent calculations, however, result in a ratio closer to 1:1, with an estimated 1013 human cells and 1013 – 1015 bacterial cells. No matter the exact proportion of bacteria in the human body, the impact of the microbiota on our physiology is substantial.

It has been known for decades that animals raised without normal flora display a variety of health effects across many body systems. Not surprisingly, neither the digestive system nor the immune system develops properly. The cecum tends to be enlarged and other GI abnormalities appear. The immune system is underdeveloped. More recently it has been shown that the central nervous system, including the brain, does not develop properly in these animals. Because bacteria produce vitamins necessary for animal nutrition (most notably vitamin K), animals without normal flora suffer from vitamin deficiencies. Lack of normal flora also makes animals more susceptible to infection with a variety of pathogens, particularly those that infect the GI tract. Although lack of normal flora generally has negative effects, it does also result in an absence of dental caries and lower body fat.

Normal flora is found in all areas of the human body exposed to the environment (one exception is the lungs), but internal organs and body fluids are considered sterile in a healthy individual. This is generally true, although bacteria are sometimes found in these “sterile” tissues even in healthy people. For instance, a person’s blood will become bacteremic (contain bacteria) for up to three hours after brushing their teeth.

Each area of the human body contains a characteristic population of microbes (Figure (PageIndex{1})), although the exact composition of each person’s flora is unique. The diversity of the bacteria populating the human gut alone is enormous, with an estimated 40,000 species. An increasing number of studies associates such shifts in the gut microbiota with outcomes such as susceptibility to infection, immune disorders, metabolic changes, and altered mood and behavior. Each of these physiological effects can be linked directly to chemical communication within the microbiota and between the microbiota and human.

Flora of the Skin

The exact microbial population on the skin depends on the specific body area. Moist areas, such as axilla (armpits) and groin, tend to have more (and different) bacterial growth compared to drier areas. The most common bacteria of the skin flora are the Gram-positive, catalase positive cocci of the genera Staphylococcus and Micrococcus. Although S. aureus can occasionally be found on the skin, it is more commonly found in the nose in those people that carry it in their normal flora.

Flora of the Mouth and Upper Respiratory Tract

The flora of the mouth and upper respiratory tract is typically associated with a more diverse set of microbes. Streptococci, specifically, alpha-hemolytic Streptococci often referred to collectively as the “viridans Streptococci”are very prominent in the mouth. These include S. mutans, S. sanguis, and S. mitis. S. mutans in particular plays a critical role in the formation of plaque and dental caries (cavities). Although both Staphylococci and Streptococci are Gram-positive cocci, unlike the Staphylococci the Streptococci are catalase-negative, consistent with the low-oxygen environment of the mouth.

Other inhabitants of the mouth and upper respiratory tract include bacteria in the genera Neisseria and Haemophilus. As mentioned above, Staph. aureus is most often found in the nose of those individuals who carry it in their normal flora. The fungal genus Candida is also common in the mouth and upper respiratory tract.

Flora of the Intestines

The most studied population of normal flora in the microbes living in the intestines, often referred to as the gut microbiota. Although the bacterium most commonly associated with the intestines is E. coli, it is actually not the most numerous in the intestine. Bacteria in the phylum Bacteroidetes form a large proportion of bacteria in the gut. The Gram-positive Firmicutes (such as Lactobacillus and Clostridium) and Actinobacteria (including Bifidobacterium) can be equally numerous. In healthy individuals, proteobacteria (including E. coli and other Enterobacteriaceae) are the least abundant of the major bacterial groups in the intestines. There are many other groups of microbes found in the intestines, including fungi such as Candida. It is shifts in the proportions of these groups of microbes that are typically studied when investigating the role of normal flora on human health.

Acquiring Normal Flora

The first introduction of microbiota to a human occurs at birth (a fetus in utero should be microbe-free). Typically, this introduction of flora is from the mother’s vaginal flora. Infants born by caesarean section have significantly different microbiota than those born vaginally. In contrast to the “normal” composition of the gut microbial community, the microbiota of infants born by caesarean section tend to have a high proportion of bacteria normally found on the skin. Although the effects are minor, this difference in the composition of their microbial community have been linked to a variety of health effects including development of the GI tract and immune system.

An infant’s diet also has a substantial effect on the establishment of a healthy microbiota. Human breast milk contains specific oligosaccharides that cannot be digested by the infant but are readily utilized by beneficial gut bacteria such as Bifidobacterium.

Throughout early childhood a person’s microbiota develops as they encounter new microbes, change their diet, and are exposed to a variety of environmental factors. The immune system plays an important role in promoting the establishment of beneficial bacteria and removing those that could be harmful. There is some evidence that children who are not exposed to a variety of microbes early in life or frequently take antibiotics display the effects of an altered microbiome later on such as allergies, metabolic disorders and obesity, and possibly even certain mental disorders. A person’s microbiota is fully established by about 3 years of age. It remains relatively stable through adulthood but begins to decline at about 65 years old (Figure (PageIndex{2})). Throughout a person’s lifetime a variety of factors can influence the composition of their microbiota including diet, environmental factors, and genetics.

Microbial Flora of Human Body Normal Flora NORMAL

NORMAL FLORA: These are mixture of micro-organisms regularly found at any anatomical site on or within the body of a healthy person.

Factors influencing normal flora: • The makeup of the normal flora depends upon various factors, including: – Genetics – Age – Sex – Stress – Nutrition – Diet – Antiobiotic & other drugs

Normal Microbial Flora: • Resident Flora: – Microbes that are always present on or within body • Transient Flora: – Microbes that live in or on the body for a period of time (hours, days, weeks, months) then move on or die off

Anatomical sites involved: • Skin • Eyes (i. e Conjunctiva) • Nose (i. e Respiratory tract) • Mouth (i. e Human Oral Cavity) • Ears • Genitourinary tract • Alimentary canal

EXAMPLES OF TISSUE TROPISM OF SOME BACTERIA ASSOCIATED WITH HUMANS BACTERIUM TISSUE Corynebacterium diphtheriae Throat N. gonorrhoeae Urogenital epithelium S. mutans Tooth surfaces S. salivarius Tongue surfaces E. coli Small intestine epithelium S. aureus Nasal membranes S. epidermidis Skin

Normal flora of Skin: Important bacteria: 1. Staphylococcus epidermidis 2. Micrococcus sp. 3. Corynebacterium sp. 4. Mycobacterium smegmatis

Normal Flora of the Conjunctiva: 1. Staphylococcus epidermidis 2. Corynebacterium spp. 3. Propoinibacterium acnes 4. Staphylococcus aureus 5. Viridans streptococci 6. Neisseria spp. 7. Haemophilus influenzae

Normal Flora of the Respiratory Tract: A). The nares (nostrils) : 1. Staphylococcus epidermidis 2. Corynebacteria spp. 3. Staphylococcus aureus 4. Neisseria spp. 5. Haemophilus spp. 6. Streptococcus pneumoniae

Normal Flora of the Respiratory Tract: B) The upper respiratory tract (nasopharynx): 1. Non-hemolytic streptococci 2. Alpha-hemolytic streptococci 3. Neisseria spp. 4. Streptococcus pneumoniae 5. Streptococcus pyogenes 6. Haemophilus influenzae 7. Neisseria meningitidis

Normal Flora of the Respiratory Tract: C) The lower respiratory tract: (trachea, bronchi, and pulmonary tissues): • Usually sterile. • The individual may become susceptible to infection by pathogens descending from the nasopharynx: e. g. H. influenzae, S. pneumoniae

Normal Flora of the Human Oral Cavity: Oral bacteria include: 1. Viridans streptococci 2. Lactobacilli 3. Staphylococci (S. aureus and S. epidermidis) 4. Corynebacterium sp. 5. Bacteroides sp. 6. Streptococcus sanguis (dental plaque) 7. Streptococcus mutans (dental plaque) 8. Actinomyces sp.

