Question 2.

2. “One distinct difference among commensal microbes, opportunist microbes, and pathogens is that pathogens have evolved the genetic ability to breach the cellular and anatomic barriers that ordinarily restrict other microorganisms" -Stanley Falkow


Intro

The above comment is true – the breach of host barriers and ability to invade tissues is often integral to pathogenicity. The type of barrier breached (and subsequent localisation of microbe) is also a determining factor in the type of disease caused. This is not the only possible scenario, however. Also discussed here
- pathogenicity in the absence of microbes breaching host defenses
- breach of host defenses not resulting in disease

Cellular and anatomic barriers include
- Skin
- mucus
- hairs in nose, eyelashes
- lacrimal fluid in eyes (lysozyme)
- acidic pH in stomach
- innate immune response (macrophages, NK cells, neutrophils)
- adaptive immune response (B and T lymphocytes)
- blood brain barrier
- cellular membrane

Compartments protected by these barriers include
- blood
- lower respiratory tract
- brain
- organs, nerves and other internal tissues
- hair follicles
- intracellular spaces
- gastrointestinal tract
- genitourinary tract

Symbiotic relationships are commensalism (whereby one organism benefits while the other is not harmed), mutualism (whereby both organisms benefit) and parasitism (whereby one organism benefits and the other is harmed). Pathogens would fall under the latter category. Opportunistic pathogens are those that cause disease in hosts that are compromised e.g. by age, immunosuppression.


Pathogens breaching host defense barriers through intrinsic mechanisms

The body has many defenses designed to keep harmful microbes out. It follows intuitively that those microbes able to cause disease have some intrinsic mechanism of bypassing some of these defenses. A direct example of pathogenicity resulting from the ability to breach the cellular barrier is found in E. coli, which can exist as normal flora in the GIT or be pathogenic. Pathogenic strains of E. coli differ from harmless strains in that the pathogens possess genes allowing them to attach and efface the lining of the GIT ( Whittam, T.S., Wachsmuth, I.K., Wilson, R.A. (1988) Genetic evidence of clonal descent of Escherichia coli O157:H7 associated with hemorrhagic colitis and hemolytic uremic syndrome. Journal of Infectious Diseases, 157(6): 1124-33). Other examples of pathogenesis resulting from breach of defensive barriers:
- Trypanosomes (protozoan species) breaching blood brain barrier and causing sleeping sickness
- Shigella, Salmonella invade cells to cause gastroenteritis or dysentery
- Plasmodium entering erythrocytes and hepatocytes

Many microbes that are successfully excluded by host barriers may cause disease if the host barrier is breached by other mechanisms e.g. S. epidermidis can invade hair follicles and cause furuncles if the skin is cut. In this case, they may be considered opportunistic pathogens. The ability to breach barriers is not intrinsic, as with true pathogens. Genes responsible for ability to breach defenses and exist in protected compartments include:
- acidity resistance (Shigella)
- macrophage resistance (Mycobacterium tuberculosis)
- adhesion and effacing (E. coli O157:H7)
- invasion of cells (Shigella, Salmonella)
- glycocalyx (Anthrax )
In many cases, these genes separate pathogens from commensals and opportunists.

Having breached the host defense, the subsequent localisation of the pathogen is important to the type of disease caused. Some examples of microbes causing different disease symptoms in different body compartments (barrier breached, disease caused) are:
- Anthrax (skin – cutaneous form, respiratory tract – inhalation form, GI tract – gastrointestinal form)
- Varicella (skin – chicken pox, nerves – shingles)
- Staph aureus (blood brain barrier – meningitis, blood – toxic shock syndrome). NB S. aureus can also be normal flora on skin
- Trypanosomiasis (sleeping sickness) – blood phase and neurological phase


Pathogens not breaching barriers and harmless microbes breaching barriers

While the intrinsic ability to overcome host defences is important, it is not the only means by which a microbe may be rendered pathogenic. Of equal importance is the production of toxins. Pathogens that produce toxins do not necessarily have to breach barriers themselves to cause disease.
- Clostridium botulinum – causes botulism, does not need to invade host

By contrast, some microbes that penetrate host defenses do not cause disease.
- Lactobacillus acidophilus (survives acidic pH of vagina, beneficial in that it competes with other microbes)

- Many bacteria survive the acidity and enzymes of the gastrointestinal tract and do not cause disease e.g. E. coli, Clostridium, Bacterioides.


Conclusion

The intrinsic ability to breach cellular and anatomic barriers is an important factor in the ability of a microbe to cause disease, and the type of disease caused. However, it is not the only mechanism by which an organism may be rendered pathogenic. The production of toxins is a characteristic of many pathogens meaning that they are able to cause disease without breaching host barriers themselves. In addition, several microbes that have the intrinsic ability to penetrate host barriers do not cause disease.