Not all microorganisms cause disease, however pathogens are disease causing microorganisms. The reason why exposure to some microorganisms but not other result in pathology has many explanations and will be discussed in the context of commensals, bacterial adaptation, over active immune responses, and probiotics.
The gut microbiota protects from pathogens and shapes the immune response, exhibiting a symbiotic relationship known as commensalism. This is where one species benefits whilst the other is unaffected. It is crucial for the immune system to be able to distinguish between pathogens and commensals as patients affected with HIV, burn victims or patients on immune suppressant drugs (e.g transplant patients) and cancer therapy are most vulnerable to opportunistic commensal-induced infections.
Candida Albicans is an ascomycete fungus which grows on mucosal membranes of the mouth and urogenital tracts in 50% of healthy patients as commensals however can cause pathology under certain circumstances. Candida Albicans have the ability to interconvert between a yeast and fungal form depending on environmental conditions. When under starvation at 37 degrees or pH at 7 they start to form Hyphae. The yeast form can adhere to and colonise the host epithelial tissues, whilst the fungal form is adapted to spreading within the blood stream. The yeast converts back to the hyphal form which can then invade host tissue, causing damage. Mutants where Candida Albicans have been unable to convert to the hyphal form have prevented from causing disease.
High exposure to antibiotics can kill commensals within the gut. Clostridium difficile is a bacterium that can infect the bowel and cause diarrhoea, it takes advantage of the lack of commensals within the mucosa and produces toxins to degrade connective tissue. Bowel disease is a chronic remitting inflammatory disorder where the host epithelial barrier integrity is reduced in addition to the absorption of nutrients. Chronic inflammation in the gut results in a compromised epithelial layer with reduced mucosal layer and so commensals invade through the epithelial layer. In healthy patients IL-10 and T-reg cells are produced to prevent commensal-induced inflammation in addition to IgA antibodies, when this system fails for immunocompromised patients then pathology occurs.
The host can detect pathogens via the secretion systems they use to transport virulence proteins out of the cell however both pathogens and commensals use secretion systems. As a result bacteria have adapted and evolved to lose a certain secretion system from the cells membrane to enable invasion of the host immune response and cause pathology. Bpp5 in Bordetella pertussis has genes missing in the middle of the type 6 secretion system (T6SS) locus. This strain has shown to cause pneumonia in sheep. This may have occurred due to reduced competition of other bacterial species from the loss of the T6SS. Illustrating how certain members of a species can be disease causing other members of the same species are not able to do so.
The immune response must proceed with caution to prevent over response to commensals which can also result in pathology. Tumour necrosis factor alpha (TNFa) is a cell signalling cytokine which under standard conditions would not cause pathology. During standard innate immune response macrophages are activated by damage-associated molecular patterns (DAMPs) and pathogen associated molecular patterns (PAMPs). TNFa is produced which then recruit and activate neutrophils and NK cells to the infection site. This causes tissue swelling, heat and induces fever. Immune cells have evolved to function well at higher temperatures but microbes are not able to function in this condition, hence fever is induced to make an uninhabitable environment. These innate cells reinforce each other, inducing a stronger response. Initiation of the adaptive immunity results in pathogen killing, T cells require 2 signals to respond to pathogens, signal 1 communicates antigen specifics presented by dendritic cells whilst signal 2 stimulate PAMPs to upregulate B7 to T cells on antigen presenting cells via CD28. Signal 1 without signal 2 means the T cell is recognising itself or food. The infection site must then be resolved because if PAMPS cannot be cleared they can then act as toxins and so a systemic infection occurs.If the pathogen is not being killed easily or quickly enough especially in cases for Immunocompromised and elderly patients with downgraded IL-10, they will have sustained immune activation, and so more TNFa continues to be produced. Increasingly high levels of TNFa can inhibit heart contractions, cause cachexia, reduce blood pressure, and as a final result: septic shock, organ failure then death. Toll-like receptor four (TLR4) is a pattern recognition receptor for lipopolysaccharide, polymorphisms in TLR4 are associated with increased susceptibility to sepsis.
Probiotics such as Lactobacillus casei are live bacteria and yeasts that help restore the natural balance of bacteria in gut. Without probiotics, antibiotics have the ability to wipe out the protective gut bacteria such as lactobacillus and so resulting in vulnerability to pathogens. Probiotics are thought to directly kill or inhibit growth of pathogenic microorganisms. Probiotics also enhance gut-specific IgA responses, which are often defective in children with food allergens however Lactobacillus GG was effective in prevention of early atopic disease in children at high risk. At birth, the gastrointestinal (GI) tract is sterile, but in the first months and years of life a rapid sequential colonisation occurs until a stable indigenous gut microflora is established. Simultaneously, the T-helper-2-dominant immunity of neonates is intensified in atopic individuals, with the subsequent expression of atopic disease. Dietary antigens also strongly affect the neonatal GI system, induction of oral tolerance, IgA production, as well as generation of transforming growth factor which suppresses T-helper-2-induced allergic inflammation. Oral lactobacilli in atopic children enhance transforming growth factor ß and IL-10 production in vivo, findings from clinical and experimental studies suggest that these anti- inflammatory cytokines have a crucial role in prevention of pathology.
It can be concluded from this discussion that pathology occurring due to exposure to some microorganisms but not others is simply circumstantial. Certain bacteria have adapted to remain undetected by the immune system and so able to cause pathology. If the patient is immunocompromised then many commensals – such as clostridium difficle and Candida albicans – can take the opportunity to cause pathology. TNFa induces a working immune response optimal when localised, but when systemic results in pathology. Probiotics are strains of bacteria which can prevent pathology caused by atopic disease. These examples display circumstantial evidence of how exposure to certain microorganisms can result in pathology.
Global Health Challenges 