The Normal Flora of The Ears (i. e. external ear) The external ears contains a variety of micro- organisms. These include: 1. Staphylococcus epidermidis 2. Staphylococcus aureus 3. Corynebacterium sp

Normal flora of the Urogenital Tract: a) The anterior urethra: 1. Staphylococcus epidermidis 2. Enterococcus faecalis 3. Alpha-hemolytic streptococci. 4. Some enteric bacteria (e. g. E. coli, Proteus sp. ) 5. Corynebacteria sp. 6. Acinetobacter sp. 7. Mycoplasma sp. 8. Candida sp. 9. Mycobacterium smegmatis

Normal flora of the Urogenital Tract: b) The vagina: 1. Corynebacterium sp. 2. Staphylococci 3. Non-pyogenic streptococci 4. Escherichia coli 5. Lactobacillus acidophilus* 6. Flavobacterium sp. 7. Clostridium sp. 8. Viridans streptococci 9. Other Enterobacteria

Normal flora - Gastrointestinal tract Location (adult) Bacteria/gr am contents Duodenum 103 -106 Jejunum and ileum 105 -108 Caecum and transverse colon Sigmoid colon and rectum 108 -1010 1011

Normal Flora of the Gastrointestinal Tract (GIT): • In breast-fed infants : 1. Bifido bacteria account for more than 90% of the total intestinal bacteria. 2. Enterobacteriaceae 3. Enterococci 4. Bacteroides 5. Staphylococci 6. Lactobacilli 7. Clostridia

Normal Flora of the Gastrointestinal Tract (GIT): • In bottle-fed infants: • Bifidobacteria are not predominant. When breast-fed infants are switched to a diet of cow's milk or solid food, bifidobacteria are progressively joined by: 1. Enterics 2. Bacteroides 3. Enterococci 4. Lactobacilli 5. Clostridia

Normal Flora of the Gastrointestinal Tract (GIT): In the upper GIT of adult humans mainly acidtolerant lactobacilli present: e. g. Helicobacter pylori

Normal Flora of the Gastrointestinal Tract (GIT): • The proximal small intestine: 1. Lactobacilli 2. Enterococcus faecalis 3. Coliforms 4. Bacteroides

The flora of the large intestine (colon): 1. Enterococci 2. Clostridia 3. Lactobacilli 4. Bacteroides 5. Bifidobacterium (Bifidobacterium bifidum) 6. Escherichia coli 7. Methanogenic bacteria 8. Viridans streptococci 9. Staphylococcus sp. 10. Proteus sp. 11. Candida albicans (Yeast) 12. Mycoplama sp.

THE ROLE/ BENEFITS OF THE NORMAL FLORA: 1. The normal flora synthesize and excrete vitamins in excess of their own needs, which can be absorbed as nutrients by the host. For example, enteric bacteria secrete Vitamin K and Vitamin B 12, and lactic acid bacteria produce certain B-vitamins.

THE ROLE/ BENEFITS OF THE NORMAL FLORA: 2. The normal flora prevent colonization by pathogens by competing for attachment sites or for essential nutrients. This important beneficial effect, which has been demonstrated in the oral cavity, the intestine, the skin, and the vaginal epithelium.

THE ROLE/ BENEFITS OF THE NORMAL FLORA: 3. The normal flora may antagonize other bacteria through the production of substances which inhibit or kill non-indigenous species. Intestinal bacteria produce a variety of substances like non-specific fatty acids, peroxides and highly specific bacteriocins, which inhibit or kill other bacteria.

THE ROLE/ BENEFITS OF THE NORMAL FLORA: 4. The normal flora stimulates the development of certain tissues, i. e. , the caecum (in animals) and certain lymphatic tissues (Peyer's patches) in the GI tract. The caecum of germ-free animals is enlarged, thinwalled, and fluid-filled, compared to that organ in conventional animals.

THE ROLE/ BENEFITS OF THE NORMAL FLORA: 5. The normal flora stimulates the production of “cross-reactive antibodies’’. Since the normal flora behave as antigens in an animal, they induce an Ab mediated immune response. Low levels of antibodies produced against components of the normal flora are known to cross react with certain related pathogens, and thereby prevent infection or invasion.

Sterile tissues: In a healthy human, the internal tissues such as: • blood • brain • muscle • Cerebrospinal fluid (CSF) are normally free of microorganisms.

Role of Microbiologist: Accurate diagnosis: by Rapid/ quick, meaningful reporting Role of Physician: Proper treatment with antimicrobial regimen/ standard guidelines by avoiding overuse*/ misuse of antimicrobials * by treating pathogen, NOT the normal flora!!

NATURAL MICROBIAL HABITATS Soil Water Air Animals and Animal Products

Ho Int st-P er ac aras tio ite ns HOST DISEASE TRIAD PATHOGEN Microbial Interactions OTHER MICROBES ENVIRONMENT

Symbiotic Relationship: • Mutualistic/ mutualism: – Both organisms benefit – “mutually benefical” • Commensalistic/ commensalism: – One organism benefits, the other is neither helped nor harmed • Opportunistic: Under normal conditions, microbe does not cause disease, but if conditions become conducive , it can cause disease. (Immuno-compromised or immuno -suppressed conditions)

Mutualistic • Escherichia coli : – Synthesizes Vitamin K & B complex Vitamins – In return, we provide a warm, moist nutrient rich environment for Escherichia coli

Commensalistic • We have no Commensalistic relationships with Bacteria • If Bacteria are in or on our body, they are either helping us (Microbial Antagonism) or harming us.

Opportunistic: • Escherichia coli - normally in our digestive tract where it causes no problems, but if it gets into the urinary tract it can become pathogenic. • Staphylococcus aureus – commonly found in the upper respiratory tract, but if it gets into a wound or a burn it can become pathogenic

Probiotics/ Prebiotics: • Probiotic: – Oral administration of living organisms to promote health – Species specific: adherence and growth (tropism) • Prebiotic: Non-digestible food that stimulates growth or activity of GI microbiota, especially bifidobacteria and lactobacillus bacteria – Typically a carbohydrate: soluble fiber

KEY QUESTIONS: 1. Define normal microbial flora. Mention the role/ benefits of normal flora in human body. 2. Normal flora of mouth and upper respiratory tract. 3. Normal flora of skin. 4. Normal flora of gastro-intestinal tract. 5. Normal flora of genitourinary tract.

Nocardia • Morphologically resembles Actinomyces. • They are acid fast up to 1% Sulphuric acid. • Majority of them are saprophytes. Species: 1. N. asteroides. 2. N. brasiliensis. 3. N. madurae

Culture: Ø Readily grow on ordinary media. Ø Requires incubation for 3 weeks, usually produce pigmented colonies. Pathogenesis: Ø Mainly produces opportunistic infections in immuno-compromised persons. Ø Causes mainly pulmonary disease like pneumonia, lung abscess or lesion resembling tubercolosis. Ø May cause mycetoma.

Lab. Diagnosis: Specimen: Pus or sputum. Gram’s staining: Gram positive ZN Staining: Acid fast (1% Sulphuric acid) Culture:

• Treatment: • MEDICAL Rx- sulfa drugs like TMP-SMX (Cotrimoxazole) for three months. • SURGICAL Rx- drainage of abscess

The Body’s Flora (Indigenous Bacteria in the Human Body)

About one hundred trillion bacteria live inside you - Up to a 1000 species and more than TEN TIMES the number of cells you have in your body! These indigenous bacteria are referred to as the body&rsquos flora and live in many areas of your body, including the skin, intestines, mouth, nose, pharynx, urethra and vagina

Organisms are considered either &ldquofriendly&rdquo or &ldquounfriendly&rdquo - when &ldquoFriendlies&rdquo and &ldquoUnfriendlies&rdquo have an appropriately balanced presence, the body can better maintain health

Friendly Bacteria

  • &ldquoFriendly&rdquo bacterial flora provide many health benefits to the body
  • &ldquoFriendly&rdquo bacterial flora thrives on dietary fibre &ndash and other so called prebiotic foods.
    • Unfriendly organisms &ndash includes pathogenic bacteria, friendly bacteria multiplying out of control, and fungi, such as yeast e.g. Candida albicans

    Health Benefits of Beneficial Flora

    Beneficial flora / probiotics have at least 30 known pharmacological actions.

    • Anti-infective &ndash antibacterial, antiviral, antifungal
    • Immune system-supportive - upregulates glutathione (GPX) and certain glycoproteins that help regulate immune responses, including IL-4 (Interleukin-4), IL-10, IL-12 more than 60% of your I.S. is in your gut.
    • Antiproliferative &ndash apoptopic (promotes natural self-destruction of cells) Inhibits tumor necrosis factor (TNF) alpha inhibitor, NF-kappaB, epidermal growth factor receptor, +++
    • Protective &ndash antioxidant, cardioprotective, gastroprotective, radio- and chemo-protective
    • Anti-allergenic
    • Antidepressive &ndash the vagus nerve (10th cranial nerve) connects your gut to your brain, each affecting the other, explaining the link between neurological disorders and GI dysfunction (E.g. ADHD, autism). Intestinal health has been found to profoundly influence mental health.
    • Detoxifying - probiotics appear to have a role in detoxing harmful chemicals.

    How do beneficial flora /probiotics work against pathogens?

    • Beneficial flora are antagonistic / competitive towards pathogenic bacteria.
      • Probiotics help normalize acid/alkali balance in the intestine - &ldquoFriendly&rdquo bacteria decrease colonization of pathogenic organisms in the gut by secreting acids that are toxic to local pathogenic bacteria &ndash by liberating hydrogen peroxide and organic acids (E.g. Lactic, butyric and acetic acids) in the intestines, the local luminal pH is shifted downward to create an unfavourable environment for growth of pathogenic flora.

