We live in a microbial world. Our bodies are constantly surrounded by vast numbers of microbes. In addition to the microbes themselves, the molecules they produce and some molecules from other environmental sources (e.g., venom’s) can also injure body cells and tissues. The body has several mechanical, chemical, and biologic barriers that provide the first line of defence against the entry of microbes into the aseptic, nutrient-rich environment of our tissues. These barriers can be thought of as the moats and thick walls that provided the initial protection to the inhabitants of castles under enemy attack.
The initial mechanical barriers that protect the body against invasive microbes include the Epidermis and keratinocytes of the skin; the Epithelium of the mucous membranes of the gastrointestinal, respiratory, and urogenital tracts; and the cilia in the respiratory tract (Fig. 3.1). These mechanical barriers also incorporate several chemical and biologic barriers that minimize or prevent entry of potential pathogenic organisms into the body.
The epidermis or outer layer of the skin varies in thickness from 0.05 to 1.5 mm depending on location. The outermost of the five layers of the epidermis or stratum corneum is composed of dead, tightly layered, and cornified squamous cells. Produced by keratinocytes of the lower four layers, cells of the stratum corneum provide a watertight barrier that prevents our dehydration and provides a microbe-inhospitable dry environment on the surface of our skin. Continuously dividing keratinocytes and constant sloughing of the superficial epidermal layer removes microbes attached to cutaneous surfaces.[1]
The epithelium of mucous membranes lines all of the body’s cavities that come into contact with the environment, such as the respiratory, gastrointestinal, and urogenital tracts. This epithelium contains goblet cells that secrete mucus. It is estimated that 4 L of mucus are secreted within the gastrointestinal tract alone on a daily basis (although much of it is resorbed in the large intestine). In the respiratory tract, the mucus traps inhaled bacteria, fungi, and other particles. In the gastrointestinal tract, the mucus and mucous membranes help to protect the epithelial cells and underlying tissues from damage by digestive enzymes and to propel ingested matter through the tract.
Mucosal surfaces of the moist epithelium facilitate the exchange of molecules with the environment while also resisting microbial invasion. Additionally, the sloughing of the intestinal epithelial cells has a protective effect similar to that of the sloughing of keratinocytes in the skin.[2]
Air turbulence caused by hairs within the nostrils deposits particles larger than 10 mm in the nasal mucosa. The hairlike cilia of the epithelia lining the respiratory tract passages help the tract clean by moving the secretions containing trapped microbes and particles outward for expulsion by coughing and sneezing. The rhythmically beating cilia of the respiratory epithelium are commonly disrupted by chronic smoking and chronic alcohol consumption, leading to an increased risk of respiratory infections. The importance of the mucus secreted by the membranes of the respiratory system is illustrated by the genetic disorder cystic fibrosis. Cystic fibrosis is caused by a mutant gene that encodes a defective chloride ion channel, leading to abnormally thickened and viscous secretions that can obstruct the respiratory tract. As a result, individuals with cystic fibrosis have recurrent respiratory infections with bacteria such as Pseudomonas aeruginosa.
Urinary tract
Similar to the outward movement of secretions of the respiratory tract, urination helps to inhibit movement of microbes from the environment up into the bladder and kidneys. The periodic voiding of sterile urine provides an externally directed fluid pressure that inhibits the inward movement of microbes along the urinary tract. This simple protective mechanism can be disrupted by the therapeutic insertion of a catheter, which increases the risk of urinary tract infections by facilitating entry of microbes into the urinary tract.[3]
Urinary tract infections due to catheterization account for nearly half of all hospital nosocomial infections. The female urogenital tract is also protected by the acidic secretions of the vagina and the presence of microcidal molecules secreted by the mucous membranes.
CHEMICAL AND ENVIRONMENTAL BARRIERS
The acidic pH of the skin, stomach, and vagina serves as a chemical barrier against microbes. Microcidal molecules such as ”-defensins, ”-defensins, cathelicidin, RNases, DNases, and lysozyme, which are secreted by various cell types, also provide protective environment barriers.
pH
Most pathogens are very sensitive to an acidic environment where an acid pH inhibits the growth of potential pathogens.
Skin: The skin contains oil and sweat glands (sebaceous and sudoriferous glands, respectively), some of whose products are slightly acidic. In general, the skin has a pH of about 5.5. Sebum is a mix of lipids produced by the sebaceous glands. Excessive sebum secretion is often associated with oily skin and acne, particularly in adolescents, as it can clog skin pores (entrapping and retaining microbes) and create less favorable pH levels for microbial growth.
Stomach: Compared to the colon, the stomach has very few bacteria because of its acidic environment (normal pH of 1.0 to 3.0). The acidic environment of the stomach prevents the colonization of the intestines by ingested microbes.
