17.2: How Pathogens Cause Disease
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- Ying Liu
- City College of San Francisco
Learning Objectives
- Summarize Koch’s postulates and molecular Koch’s postulates, respectively, and explain their significance and limitations
- Explain the concept of pathogenicity (virulence) in terms of infectious and lethal dose
- Distinguish between primary and opportunistic pathogens and identify specific examples of each
For most infectious diseases, the ability to accurately identify the causative pathogen is a critical step in finding or prescribing effective treatments. Today’s physicians, patients, and researchers owe a sizable debt to the physician Robert Koch (1843–1910), who devised a systematic approach for confirming causative relationships between diseases and specific pathogens.
Koch’s Postulates
In 1884, Koch published four postulates that summarized his method for determining whether a particular microorganism was the cause of a particular disease. Each of Koch’s postulates represents a criterion that must be met before a disease can be positively linked with a pathogen. In order to determine whether the criteria are met, tests are performed on laboratory animals and cultures from healthy and diseased animals are compared (Figure \(\PageIndex{1}\)).
Koch’s Postulates
- The suspected pathogen must be found in every case of disease and not be found in healthy individuals.
- The suspected pathogen can be isolated and grown in pure culture.
- A healthy test subject infected with the suspected pathogen must develop the same signs and symptoms of disease as seen in postulate
- The pathogen must be re-isolated from the new host and must be identical to the pathogen from postulate 2.
In many ways, Koch’s postulates are still central to our current understanding of the causes of disease. However, advances in microbiology have revealed some important limitations in Koch’s criteria. Koch made several assumptions that we now know are untrue in many cases. The first relates to postulate 1, which assumes that pathogens are only found in diseased, not healthy, individuals. This is not true for many pathogens. For example, H. pylori , described earlier in this chapter as a pathogen causing chronic gastritis, is also part of the normal microbiota of the stomach in many healthy humans who never develop gastritis. It is estimated that upwards of 50% of the human population acquires H. pylori early in life, with most maintaining it as part of the normal microbiota for the rest of their life without ever developing disease.
Koch’s second faulty assumption was that all healthy test subjects are equally susceptible to disease. We now know that individuals are not equally susceptible to disease. Individuals are unique in terms of their microbiota and the state of their immune system at any given time. The makeup of the resident microbiota can influence an individual’s susceptibility to an infection. Members of the normal microbiota play an important role in immunity by inhibiting the growth of transient pathogens. In some cases, the microbiota may prevent a pathogen from establishing an infection; in others, it may not prevent an infection altogether but may influence the severity or type of signs and symptoms. As a result, two individuals with the same disease may not always present with the same signs and symptoms. In addition, some individuals have stronger immune systems than others. Individuals with immune systems weakened by age or an unrelated illness are much more susceptible to certain infections than individuals with strong immune systems.
Koch also assumed that all pathogens are microorganisms that can be grown in pure culture (postulate 2) and that animals could serve as reliable models for human disease. However, we now know that not all pathogens can be grown in pure culture, and many human diseases cannot be reliably replicated in animal hosts. Viruses and certain bacteria, including Rickettsia and Chlamydia , are obligate intracellular pathogens that can grow only when inside a host cell. If a microbe cannot be cultured, a researcher cannot move past postulate 2. Likewise, without a suitable nonhuman host, a researcher cannot evaluate postulate 2 without deliberately infecting humans, which presents obvious ethical concerns. AIDS is an example of such a disease because the human immunodeficiency virus (HIV) only causes disease in humans.
Molecular Koch’s Postulates
In 1988, Stanley Falkow (1934–) proposed a revised form of Koch’s postulates known as molecular Koch’s postulates. These are listed in the left column of Table \(\PageIndex{1}\). The premise for molecular Koch’s postulates is not in the ability to isolate a particular pathogen but rather to identify a gene that may cause the organism to be pathogenic.
Falkow’s modifications to Koch’s original postulates explain not only infections caused by intracellular pathogens but also the existence of pathogenic strains of organisms that are usually nonpathogenic. For example, the predominant form of the bacterium Escherichia coli is a member of the normal microbiota of the human intestine and is generally considered harmless. However, there are pathogenic strains of E. coli such as enterotoxigenic E. coli (ETEC) and enterohemorrhagic E. coli (O157:H7) (EHEC). We now know ETEC and EHEC exist because of the acquisition of new genes by the once-harmless E. coli , which, in the form of these pathogenic strains, is now capable of producing toxins and causing illness. The pathogenic forms resulted from minor genetic changes. The right-side column of Table \(\PageIndex{1}\) illustrates how molecular Koch’s postulates can be applied to identify EHEC as a pathogenic bacterium.
| Molecular Koch’s Postulates | Application to EHEC |
|---|---|
| (1) The phenotype (sign or symptom of disease) should be associated only with pathogenic strains of a species. | EHEC causes intestinal inflammation and diarrhea, whereas nonpathogenic strains of E. coli do not. |
| (2) Inactivation of the suspected gene(s) associated with pathogenicity should result in a measurable loss of pathogenicity. | One of the genes in EHEC encodes for Shiga toxin, a bacterial toxin (poison) that inhibits protein synthesis. Inactivating this gene reduces the bacteria’s ability to cause disease. |
| (3) Reversion of the inactive gene should restore the disease phenotype. | By adding the gene that encodes the toxin back into the genome (e.g., with a phage or plasmid), EHEC’s ability to cause disease is restored. |
As with Koch’s original postulates, the molecular Koch’s postulates have limitations. For example, genetic manipulation of some pathogens is not possible using current methods of molecular genetics. In a similar vein, some diseases do not have suitable animal models, which limits the utility of both the original and molecular postulates.
Key Concepts and Summary
- Koch’s postulates are used to determine whether a particular microorganism is a pathogen. Molecular Koch’s postulates are used to determine what genes contribute to a pathogen’s ability to cause disease.
Footnotes
- 1 Food and Drug Administration. “Bad Bug Book, Foodborne Pathogenic Microorganisms and Natural Toxins.” 2nd ed. Silver Spring, MD: US Food and Drug Administration; 2012.
- 2 M. Otto. “ Staphylococcus epidermidis --The ‘Accidental’ Pathogen.” Nature Reviews Microbiology 7 no. 8 (2009):555–567.
- 3 The O in TORCH stands for “other.”
- 4 D. Davies. “Understanding Biofilm Resistance to Antibacterial Agents.” Nature Reviews Drug Discovery 2 (2003):114–122.