      Williams NT. Probiotics. Am J Health-Syst Pharm. 201067:449-458.
      Alvarez-Olmos MI, Oberhelman RA. Probiotic agents and infectious diseases: a modern perspective on a traditional therapy. Clin Infect Dis. 200132:1567-1576.

      Macintyre A, Cymet TC. Probiotics: the benefits of bacterial cultures. Compr Ther. 200531:181-185.

      Resident Flora

      Healthy people live in harmony with most of the microorganisms that establish themselves on or in (colonize) nonsterile parts of the body, such as the skin, nose, mouth, throat, large intestine, and vagina. The microorganisms that usually occupy a particular body site are called the resident flora. Cells of the resident flora outnumber a person's own cells 10 to 1. Microorganisms that colonize people for hours to weeks but do not establish themselves permanently are called transient flora.

      The resident flora at each site includes several different types of microorganisms. Some sites are normally colonized by several hundred different types of microorganisms. Environmental factors, such as diet, antibiotic use, sanitary conditions, air pollution, and hygienic habits, influence what species make up a person’s resident flora. If temporarily disturbed (for example, by washing the skin or using antibiotics), the resident flora usually promptly reestablishes itself.

      Rather than causing disease, the resident flora often protects the body against disease-causing organisms. However, under certain conditions, microorganisms that are part of a person’s resident flora may cause disease. Such conditions include

      A weakened immune system (as occurs in people with AIDS or cancer, people taking corticosteroids, and those receiving cancer chemotherapy)

      When antibiotics used to treat an infection kill a large proportion of certain types of bacteria of the resident flora, other resident bacteria or fungi can grow unchecked. For example, if women take antibiotics for a bladder infection, the antibiotics kill some of the resident flora, allowing yeast in the vagina to multiply and cause a vaginal yeast infection.

      Injury or sometimes surgery can allow resident flora to enter areas that are not supposed to have bacteria and cause infection. For example, a cut on the skin can allow resident skin flora to cause an infection under the skin. Surgery on the large intestine sometimes allows the resident flora in the intestine to spill into sterile areas in the abdomen and cause very serious infection.

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      The difference between rod and cone cells is primarily due to the difference in the factors like response to light stimulus, location within the retinal system of an eye, photopigments and the type of vision they form. Response to light stimulus: Rods are more receptive towards light and function at scotopic (low) illumination levels. Conversely, &hellip

      Soil microflora contributes to the biological property of the soil, whose number and activity has a considerable impact on the soil system. The physical and chemical factors like pH, temperature, available moisture, and nutrients influence the growth and activity of the soil microflora. The root system in the soil also influences a wide range of &hellip

      Human microbiota: The microorganisms that make us their home

      What makes a human body? According to researchers, human cells tell but half the story. The other half involves the myriad of microorganisms that make up the microbiota — “alien” environments all over our bodies that, as long as there is a healthy balance, help us thrive.

      Share on Pinterest Researchers continue to investigate the role of gut bacteria in the health of the brain and other areas of the body.

      The human body contains trillions of specialized cells — tiny building blocks that come together to support the development and functioning of the body.

      But human cells are not the only “materials” that make up our bodies. In fact, we live in symbiosis with trillions of microorganisms, too.

      Researchers have long debated the true ratio of human cells to microorganisms in the average body. Estimates have fluctuated, but the most recent study to consider the matter — which appeared in PLOS Biology in 2016 — suggests that we likely have about as many microorganisms in and on our bodies as we do human cells.

      In addition to bacteria and viruses, these microorganisms include archaea, primitive organisms with no nucleus, and eukaryotic microorganisms, or eukarya, a type with a nucleus that protects its chromosomes. In the latter group are fungi and protists, tiny organisms at the “border” between a plant and a fungus.

      All of these together make up various microbiota: communities of microorganisms present at different sites on or in the human body.

      The various microbiota make up the human microbiome: the totality of microorganism communities spread around the human body.

      Collections of microorganisms in different areas play a crucial role in helping maintain our health — though to do so, the numbers of various types of bacteria, fungi, and other microorganisms have to remain in perfect balance.

      When that balance is tipped and, for instance, one bacterial species overpopulates, this can lead to infections and other health problems.

      This feature describes the various organisms that make their homes in the gut, mouth, vagina and uterus, penis, skin, eyes, and lungs.

      The most talked-about environment for colonizing microorganisms, especially bacteria, is the human gut.

      Studies show that the human gastrointestinal tract houses a vast “collection of bacteria, archaea, and eukarya” that play important roles in gut homeostasis , helping maintain the health of the gastrointestinal system.

      Research has also suggested that gut bacteria moderate the connection between the gut and the brain through an interaction with the enteric nervous system and other mechanisms, which may be hormonal or immunological.

      The main bacterial phyla, or types, present in the gut are Firmicutes and Bacteroidetes, which make up 90% of the gut microbiota.

      Others are Actinobacteria, Proteobacteria, Fusobacterua, and Verrucomicrobia. These include some familiar bacterial groups, or genera, from the Firmicutes phyla, such as Lactobacillus, which is known for its positive impact on health.

      On the other hand, some Firmicutes species can rapidly cause illness if they overgrow — such as Staphylococcus aureus and Clostridium perfringens.

      The Proteobacteria phylum includes some well-known pathogenic groups, such as Enterobacter, Helicobacter, Shigella, and Salmonella bacteria, as well as Escherichia coli.

      Meanwhile, the Actinobacteria phylum includes the Bifidobacterium bifidum species, which is generally beneficial for healthy individuals.

      This list, however, is by no means exhaustive. There are around 2,172 bacterial species in the human gastrointestinal tract, according to compiled data.

      If some of these names sounded uncomfortably familiar, it is because many of these bacteria can cause infection if they over-colonize. And some strains can infect the gut through food that has gone bad or contact with unclean surfaces.

      Some strains of E. coli can cause infections that lead to diarrhea and vomiting, some strains of S. aureus can become resistant to antibiotics and cause severe illness, and Salmonella infections can cause diarrheal illness.

      But gut bacteria can typically be strong allies in health maintenance, and specialists continue to study the many ways in which these microorganisms help keep us in good form.

      “This is a new frontier of medicine, and many are looking at the gut microbiota as an additional organ system,” said infectious disease specialist Dr. Elizabeth Hohmann in an interview with Harvard Medical School.

      “[The gut microbiota is] most important to the health of our gastrointestinal system but may have even more far-reaching effects on our well-being,” she added.

      Other microorganisms present in the gut are viruses, but not the ones that typically cause illness. They are a type called “bacteriopha ges” — literally, bacteria eaters — that help maintain microbial balance by taking over the inner workings of bacteria.

      Bacteriophages “make up the vast majority of the viral component of the gut microbiome,” and researchers have argued that part of their role is to infect certain bacteria to preserve a healthy balance of microorganisms in the gut. Still, much about them remains poorly understood.

      Like the gut, the mouth also contains numerous bacteria necessary for homeostasis.

      “A wide range of microorganisms are present in the oral cavity. It is in constant contact with and has been shown to be vulnerable to the effects of the environment,” explain the authors of a review published in the Journal of Oral and Maxillofacial Pathology in 2019.

      They continue, noting that “Different surfaces in the mouth are colonized preferentially by the oral bacteria,” depending on the type of surface that they are adhering to, that of the cheek, tongue, or teeth, for instance.

      The oral microbiota contains 12 bacterial phyla — Firmicutes, Fusobacteria, Proteobacteria, Actinobacteria, Bacteroidetes, Chlamydiae, Chloroflexi, Spirochaetes, SR1, Synergistetes, Saccharibacteria, and Gracilibacteria — with multiple species, named or unnamed.

      But the mouth also houses other microorganisms, namely protozoa, the most common of which are Entamoeba gingivalis and Trichomonas tenax, as well as fungi and viruses.

      There are 85 genera of fungi in the oral environment, including Candida, Cladosporium, Aureobasidium, Saccharomycetales, Aspergillus, Fusarium, and Cryptococcus.

      “[The oral microbiota] plays a crucial role in maintaining oral homeostasis, protecting the oral cavity, and preventing disease development,” write the authors of the 2019 review.

      As with other microbiota, if the numbers of microorganisms that populate the mouth become imbalanced, it can lead to the development of illness, such as various bacterial infections.

      Human genitals and urinary tracts also harbor a large number of microorganisms.

      In the vagina, research suggests that “bacteria dominate” the landscape, though which bacteria and in what quantities are questions not easily answered.

      Recent studies indicate that the components of bacterial populations in the vagina may not only fluctuate at different stages of the menstrual cycle, but may also vary among individuals of different races and ethnicities.

      Some types of bacteria identified in the vaginal canal include Lactobacilli, Prevotella, Dialister, Gardnerella, Megasphaera, Eggerthella, and Aerococcus.