Vagina: The acidic environment of the vagina and cervical in healthy women is normally pH 4.4 to 4.6. This acidic environment is the result of lactic acid production by the commensal bacteria Lactobacilli spp.
Microcidal action of secreted molecules
Several tissues that are in contact with the environment synthesize and secrete various microcidal molecules that act to inhibit or kill microbes that are attempting to colonize. A few of the primary microcidal molecules are discussed here.
Skin: The skin is protected in part by several antimicrobial peptides secreted by various cell types found within the skin. Among these are ”-defensins, ”-defensins, and cathelicidin. All are able to inhibit microbial growth by direct action on the microbes, perhaps by damaging the microbial membranes and causing lysis. They can also act as chemoattractants for cells of the innate immune system and facilitate the ingestion and destruction of microbes by phagocytes. Fatty acids released by some of the commensal microbes that are present on the skin also act to inhibit growth by some other bacteria.
Other molecules with enzymatic activity are present in the skin as well. Sweat contains lysozyme, an enzyme that breaks down peptidoglycan (a constituent of most bacterial cell walls). Also present in the skin are molecules that act on the RNA and DNA of a wide range of microbes. RNases and DNases, in fact, are powerful enough to require the wearing of protective gloves while performing molecular biology procedures’not to protect the hands but to protect the material that is being manipulated from destruction by the enzymes on the skin. Finally, the evaporation of sweat creates a slightly salty environment that inhibits growth of many bacteria.
Respiratory tract: To protect the mucosal surfaces of the lungs, some cells of the respiratory epithelium secrete microcidal molecules such as ”-defensins. These and other molecules in the respiratory tract can attach to microbes and make them more susceptible to ingestion and destruction by phagocytic cells.
Gastrointestinal tract: The gastrointestinal tract defends against pathogens in many ways. In addition to the low pH of the stomach, some epithelial cells secrete microcidal molecules such as ”-defensins and cryptidin that help to destroy many potential pathogens. Approximately 22 different digestive enzymes are released from the salivary glands, stomach, and small intestine. Among these is lysozyme found in saliva. These enzymes help the digestive process but are also effective in killing and degrading many potential pathogens that may be ingested.
Lacrimal secretions: Lacrimal glands are small almond-shaped structures, located above the outer corner of the eye, that produce tears. As part of protecting the eyes, the secretions of lacrimal glands contain lysozyme.
BIOLOGIC BARRIERS: COMMENSAL MICROBES
Commensal microbes are those that exist in a symbiotic relationship with the body. The skin and the gastrointestinal tract are colonized by more than 500 commensal bacterial and other microbial species that are estimated to make up more than 95% of the cells present in a normal human body. Commensal microbes colonizing the skin and gastrointestinal tracts ‘defend’ their territory and inhibit the establishment of other potentially pathogenic microbes. In the gastrointestinal tract, these microbes also assist in the digestive process.[4]
PROBLEM WITH IMMUNE DYSREGULATION
MUCOSAL IMMUNITY
Host defence at mucosal barriers.
Cytokines produced by TH2 cells are involved in blocking entry and promoting expulsion of microbes from mucosal organs, by increased mucus production and intestinal peristalsis. Thus, TH2 cells play an important role in host defence at the barriers with the external environment, sometimes called barrier immunity.[5]
Th-17 Gut Mucosal Defence
Functions of TH17 Cells
TH17 cells combat microbes by recruiting leukocytes, mainly neutrophils, to sites of infection. Because neutrophils are a major defence mechanism against extracellular bacteria and fungi, TH17 cells play an especially important role in defence against these infections. Most of the inflammatory actions of these cells are mediated by IL-17, but other cytokines produced by this subset may also contribute.[6]
Regions of Mucosal Immunity
Regional immune systems include the mucosal immune systems, which protect the gastrointestinal, bronchopulmonary, and genitourinary mucosal barriers, and the cutaneous (skin) immune system. The gastrointestinal immune system is the largest and most complex. By two simple metrics’the number of lymphocytes located in the tissue and the amount of antibodies made there’the gastrointestinal system dwarfs all other parts of the immune system combined. The human intestinal mucosa is estimated to contain approximately 50 ” 109 lymphocytes. The dedication of so many immune system resources to the gut reflects the large surface area of the intestinal mucosa, which has evolved to maximize the primary absorptive function of the tissue but must also resist invasion by trillions of bacteria in the lumen. The skin is also a barrier tissue with vast surface area that must be protected from the environmental microbes that have ready access to the external lining. The total number of lymphocytes in the skin is estimated to be about 20 ” 109, about twice the total number of circulating lymphocytes. The different physical features of the mucosa (soft, wet, and warm) and the skin (tough, dry, and cool) favour colonization and invasion by different types of microbes. Therefore, it is not surprising that the immune system is specialized in different ways in these two types of tissues.[7]
HYGIENE HYPOTHESIS
The postmodern rise in allergic diseases often has been imputed to the notion of increased hygiene standards and hence decreased microbial infections, the so-called ‘Hygiene Hypothesis’ was first suggested in 1989. Allergic diseases are now affecting 20’40% of the population of highly industrialized, economically advanced regions of the world. The incidence of these disorders appears to have dramatically increased in the United States of America and Europe, but also in developed Asian countries. Changes of lifestyle are most evident among young children, and therefore, children are the most vulnerable to develop allergic diseases. Very recently, a detailed account of the historical recordings of the allergy epidemics, from the first reported hay fever case in 1870 until 2010, was published by Platts-Mills in 2015.