      “The human vaginal microbiota seem to play a key role in preventing a number of urogenital diseases, such as bacterial vaginosis, yeast infections, sexually transmitted infections, urinary tract infections, and HIV infection,” says a PNAS review.

      This is why specialists advise extreme care when it comes to intimate hygiene: Many products can destroy the delicate bacterial balance in the area.

      However, the PNAS review also notes that “The means by which [bacteria protect against infection] are poorly understood.”

      Furthermore, little is known about the microbiota of the uterus. Scientists have only started to study it recently and, so far, only in small cohorts. One study found that Lactobacillus and Flavobacterium appeared to be the most common bacteria in the uterus, regardless of whether a woman is pregnant. More in-depth research is ongoing.

      Little is also known about the microbiota of the female bladder and urethra. A study published in Current Opinion in Urology in 2017 notes that “The vast majority of urinary health research has been conducted without knowledge or consideration of the female urinary microbiota.”

      Following recent investigations, it appears that the most common types of bacteria in the female urethra are Lactobacillus, followed by Gardnerella, Corynebacterium, Streptococcus, and Staphylococcus.

      And while some researchers suggest that the microbiota of the bladder and female urinary tract are largely the same, others beg to differ. One study published this year in the Journal of Urology has found significant differences.

      Its authors also hypothesize that the bacterial populations of the female lower urinary tract may vary with age, level of sexual activity, and whether or not the person has entered menopause.

      If researchers still know little about the microbiota of the female urogenital areas, they appear to know even less about those present in the male urogenital regions.

      A PLOS One study from 2010 found differences in microbial communities on circumcised, compared with uncircumcised, penises, in a culture-independent investigation.

      More specifically, bacteria of the Clostridiales and Prevotellaceae families appeared to be more abundant on uncircumcised penises.

      Such differences, the paper’s authors note, may play a role in inflammation and exposure to infections.

      “Men who are uncircumcised have significantly more bacteria on their penis, and the types of bacteria are also very different,” noted study co-author Dr. Cindy Liu in an interview.

      Other than this, very little is understood about the penile microbiota. In the same interview, Prof. Deborah Anderson, who teaches obstetrics, gynecology, and microbiology at the Boston University School of Medicine, commented that:

      “The penis is understudied. There could be a very interesting story there, but we haven’t really done the proper research.”

      Much like the gut, the human skin houses a multitude of bacteria and many types of fungi.

      A review — published in Nature Reviews Microbiology in 2018 — explains that the bacterial populations vary widely by skin region and also depend on a range of factors, such as the moisture of the skin and the amount of natural oil, or sebum.

      According to the review, “Sebaceous sites were dominated by […] Propionibacterium species, whereas bacteria that thrive in humid environments, such as Staphylococcus and Corynebacterium species, were preferentially abundant in moist areas, including the bends of the elbows and the feet.”

      Communities of fungi, however, appear to be fairly consistent in composition, regardless of the type of skin populated.

      All over the body and on the skin of the arms, fungi of the genus Malassezia are the most common, according to the researchers. By contrast, a combination of Malassezia, Aspergillus, Cryptococcus, Rhodotorula, and Epicoccum, among others, are most abundant on the skin of the feet.

      The most abundant microorganisms on human skin are bacteria, while the least common appear to be fungi.

      Bacteria on the skin can serve to prevent the invasion of pathogens and promote disease, depending on which colonies prevail. As the study authors write:

      “Interactions between members of the microbiota both shape the resident microbial community and prevent colonization by pathogenic bacteria in a process termed ‘colonization resistance’.”

      “In certain contexts,” they continue, “bacteria that are ordinarily beneficial to their hosts can become pathogenic. Many common skin diseases are associated with changes in the microbiota, termed dysbiosis .”

      Bacteria prevail on many stretches of epithelial tissue, including the conjunctiva, the tissue lining the inside of the eyelids.

      According to a study from 2011 , at least five bacterial phyla and 59 genera are present on the healthy human conjunctiva.

      The predominant bacterial genera are: Pseudomonas, Propionibacterium, Bradyrhizobium, Corynebacterium, Acinetobacter, Brevundimonas, Staphylococci, Aquabacterium, Sphingomonas, Streptococcus, Streptophyta, and Methylobacterium.

      Some fungi are also present, and these include species of Candida, Aspergillus, and Penicillium.

      For now, the role of the conjunctiva microbiome remains unclear.

      We often think of bacteria in the lungs only in the context of respiratory diseases. However, bacteria are present in healthy lungs, too.

      Some of the most common bacterial phyla in healthy lungs are Firmicutes, Bacteriodetes, Proteobacteria, Fusobacteria, and Actinobacteria, according to a review from 2017. Some of the most common genera are Prevotella, Veillonella, and Streptococcus.

      When the delicate balance of bacterial populations in the lungs is upset, it could lead to the development of diseases such as asthma and chronic obstructive pulmonary disease.

      In asthma, for instance, Haemophilus and Neisseria bacteria increase in numbers, while numbers of Prevotella and Veillonella decrease. This supports the hypothesis that dysbiosis of the lung microbiome may be an underlying cause of asthma.

      The team behind the 2017 review highlight a need for further investigations into the microbiota-related mechanisms that may be affecting lung health, noting that “The likely complex interactions between bacteria, viruses, and fungi should be considered in future research.”

      The human microbiome is an intricate system, and researchers are continuing to discover more about its important role in human health and disease. Going forward, scientists strive to dive deeper into the mysteries of this microcosm.

      Human Body&rsquos Natural Barriers to Foreign Invaders

      The human body is provided with a number of natural barriers which protect it from all types of foreign invaders. These include: 1. Skin 2. Mucous Membrane 3. Chemical Factors 4. Commensal Organisms 5. Cellular Components 6. Some Proteins Involved in Non-Specific Defense 7. Inflammation.

      1. Skin:

      The human body is externally covered by skin which gives the first line of defense against the microbial invaders. The skin has two distinct layers — an outer layer called epidermis and an inner one called dermis. The epidermis is a comparatively thin layer consisting of tightly packed cells covered externally by dead cells which are continuously sloughed off as the skin grows.

      These cells are rich in keratin, a type of protein which is very resistant to microbial decomposition. The dry dead epidermal cells are inhospitable to microbes. Also, if any microbe settles on the epidermal cells, the chance of its elimination through natural sloughing is high. All these features make the skin an effective barrier to all types of microbes.

      However, the intact skin may be breached accidentally through a cut or bruise or burn injuries or by an insect sting. Such a breach in the skin makes open a passage through which microbes may enter into the tissues underlying the skin.

      In case of stinging insects like mosquitoes, tsetse-fly, sand-fly, ticks etc., the sting not only pierces the skin, but also specific pathogens carried in the mouthparts of those insects are injected in the interior of the body. As a result, diseases like malaria, sleeping sickness, yellow-fever or plague may develop.

      A diagrammatic sketch of an intact skin layers is shown in Fig. 10.1:

      In case a breach of the skin occurs either accidentally or by stinging insects and microbes gain entry into the deeper layers of the skin, they face the next line of defense. This is provided by certain cells of the dermis, known as Langerhans cells.

      These cells can recognize microbes as foreign elements with the help of their innate receptors. They phagocytize the microbial cells and destroy them. Langerhans cells form a part of the skin associated lymphoid tissue (SALT).

      They are able to process antigens (microbes) and present them to T-lymphocytes. T-lymphocytes play an important role in the specific defense. Thus, SALT forms an important link between non-specific and specific defense systems. Langerhans cells are a type of dendritic cells. These cells have an elaborately branched folded membrane giving the appearance of a branched tree from which its name is derived (Fig. 10.2).

      2. Mucous Membranes:

      While the skin covers the external surface of the body, the mucous membranes line the passages like GI tract, respiratory tract etc. The mucous membranes consist of an epithelial layer and underlying tissues. The epithelium is mostly a single cell layer, except in mouth, urinary bladder and vagina.

      As most of these passages come in contact with materials from outside, like food, air etc., they are exposed to microbes and viruses and therefore need protection against microbial attack. This is provided by the mucous membranes, although they are not as effective as the skin.

      The protective power of the mucous membranes is primarily due to the secretion of a thick sticky substance called mucus which consists of some proteins and polysaccharides. Mucus forms a viscous covering over the epithelial layer lining the tracts. Its main function is to trap microbes.

      As mucus is continuously formed and diffuses into the passages, the trapped microbes are also removed. In case of the GI tract, the washed out microbes are transferred to the stomach where the acidic environment and proteolytic enzyme kill them.

      The elimination of microbes and other particulate bodies from the lower respiratory tract is facilitated by the presence of ciliary cells on the epithelial layer. Synchronous movement of these cells propels mucus with embedded microbes and particles upwards towards the throat from where they are ejected outside by cough or sneeze. Mucus is secreted by goblet cells of the epithelial layers.

      A diagrammatic sketch of a longitudinal view of mucus membrane and ciliary movement is shown in Fig. 10.3:

      As the microbes are trapped in the mucus, they are unable to attach to the epithelium which is necessary for entering the body. Thereby, the chance of infection is minimized. Like mucus, saliva secreted in the mouth from salivary glands helps to keep the mouth and teeth relatively free of microbes by continuous washing. The microbes entering through food and drink are washed down into the stomach where most of them are killed, though some organisms, like Helicobacterium pylori, can grow in the stomach.

      Although eyes are not protected by mucous membrane, tears produced by tear glands exert a protective role. Like saliva, tears are produced continuously to keep the eye surface moist and wash away dirt and microbes present in air. Tears are passed into the nose through the nasal duct and eliminate foreign matters.

      Similarly, urine helps to keep the urinary tract clean by periodic washing. Vaginal secretions likewise protect the female genital tract. The secretions like mucus, saliva and tears besides giving physical protection to the inner tissues of the human body, also contain chemical factors which have antimicrobial properties.

      3. Chemical Factors:

      One of the potent antibacterial chemical agent which occurs in tears, saliva, nasal secretion and tissue fluids is an enzyme called lysozyme. It can cause hydrolytic cleavage of the muropeptide which forms the backbone of bacterial cell wall, thereby causing lysis of bacteria, specially the Gram-positive ones.

      The oil-glands present in skin produces an oily substance called sebum which also has antibacterial activity. Sebum contains, among other ingredients, unsaturated fatty acids which can inhibit microbial growth. Besides, sebum helps to maintain an acidic reaction of the skin surface which discourages microbial proliferation. Sebaceous glands of the ear produces a waxy material called cerumen. This substance forms a coating in the ear-hole and prevents attachment of microorganisms.

      The epithelial cells of the GI tract and the respiratory tract elaborate several small peptides having molecular weights of 3,000 to 5,000 Dalton. These peptides also possess antibacterial properties. Among such peptides are cecropins and magainins which have bacteriolytic activity, as also defensins which can make holes in bacterial membrane.

      Another group of antibacterial proteins present in mucus and blood are the transferrins. These compounds bind iron by chelation. They inhibit bacterial growth by depriving iron which is required by microbes for synthesis of iron-containing enzymes, like cytochromes.

      The environment in the stomach and the small intestine is also not conducive for microbial growth. The stomach acid and enzymes in gastric juice are inhibitory for most microbes. Other enzymes secreted in the small intestine as well as bile destroy most microbes by attacking the structural components of microbial cells, like polysaccharides, proteins and lipids. All these chemical and biochemical factors contribute substantially to protect the body from microbial invaders, each having its own sphere of action.

      4. Commensal Organisms:

      Skin and the mucous membranes of different passages harbour a microbial flora, characteristic for each. The organisms in these flora under normal conditions, are not only non-pathogenic, but beneficial to the human body. They play an important role in warding off the pathogens, thereby protecting the body in a nonspecific manner. These normally resident micro-flora are known as commensal organisms and the relationship with the host is commensalism.

      In general, the commensal organisms — which are mostly bacteria — exert their beneficial effect by competitive elimination of the pathogens. The commensals by virtue of their great number, occupy most of the attachment sites and consume available oxygen and food. The pathogenic invaders which are smaller in number, are thus deprived of space and food.

      Beside such passive resistance through competition, commensals may also produce chemical agents which actively antagonize pathogenic microbes. For example, Escherichia coli, which colonize the human colon (large intestine), produces colicins which inhibit the growth of other enterobacteria, such as Salmonella.

      Besides colicins, the colon-commensals produce various organic acids by fermentation which are inhibitory to many pathogens. Lactobacilli which are resident in the vaginal tract produce lactic acid fermentation. This keeps the pH acidic enough to prevent growth of protozoans, like Trichomonas vaginalis and yeast, like Candida albicans.

      The commensal organisms, which are normally beneficial when they colonize the organ or part of the body where they are best suited, may sometimes turn into opportunistic pathogens. For example, E. coli has a beneficial role so long it grows in the colon, but may be pathogenic when it infects the urinary tract.

      5. Cellular Components:

      Apart from the physical barriers, chemical factors and deterrent effects of commensal organism, there are several types of cells in the human body which actively participate in the non-specific defense against pathogenic agents. These cells include the different types of phagocytes, the natural killer cells, the mast cells and basophils, and the dendritic cells. The functions of the cells are discussed below. It would be rewarding to have knowledge of the different blood cells and the lymphatic system of the human body.

      (i) Blood Cells:

      There are three main types of blood cells. These are erythrocytes or red blood cells (RBC), the leucocytes or white blood cells (WBC), and the thrombocytes or platelets. The mature RBC and platelets are without a nucleus, while all types of WBCs are nucleated cells.

      The fluid portion of blood in which the cells are suspended is called serum. The serum is an aqueous solution of minerals, proteins and other organic compounds. When the fluid contains the clotting agents, like fibrinogen and prothrombin, it is called plasma.

      Among the three main types of blood cells, the leucocytes play important roles in both non­specific as well as specific defense. Erythrocytes are mainly involved in carrying oxygen to different tissues, while the platelets function in blood clotting.

      All types of blood cells are differentiated from the haemopoietic stem cells which are present in the foetal liver spleen and bone-marrow and in adults only in the bone marrow. From the point of view of the body’s defense, the leucocytes are of special importance. These non-pigmented nucleated blood cells are differentiated into five types depending on their nuclear shape, cell inclusions and function.

      The different types of leucocytes, their characteristics and their relative number in normal blood are shown in Table 10.1:

      (ii) The Lymphatic System:

      The fluid that bathes the tissues and cells and fills the intercellular spaces is known as lymph. The liquid fraction of blood filters out of the capillaries and feeds the tissue cells with oxygen and nutrients, as well as it collects the waste products. This fluid is then taken up in tiny vessels (lymph capillaries). From these vessels, the fluid passes into larger vessels called lymphatic’s and finally, the fluid is returned to a vein through which it is channelized into the heart. Thus, the fluid that flows out of the capillaries is returned to the main stream — the cardiovascular system.

      The lymph channels have pockets of lymphatic tissues called lymph nodes. Lymph nodes are spherical to ovoid solid structures, measuring 2 to 10 mm in diameter. As the lymph capillaries are very thin-walled, they are permeable and microorganisms can enter them. A major function of the lymph nodes is to act like checkpoints and remove any microbial intruder by the phagocytes present in the lymph nodes.

      They also contain the lymphocytes that are actively involved in the specific defense. Lymph nodes are mainly concentrated in certain parts of the human body like the neck, armpits, groins and the mesentery. These nodes sometimes swell due to infection when they are commonly called swollen glands.

      A diagrammatic representation of a lymph node is shown in Fig. 10.4:

      (iii) Phagocytic Cells & Phagocytosis:

      The phagocytes of the human body are of two main types — the neutrophils, belonging to the polymorphonuclear leucocytes (PMNs) and the cells derived from monocytes, like macrophages, Kupffer cells in the liver, microglial cells of brain, mesangial cells of kidney etc.

      The neutrophils circulate in the blood stream they are the mobile phagocytic cells of the human body. They constitute some 60 to 65% of the total leucocytes and blood contains about 8 million of them per ml. But they have a short life-span and are continuously regenerated from the stem cells.

      Whenever they happen to meet a microbe in course of circulation, they phagocytize and kill it with the help of hydrolytic enzymes contained in their granules. These enzymes include peroxidase and phosphatases. Neutrophils also produce small antibacterial peptides, called defensins.

      In contrast to the mobile neutrophils, the phagocytic cells derived from monocytes are stationary in different tissues of the body, although the precursors, i.e. monocytes are mobile in the blood stream. They migrate from blood capillaries into tissues and are transformed into phagocytic cells of different types as named above. The general name of these phagocytes is macrophage which is much larger in size than its precursor and has an irregular shape (Fig. 10.5).

      The phagocytic cells derived from monocytes, together with the monocytes, constitute the mononuclear phagocyte system, which was previously called the reticulo-endothelial system. The main function of this system is to eliminate microbial invaders as well as removal of dead body-cells by phagocytosis. The macrophages also play important functions in acquired defense of the body, like processing and presentation of antigens as well as secretion of cytokinin.

      Phagocytosis is a natural phenomenon exhibited by many lower organisms, like amebae which engulf solid food particles including microbial cells and digest them inside their body. The process was first observed in 1884 by Metchnikoff (1845-1916), a Russian zoologist working in Pasteur’s laboratory.

      Later, he discovered that certain white blood cells behaved in a similar manner. He claimed that phagocytosis was responsible for human defense against pathogenic microbes. The importance of his claim was not appreciated immediately, but recognized later and he was awarded the (with Paul Ehrlich) Nobel Prize in 1908.