In order to understand the adaptability of human nature towards a modernized culture, one should consider the human adaptation in an evolutionary perspective. The history of highly industrialized, postmodern civilization, however, has but a span of at most one century, and therefore, represents merely a few millionth parts of 1% of the evolution of mammals. In evolutionary perspective, one could also say this civilization is a brand-new change of lifestyle but not-yet-adapted to our natural environmental conditions. Allergic reactions do not belong to the well-adapted functions of the immune system, because they are harmful to animals. Since the early branching of vertebrate taxa during evolution, some 300 million years ago, vertebrates have been living in close association with a variety of Helminths (non-systematic group name of parasitic worms of the phyla Annelida, Platyhelminthes, Nematoda and Acanthocephala). In fact, their cohabitation with helminthic worms had some advantage for their immune system. Therefore, it may be described as a form of commensalism, a relationship between two species in which one obtains nutritional substances or other benefits from the other without damaging or exhausting the other. This commensalism was also helpful to their evolutionary success.
The first, hard evidence of a link between modern hygienic conditions and the prevalence of allergy was demonstrated by Strachan (1989), showing an inverse correlation between the numbers of older siblings in the household and the prevalence of hay fever. However, Strachan (1989) did not make an explicit connection to the changes in the biodiversity of the domestic environment. The dramatic reduction in the biodiversity of house, food, soil and skin micro-organisms was not the focus of his article (Strachan 1989), but also not in the recent review by Platts-Mills (2015). Nonetheless, a rational explanation of the increased prevalence of IgE-mediated diseases and their clinical manifestation cannot be reduced to modern behavioral changes in se. In particular, it needs a careful examination of the involvement and dynamics of antigen-specific IgE-cross-linking and postreceptor signal transduction. On the other hand, the first connection between a low prevalence of autoimmune diseases and hygiene status in an underdeveloped population of Nigeria was already suggested by Greenwood (1968). Strachan’s thesis, stating that the dramatic reduction of infections due to a ‘better’ hygiene was countered by an impaired balance and increase in immunemediated diseases, was demonstrated by a large scale cohort study of more than 17,000 children born in 1958, followed for 23 years.
In modern societies, the dramatic rise of allergy prevalence is directed towards a limited number of specific, non-infectious environmental substances. For most patients residing in a local region, they are sensitive to less than a few dozens of antigens among the millions of environmental substances, and among those, dust mites, animal dander, pollens of a few species of trees, grasses and weeds are prominent. This phenomenon was explained by Tse Wen Chang to be caused by a changing pattern of antigen exposure, called the ‘skewed antigen exposure’ hypothesis, in addition to the Hygiene Hypothesis.[8]
CHANGING BUGS
Microbes present our best examples of the general principles of evolution. Short generation times, small genome sizes, and powerful genetic tools make for ideal organisms in laboratory evolution experiments. Microbes can serve as model systems to study most of the major aspects of evolution. Their vast species richness, physiological and behavioural sophistication, and intricate ecologies encompass a wide diversity of evolutionary questions.
Despite these advantages, the interpretation of microbial evolutionary experiments can often be difficult. Numerous studies have shown that, when given sufficient rounds of evolution, microbial populations eventually adapt to surmount diverse challenges. Beyond this nearly universal observation, quantitative prediction of most aspects of the adaptation process remains beyond our reach. For example, we cannot presently predict how long adaptation will take or in what form it will appear, how many mutations will occur, or how adapted the organisms will become. As in many complex systems, one does not expect to predict trajectories precisely, because of their intrinsically stochastic dynamics. Yet, with a theory in hand, one would like to predict correctly the distribution of outcomes. Theory should reveal the structure of dynamical laws that govern the adaptation process while enabling the construction of accurate, predictive models of real systems. Do dynamical laws even exist in complex evolutionary systems? In recent experiments on closed microbial ecosystems, species’ densities were continuously observed over the timescale of months. Data collected on replicate populations demonstrated that their independent trajectories comprise a meaningful ensemble whose dynamical laws could be extracted by analyzing fluctuations.