      From an immunological standpoint, phagocytosis refers to ingestion of a microbe (or a microbe-infected body cell, or a dead body-cell) by a phagocyte of the body leading in most cases to complete destruction. In rare cases, an ingested microbe may withstand killing and may even multiply within a phagocyte. An example of this type of microbe is Mycobacterium tuberculosis.

      Phagocytosis occurs in a number of steps. The process begins with migration of phagocytes towards a microbe. This is mediated by chemical attractants (chemo-taxis). The attracting chemicals may be microbial products e.g. muramyl dipeptide, or components of complement (complement is a set of constitutive serum proteins). The phagocytes have specific receptor sites for these attractants on their surface and they migrate towards the site where a microbe has breached the mechanical barrier and has entered the tissue.

      The next step consists of attachment of the microbial cell to the phagocyte. In this process, the surface receptors of the phagocyte bind to the surface molecules, like sugars and lipids of the microbial cell. A complement protein (C3b) helps in this binding.

      The interaction between the phagocyte and the microbial cell leading to phagocytosis is greatly facilitated by a process known as opsonization in which the microbial cell is coated by complement proteins and by antibodies.

      These agents are called opsonins. While complement proteins are constitutive elements of the blood, antibodies are synthesized only in response to antigens. They are constituents of the acquired defense system. Thus, opsonization forms a link between the non-specific innate defense system and the specific acquired defense.

      At the next step following attachment, the microbial cell is internalized by the phagocyte through the process of endocytosis. The membrane of the phagocyte folds and surrounds the target cell forming a phagocytic vesicle, called a phagosome. After internalization is completed, the phagosome becomes an intracellular body containing the endocytosed microbial cell. The phagosome membrane next fuses with the membrane of a lysosome present in the phagocyte’s cytoplasm and gives rise to a phagolysosome.

      The interior of the phagolysosome contains lytic enzymes which attack the ingested microbe. The pH of the phagolysosome becomes acidic due to active pumping of H + -ions. Lysosomal enzymes that attack bacterial cells include lysozyme which cleaves peptidoglycans of cell wall and a peroxidase which produces superoxide radical (O2 – ).

      Superoxide is highly toxic to bacteria. Another important killer of bacterial cells, nitric oxide (NO), is believed to be involved in destroying the ingested microbe. Most bacteria are killed within 10 to 30 minutes after phagocytosis. After the microbe has been digested, the residual material in the phagolysosome (now it is a residual body) moves towards the periphery of the phagocyte and is released as waste products outside.

      The events occurring in phagocytosis are shown in Fig. 10.6:

      (iv) Natural Killer Cells:

      Natural killer cells, also known as null cells, are also leucocytes which circulate mainly in the blood and lymph, but are present in the tissues as well. They resemble other granulated leucocytes having diameters of 12 to 15 but are not phygocytic.

      They are components of the innate defense system and kill virus-infected and cancer cells by a mechanism more or less comparable to that of cytotoxic T-lymphocytes. The latter cells are components of the cell-mediated immunity produced as a result of immune response, i.e. the acquired defense system, whereas natural killer cells are normally present in the body without immune response.

      The natural killer cells are able to distinguish the virus-infected body cells or cancer cells from normal body cells by means of specific receptors present on their surface. Although they can bind to both normal body cells as well as to abnormal cells (virus-infected and cancer cells), specific receptors send a signal which prevents destruction of a normal cell.

      On the other hand, an abnormal cell is killed through release of cytotoxic molecules from the granules of the killer cell. The cytotoxic molecules include perforins which makes a hole in the membrane of the target cell through which proteolytic enzymes contained in the granules are transmitted resulting in death of the target cell.

      Natural killer cells, when they interact with virus-infected body cells, are known to secrete y-interferon (IFNy) which helps to protect neighbouring body cells from virus infection. IFNy has also other functions in acquired defense system.

      (v) Other Cells Involved in Non-Specific Defense:

      These include the dendritic cells, mast cells, basophils, and eosinophil’s. The dendritic cells (Fig. 10.2) have a highly folded surface. They include the Langerhans cells present in skin, the follicular dendritic cells in the lymphoid tissues, and the interdigitating cells of the lymph nodes.

      The main function of these cells is to process and present antigens to lymphocytes which bind to these cells with the help of specific receptors. The dendritic cells are able to recognize the microbial antigens with the help of innate receptors. Thus, the dendritic cells form a link between the innate and acquired defense systems.

      Mast cells and basophils are granular leucocytes (granulocytes). On activation, they release the cytoplasmic granules which contain several chemical substances, like histamine and cytokines. These substances cause dilation of the capillaries (vasodilation) and attraction of the phagocytic cells, like neutrophils to an infection site, required for developing inflammation.

      Eosinophil’s are also granular leucocytes. They also exhibit some phagocytic activity. But their main function is to kill large parasites, like worms, with the help of toxic substances contained in their cytoplasmic granules. They bind to the antibody-coated parasite and release the lethal cell-contents on the parasite’s body to kill it.

      6. Some Proteins Involved in Non-Specific Defense:

      Besides the mechanical barriers, chemical factors and the cellular components, there are also some protective proteins which are actively engaged in affording protection of the body against foreign invaders. Among these non-specific proteins, the most important are the complement system, and the interferons. In addition, there are some other proteins which have protective functions.

      These are briefly discussed:

      (i) Complement:

      Complement is a group of more than 20 constitutive serum proteins constituting the complement system. The components of this system are interdependent and activation of the first one leads to activation of the second. This proceeds sequentially to activate all the components of the system. The activated complement takes part both in non-specific and in specific defense systems.

      The complement proteins are synthesized by hepatocytes and monocytes, and the proteins circulate in the blood stream forming about 5% of the total serum protein. They are normal constituents of the serum, independent of immune response, but they can participate in both non-specific and specific defense systems. They are known as complement, because they bind to antigen-bound antibody molecules and help or complement their function in acquired immune response. The binding of complement to antigen-antibody complex is known as complement fixation.

      The components of complement system are designated as C1, C2, C3, C4, C5, C6, C7, C8 and C9 (C standing for complement). Some of these have subcomponents, e.g. CI has three Clq, Clr and Cls. In addition, there are some other proteins, like factors B, D and P.

      The total number of components is at least 20, may be more. The components remain normally in an inactive form. They are activated to become functional. Activation of the complement proteins occurs in an ordered sequence through a cascade of reactions. Except C4, other components are activated according to the numerical sequence.

      That is, CI is activated first and the product activates C2, and so on. During such activation, a component is usually cleaved to form subcomponents which have different functions. For example, one subcomponent may act as opsonin helping phagocytosis and another may have an enzymatic activity.

      Activation of the complement system may occur through two pathways. One is called the classical pathway and the other is called the alternative pathway. The activation of complement by the classical pathway involves antibodies produced as a consequence of immune response, while the other pathway becomes operative through direct interaction of complement and microorganisms without any involvement of the immune system or antibodies.

      Obviously, complement activation by the alternative pathway is part of the innate defense of the body and plays a very important role in destruction of the invading microbes. In fact, the complement is the first line of internal defense which a microbe has to counter when it breaks through the mechanical barriers, specially skin and the mucous membrane. For the present, we shall consider the alternative pathway of complement activation and the consequences of such activation.

      Alternative pathway of complement activation:

      The alternative pathway does not involve complement components C1, C2 and C4, though they participate in the classical pathway. In both, complement C3 plays a crucial role. On the other hand, the complement proteins called factors B, D and P are involved in the alternative pathway, but not in the classical one.

      Complement activation by the alternative pathway occurs by direct interaction with certain surface molecules of microbes, while activation by the classical pathway occurs by interaction with antibodies bound to microbes or any other antigen.

      Microorganisms like Gram-negative bacteria have lipopolysaccharides (LPS) in their outer membrane and Gram-positive bacteria possess lipoteichoic (LTA) acid chains on their cell wall. These molecules can interact with the complement. The complement component C3, which is present in considerable amount in serum and body fluids, plays the pivotal role in such interaction with microbial surface molecules.

      The C3 protein is cleaved normally at a low level into two fragments, — C3a and C3b. Of them C3b is a highly reactive protein which binds covalently, both with the bacterial surface molecules, such as LPS and LTA on one hand and with the surface receptors of neutrophils (PMNs) on the other.

      This helps to bring the phagocyte and the bacterial cell close to each other — facilitating phagocytosis. In this process, the complement subcomponent C3b coats the bacterial surface and acts as opsonin by binding with LPS or LTA. Thus, C3b facilitates phagocytosis by opsonization.

      A more important role of the activated complement system is direct killing of microbial cells and other foreign cells by the process of cytolysis. The binding of C3b to an invading cell triggers activation of another complement protein, factor B, leading to its cleavage into two fragment Ba and Bb. The C3b and Bb subcomponents then combine to form a complex C3b-Bb — a proteolytic enzyme.

      This enzyme then attacks the component C5 and cleaves it into two subcomponents — C5a and C5b. The latter (C5b) then combines with the components C6, C7, C8 and C9 one by one to form a large complex known as the membrane attack complex. This complex attacks the membrane of the target microbial cell producing a hole or pore with a diameter of about 10 nm. The attacked cell loses its cell contents through the pore and undergoes lysis. The component C9 possibly plays a key role in the formation of such trans membrane pore.

      A third consequence of complement activation is that the cleavage products — C3a and C5a — contribute to the development of inflammation another non-specific defense mechanism. C3a and C5a can bind to mast cells, basophils and thrombocytes causing release of histamine which increases vasodilation. This helps migration of phagocytic blood cells from capillaries into tissues. C5a acts also as chemo attractant for guiding the phagocytic cells to the site of infection where complement has been activated by the invading microbes. Thus, complement activation leads to a three-pronged attack on the invading microbes as shown in Fig. 10.7.

      The activation of complement by the alternative pathway is shown in Fig. 10.8:

      (ii) Interferons:

      Interferons are small proteins (M.W. 15,000-30,000 Daltons) synthesized by eukaryotic nucleated cells infected by virus. Interferons themselves are not antiviral, but they protect the neighbouring cells from virus infection by inducing production of antiviral proteins. These antiviral proteins inhibit translation of viral m-RNAs in the host cells and stop viral multiplication (Fig. 10.9).

      Interferons are non-specific in the sense that an interferon induced by a particular virus can protect other cells not only from that virus, but also from other viruses. On the other hand, interferons are species specific which means interferons produced only by human cells are effective for humans. Interferons produced by other animals are not effective in humans.

      These proteins are produced in very small quantities by many types of cells including macrophages and dendritic cells in response to virus infection and protect adjacent cells. As interferon synthesis is not directly related to the immune system, they are considered as a component of the innate defense system. Besides having antiviral property, interferons also act as signals of communication between cells (cytokines).

      Interferons are broadly divided into two types. Type I includes alpha-interferon (IFNα) and beta- interferon (IFNβ). IFNα includes at least 12 different proteins which are closely related to each other. IFNP has only one protein. The genes controlling both IFNα and IFNP are located on human chromosome 9. Type II interferon is represented by gamma-interferon (IFNy). The gene for IFNy is located on human chromosome 12.

      Type I interferons are produced by several types of cells, specially by the fibroblasts, leucocytes, dendritic cells and epithelial cells. They function not only as antiviral agents, but also as cytokines for stimulation of the major histocompatibility complex (MHC) Class I genes.

      Type II interferon (IFNy) is produced by certain specialized cells, like natural killer cells and T-helper lymphocytes. TFNy, besides having antiviral property, also stimulates expression of MHC Class I and MHC Class II genes and it plays a major role in activation of macrophages, thereby enhancing considerably the killing power of these phagocytes, particularly of the intracellular parasites.

      (iii) Other Proteins:

      An assortment of different proteins, normally present in the serum, take part in innate defense system. Their concentration in serum increases many-fold during inflammation. Their main functions are to stimulate phagocytosis by acting as opsonins and activate the complement system.

      They are commonly known as acute phase proteins, because of their amplification during acute inflammatory response. They include the C-reactive protein which binds to phosphoryl choline of bacterial cells, mannose-binding protein, the serum amyloid protein A etc.

      The C-reactive protein acts as an opsonin and it stimulates phagocytosis. The mannose-binding protein binds to mannose residues of bacterial glycoproteins as well as to specific receptors of phagocytes. It also functions as an opsonin and facilitates phagocytosis. The serum amyloid protein activates the complement component Clq and, at the same time, acts as an opsonin. The C-reactive protein also activates complement component Clq.

      Another group of proteins involved in the innate defense are the collections. These proteins bind to carbohydrate molecules present on the surface layers of microorganisms. One such protein binds to magnesium on the surface of macrophages and it acts as an opsonin. Conglutinin is another protein of this group. In general, these proteins function as opsonin and play an important role in elimination of microbial invaders by phagocytosis.

      7. Inflammation:

      Inflammation is a non-specific defensive response triggered by damage to the tissues caused by a variety of agents. Such agents include microbial infection, chemical irritants like corrosive acids or alkalis, radiations like heat, ultraviolet’, trauma like cuts, abrasions, blows etc. An inflammatory response is characterized by four well-known external symptoms viz. swelling of the affected part due to infiltration of plasma (tumor or edema), redness due to accumulation of blood (rubor or erythema), pain due to injury of the nerve-endings (dolor) and heat due to increased blood circulation to the area (calor).

      Although these symptoms make a person uncomfortable, the ultimate effect of inflammation is beneficial, because through this process the body attempts to remove the injurious effects of the cause and finally to repair the injured tissues.

      As the inflammation subsides, a residual debris consisting of a mixture of fibrin (clots), remains of microbial cells (if the cause is microbial attack), the dead phagocytic cells and tissue cells is left behind at the site of injury. This residual matter is known as pus which may accumulate to form an abscess and may require surgical intervention for removal. An inflammatory response results due to complex interaction of many factors.

      The main events occurring in inflammation caused by entry of a microbe through a wound are briefly discussed:

      (i) Vasodilation:

      As soon as a tissue is damaged by a cut or by other means, the capillary blood vessels in that area increase in diameter making the thin delicate wall (endothelium) more permeable. This is called vasodilation. Due to increased permeability, the fluid portion of the blood diffuses into tissues causing swelling and increased temperature. Flow of blood through dilated capillaries also increases causing redness of the affected part. Pain felt in that part may be due to injured nerves or due to increased pressure produced by swelling.

      Vasodilation is mediated by several chemical factors. An important one among these is histamine which is present in a type of basophils in the tissues, called mast cells, as well as in the basophils and platelets of blood. The mast cells play a central role in the development of acute inflammation.

      They occur mostly in the connective tissues and close to blood vessels. When the mast cells are activated by complement components C3a and C5a, they release their cytoplasmic granules which contain histamine. Release of histamine from mast cells, basophils and platelets may occur also directly due to injury without intervention of complement components C3a and C5a.

      Among the other chemical factors contributing to vasodilation are the small proteins, known as cytokines. There are several cytokines which perform a variety of functions in both innate and acquired defense systems. Among them, interleukin 1 (IL-1) produced by activated macrophages and endothelial cells of blood vessels is an important chemical mediator of inflammation.

      It activates vascular endothelium causing vasodilation. The cytokine-producing cells have a specific receptor on their surface (CD 14) which is able to bind surface molecules present on Gram-positive and Gram-negative bacteria, like LTA, LPS and peptidoglycan. The binding of producing cells to bacteria triggers release of cytokines. Other pro-inflammatory substances causing vasodilation include leukotriene’s produced by mast cells and prostaglandins released by damaged body cells. Both of these agents increase vascular permeability.

      (ii) Transmigration of Phagocytes from Blood Vessels to Injured Tissue:

      Vasodilation resulting in increased permeability of the capillaries is a preparatory step for the next event in the process of inflammation, viz. migration of the phagocytic cells, mainly neutrophils, from the blood vessels to the site of injury. The capillary wall is composed of loosely bound single-layered endothelial cells.

      As the blood flows through the capillaries near the damaged tissues, the cytokines diffuse into the vessels through the dilated endothelium. The phagocytic polymorphonuclear leucocytes, like neutrophils as well as the monocytes of blood, are induced to bind to the endothelial cells at specific sites with the help of receptors expressed by the cytokines.

      The normally spherical neutrophils become flattened and they are squeezed through the endothelial cells by pushing these cells apart. AS a result, the neutrophils as also monocytes migrate from the capillaries into the tissues at the site of injury (Fig. 10.10). This process of transmigration of blood phagocytic cells is called extravasation.

      (iii) Chemo taxis of the Phagocytic Cells:

      After extravasation of the neutrophils and monocytes into the tissues, they are chemotactically attracted to the injured tissues. The agents causing such attraction may be products of injured tissue cells themselves or complement component like C5a, or cytokines and leucotrienes. Attracted by these chemical mediators, the phagocytes stream towards the site of injury.

      At the beginning of the inflammatory response, the neutrophils appear in the arena, but at a later stage the monocytes also appear in the field. Monocytes are transformed into macrophages and they become the predominant phagocytes. Macrophages are larger in size and have a much greater phagocytic activity.

      (iv) Phagocytosis:

      The accumulated phagocytic cells — the neutrophils and the macrophages — are then engaged in phagocytosis of not only the invading microbes, but also the damaged tissue cells. Phagocytic process is greatly enhanced by opsonization of the target cells. The cleavage of the complement component C3 into C3a and C3b is triggered by bacteria in the alternative pathway of complement activation.