Understanding how evolutionary dynamics arises from organismal physiologies and interactions poses a challenging open question. In this review, we introduce the major components of this puzzle and survey quantitative studies that could provide a basis for its solution.[9]
Influenza A Viruses ‘ The real baddy!
Influenza A viruses (IAVs) are contagious pathogens responsible for severe respiratory infection in humans and animals worldwide. Upon detection of IAV infection, host immune system aims to defend against and clear the viral infection. Innate immune system is comprised of physical barriers (mucus and collectins), various phagocytic cells, group of cytokines, interferons (IFNs), and IFN-stimulated genes, which provide first line of defense against IAV infection. The adaptive immunity is mediated by B cells and T cells, characterized with antigen-specific memory cells, capturing and neutralizing the pathogen. The humoral immune response functions through hemagglutinin-specific circulating antibodies to neutralize IAV. In addition, antibodies can bind to the surface of infected cells and induce antibody-dependent cell-mediated cytotoxicity or complement activation. Although there are neutralizing antibodies against the virus, cellular immunity also plays a crucial role in the fight against IAVs. On the other hand, IAVs have developed multiple strategies to escape from host immune surveillance for successful replication.[1]
The Respiratory System and the virus
Influenza A viruses primarily target and infect airway and alveolar epithelial cells, which contain the SA glycans as receptors, thus causing alveolar epithelial injury and eventually failure of gas exchange. Hence, human IAV infection may lead to acute respiratory distress syndrome (ARDS) and even death. Various subtypes of IAVs have different abilities to attach human upper respiratory tract (URT). For example, H1N1 adsorbs abundant ciliated epithelial cells and goblet cells, whereas H5N1 hardly attaches to these cells in human URT. In contrast, H5N1 infects alveolar macrophages as well as alveolar epithelial cells. Additionally, human and avian IAVs could target and infect various cells in the lower respiratory tract (LRT). It has been observed that H1N1 and H3N2 attach more abundantly to human trachea and bronchi and adsorb more cell types than H5N1. Of note, low pathogenic (LP) avian IAVs generally do not cause a severe pneumonia because they bind human submucosal gland cells and their mucus which can restrain and remove these viruses before approaching LRT. However, high pathogenic (HP) H5N1 is able to infect type II pneumocytes as these cells possess an active metabolism, therefore providing a possibility to develop severe pneumonia. Moreover, it has been shown that H5N1 reduces proliferation of infected endothelial cells and causes excessive production of cytokines, leading to the lung damage.[2]
The Empire (or Immune System) fights back
The innate immune response is the first line of defense against viral infection which is rapid in response, but nonspecific. During the IAV infection, viral conserved components called pathogen associated molecular patterns (PAMPs) are recognized by host pathogen recognition receptors (PRRs), such as retinoic acid-inducible gene-I protein (RIG-I) and toll-like receptor (TLR), leading to activation of innate immune signaling that finally induces the production of various cytokines and antiviral molecules. These PAMPs have certain characteristic of viral RNA that are not shared by cellular RNAs, such as regions of double-stranded RNA (dsRNA) or the presence of a 5′-triphosphate group.
Pathogen recognition receptors have the ability to distinguish self from non-self molecules within the infected cells. RIG-I is the main receptor to recognize the intracellular ssRNA and transcriptional intermediates of IAVs in the infected host cells. Non-self RNA and transcriptional products of IAVs in the cytoplasm are also sensed by melanoma differentiation-associated gene 5. Following the recognition of PAMPs, RIG-I is activated and its caspase activation and recruitment domains (CARDs) are exposed. Then the CARD is modulated by dephosphorylation or ubiquitination by E3 ligases, such as TRIM-containing protein 25 (TRIM25). Thus, CARD-dependent association of RIG-I and MAVS trigger the downstream transduction signaling at the outer mitochondrial membrane. Subsequently, the transcription factors, including interferon regulatory factor 3 (IRF3) and IRF7, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-”B) are activated, causing the expression of a variety of IFNs and cytokines.[3]
How many flu cases have we had over the last couple of years?
There have been more than 250,000 influenza cases reported in Australia this year (2017), up significantly from 91,000 cases last year (2016). A mutated virus and a weaker immune response from older Australians have contributed to the deadly season, which has also claimed the lives of healthy, young people.
Flu vaccine ingredients
Active Ingredients