      The C3b fraction acts as an opsonin helping in the ingestion of microbes by the phagocytes. In exerting the killing effect on the ingested microbes, phagocytes themselves are also killed in large numbers. This leads to accumulation of a debris at the site of inflammation containing the remains of microbial cells, dead leucocytes and macrophages, damaged tissue cells, blood clots etc. This accumulated product is called pus which may remain in situ and slowly destroyed, or, sometimes, it may form an abscess. On opening, either naturally or by surgical operation, the pus comes out and the wound is healed.

      An overall picture of inflammation is shown diagrammatically in Fig. 10.11:

      (v) Healing:

      Healing of the damaged tissues following an inflammation begins when the active inflammatory phase subsides and the causal agent has been removed. First of all, the pro-inflammatory chemical mediators have to be neutralized by specific inhibitors and anti-inhibitory cytokines, like interleukin 4 and 10.

      Actual repair of the damaged tissues then starts by production of new cells to replace the damaged ones. The repair process depends on the tissue that has been damaged. For example, skin has a high capacity of regeneration. Fibroblasts and macrophages take active part in regeneration of damaged tissues both of these cells synthesize collagen which is required for repair.

      The important components of the innate defense of the human body are summarized in Table 10.12:

      13.1: Normal Flora of the Human Body - Biology

      Article Summary:

      Microbial flora of ENT

      Human body is perfect natural habitat for number of microorganisms like bacteria, fungi, yeasts and some viruses which are termed as microflora or resident flora or normal flora of a body. Microflora generally consists of saprophytic microbes which are acquired during and after few days of birth of an individual. Bacteria are predominant normal flora organisms. They have an extraordinary ability to attach and colonize epithelial cells, to multiply and establish in human body. Every human being has specific normal flora and its composition is dependent on health status, diet, age and hormonal activities of that individual. Microorganisms establish harmless and beneficial commensalistic and mutualistic associations with human host. In commensalism, microbe derives nutrition from host and in mutualism both microbe and host are benefitted from each other. Normal flora microorganisms compete effectively for space and nutrient supply thereby limiting the growth of members of microflora as well as inhibiting the growth of new microbes which don't comprise normal flora. They also produce antimicrobial substances like acids or antibiotics during their metabolism which restricts the growth of pathogenic or disease causing microorganisms. Reduction in populations of microflora can promote opportunistic infections in body. Opportunistic pathogens are actually resident microbes which takes an opportunity to induce infection in absence of reduced population and competition for space and nutrients by other microflora. They also cause infection when they get entry into another region of body other than their original niche. Destruction of microflora is hazardous to individual's health and caused by excessive cleaning habits, treatment with broad spectrum antibiotics and development of drug resistance in microbes. Normal flora microbes are also responsible for serious infections in immunocompromised conditions such as in acquired immunodeficiency syndrome (AIDS).

      Microflora of ear (E): Cerumen or ear wax present in outer ear traps number of microorganisms and prevent them from entering into inner ear. Cerumen also contains antimicrobial compounds which discourage growth of pathogenic Pseudomonas aeruginosa and Staphylococcus aureus, otherwise outer ear being moist and warm would have been ideal place for microbial growth. Despite Cerumen, external ear contains Staphylococcus epidermidis, Propionibacterium acnes and α-hemolytic streptococci as normal flora. Internal ear, under normal healthy state of individual is free from any microorganisms reason is that it is closed by membranes and filled with lymph fluid. Middle ear microflora matches microbes of nasopharynx as nasal microorganisms can enter middle ear via Eustachian canal. Otitis media, an infection of middle ear is caused by Haemophilus influenzae received from nasopharynx region.

      Microflora of nose (N): Microorganisms entering the nose by breathing in are trapped by mucus. It is secreted by nasal epithelium and contains enzyme lysozyme which functions as bactericidal agent. They are also removed mechanically by ciliated epithelium present in nasal passage. Remaining air flora is swallowed in and destroyed by stomach acid. Despite these effective control measures, nose, nasal cavity and nasopharynx (region above soft palate) consists peculiar microflora. They adhere and colonize epithelial cell layer of mucus membrane, thus avoid washing away by mucus. Nasal region consist of avirulent streptococci, Moraxella lacunata, Micrococcus, Corynebacterium, Staphylococcus, Acinetobacter, Bifidobacterium, Branhamella, Neisseria and Haemophilus spp. as normal flora. Nasopharynx harbors common pathogenic bacteria causing infections of nose, throat, bronchi and lungs. Sometimes, bacteria specific to intestinal tract like Escherichia coli and Proteus spp. are also present.

      Microflora of throat (T): Actinomyces, Bacteriodes, Micrococcus, Enterococcus, Bordetella, Corynebacterium, Fusobacterium, Haemophilus, Lactobacillus, Mycobacterium, Neisseria, Peptococcus, Staphylococcus, Streptococcus, Treponema, Klebsiella, Enterobacter, Lactobacillus, Escherichia, Proteus and Veillonella constitute normal flora of throat. Species of some bacteria may turn opportunists provided favorable conditions are emerged Staphylococcus aureus, S. pneumoniae, S. pyogenes, Bordetella pertussis, Haemophilus influenzae, Mycobacterium gordonae, Neisseria meningitides, Actinomyces israelli, Streptococcus viridians, Corynebacterium diphtheriae, Fusobacterium necrophorum and Bacteriodes coagulans are some of the opportunistic pathogens present in a throat as microflora. Classical and infant meningitis infections caused by N. meningitides and H. influenzae respectively and whopping cough (B. pertussis), diphtheria (C. diphtheriae) are initiated in throat. Lung infectious agents such as Pseudomonas aeruginosa (blue pus infection), K. pneumoniae, streptococci (sinusitis) are passed via throat. β- Hemolytic streptococci responsible for tonsillitis are predominant among opportunistic normal flora. During tonsillitis, they not only infect throat and tonsils but also cause ear infections via Eustachian tube.

      Ear, nose and throat are interconnected via nasal passage and Eustachian tube. Therefore for the diagnosis of localized ear, nose or throat diseases ENT surgeon and clinician would have to look for the presence of opportunistic infectious agents from ear, nose and throat.

      What is Microflora? (with pictures)

      The word “microflora” refers to the collection of live microscopic organisms that flourish inside the organs of living creatures. These microbes, which exist in places like the stomach, pharynx, and vagina, include fungi, bacteria, and viruses they act as protective agents that strengthen the immune system or destructive agents that weaken the body. Some environs host microflora which include viruses and worms. The inhabitants of microflora, also called microbiota, can be either beneficial or malicious depending on whether they are anaerobic or aerobic. The root word “flora” suggests that microflora refers to the microbes living in flowers the word has evolved, however, to primarily refer to ecosystems inside animals.

      Benevolent and nutritive microbes inside most microfloras are typically called probiotics they are anaerobic. Bifidobacteria and lactobacilli are two of the most common probiotics in the microflora of many animals. Lactobacilli are attracted to environments that are high in sugar and starches. They produce lactic acid, which fuels the muscles with extra energy, according to many doctors in some body regions, lactobacilli produces the disinfectant hydrogen peroxide. Existing primarily in the intestines, vagina and urinary tract, lactobacilli bacteria purportedly helps the body’s positive microflora to fend off pathogens, which are microbes that cause disease.

      Bifidobacteria, much like lactobacilli, also inhabit intestines and vagina, generating protective lactic acid. These bacteria are known for preventing ulcers and diarrhea when existing in proper abundance. They also allegedly help relieve breast pain, eczema and flu. Cancer, hepatitis, and yeast infections are also helped by bifidobacteria.

      Microflora is best when balanced. Whenever the ratio of probiotics is skewed, infections and disease can result due to the high concentrations of harmful bacteria such as staphylococcus, yeasts, and streptococcus organs can also stop functioning properly. Poor nutrition, illness, and medications such as chemotherapy can kill off good bacteria and destroy the microbiota balance. Genetics, environmental pollutants, and stress can also destroy bacteria ratios.

      To restore this balance or preserve it regularly, many people augment their diets with powder or capsule supplements containing probiotics. Proper dosage depends on the individual and the body’s present ratio of good and bad bacteria. Many users experiment with increasing the recommended dosage gradually until they notice a shift in infection, irritation, or energy levels.

      Fermented foods like yogurt and alcohol can often add beneficial microflora. Breast milk delivers high levels of probiotics to the microbiota of infants. The ratio of good bacteria to bad bacteria in the intestines and elsewhere in the body is typically 85 percent to 15 percent for both infants and adults.

      Watch the video: 6. Λειτουργίες και μήκος DNA, απλοειδή - διπλοειδή κύτταρα, 6 1ο κεφάλαιο - Βιολογία Γ λυκείου. (January 2022).