Living Well with Microbes 2

What are the distinguishing characteristics of microbes that live in humans? A successful pathogen or commensal must do the following:

• Enter the human host;
• Become established, which includes successful competition with indigenous microbes;
• Acquire nutrients;
• Avoid or circumvent the host’s innate defenses and a powerful immune system;
• Above all, replicate;
• Disseminate if necessary to a preferred site; and
• Eventually be transmitted to a new susceptible host.

Whether a pathogen or a commensal, a microorganism must also possess an interactive group of complementary genetic properties that promote its interaction with the human host. For a given microorganism, the genetic traits define unique attributes that enable it to follow a common sequence of steps used in establishing infection or, in some cases, subsequent disease.

Genetic testing techniques now permit the identification, isolation, and characterization of many of these genes. The availability of the host (e.g., human) genome sequence also enables multiple synergistic approaches for understanding virulence, including the identification of host susceptibility traits, genome-wide assessments of host response, and clues about the mechanisms of host defense and pathogen counter-defense.

Smart Bugs

It has long been but a hypothesis that pathogens (take Borellia from Lyme for example) breach intact host anatomic, cellular, or biochemical barriers that ordinarily prevent entry by other microorganisms. Thus, pathogens “go where other microbes dare not.” In addition, many pathogens, such as Borellia, Mycobacterium tuberculosis, Treponema pallidum, Chlamydia trachomatis, and Salmonella typhi, have the capacity to establish persistent (often subclinical) infection in the human host and have evolved the extraordinary capacity to live in the inner sanctums of our innate and adaptive immune defenses or, in general, to compete well in the face of otherwise hostile host conditions. Some may even evoke human macrophage activity to defend itself against immune attack!

For example, Salmonella profits from the inflammatory response that it provokes in the gut by using the oxidized form of a locally produced host factor for a selective growth advantage against commensals. A distinction, then, between a primary pathogen and opportunist is that the pathogen has an inherent ability to breach the host barriers that ordinarily restrict other microbes, whereas the opportunist requires some underlying defect or alteration in the host’s defenses, whether it be genetic, ecologic (altered microbiota), or caused by underlying disease, to establish itself in a usually privileged host niche. Clearly, the nature of the host plays as important a role as the pathogen in determining outcome.

An initial step required of a pathogen is to gain access to the host in sufficient numbers. Such access requires that the microorganism not only make contact with an appropriate surface but also then reach its unique niche or microenvironment on or within the host. This requirement is not trivial. Some pathogens must survive for varying periods in the external environment. Others have evolved an effective and efficient means of transmission. To accomplish this goal, the infecting microbe may make use of motility, chemotactic properties, and adhesive structures (or adhesins) that mediate binding to specific eukaryotic cell receptors or to other microorganisms (piggy-backing on other microbes).

Pathogens that persist at the surface of skin or mucosa usually rely upon multiple redundant adhesins and adherence mechanisms. If the adhesin is immunogenic, expression is usually regulated; in addition, antigenic variants may arise. Preexisting microorganisms (the host’s existing microbiota) provide competition against establishment of the newcomer so long as it is healthy and abundant.

Normal inherent host defense mechanisms should pose the most difficult set of obstacles for pathogens and commensals in establishing themselves in a host. For any set of specific host defenses, an individual pathogen will have a unique and distinctive counterstrategy. Some of the best-known mechanisms that pathogenic microbes use for countering host defenses include the use of an antiphagocytic capsule and the elaboration of toxins and microbial enzymes that act on host immune cells and/or destroy anatomic barriers. These are smart bugs, after all.

Microorganisms also use subtle biochemical mechanisms to avoid, subvert, or, as we now increasingly understand, manipulate host defenses. These strategies include the elaboration of immunoglobulin-specific proteases, iron sequestration mechanisms, coating themselves with host proteins to confuse the immune surveillance system, or causing host cells to signal inappropriately, leading to dysregulation of host defenses or even host cell death. It really is quite amazing!

Examples of these mechanisms include the production of immunoglobulin A1 protease by the meningococci, the use of receptors for iron-saturated human transferrin and lactoferrin by N. gonorrhoeae, and the coating of T. pallidum with human soluble fibronectin.

Yersinia, Mycobacterium, and Bordetella stimulate a TH2 response and diminish the killer cells by inducing host cell production of interleukin-10, which is a potent immunosuppressive cytokine so it can slip past defense like a cunning spy. Antigenic variation and intracellular invasion are other common strategies used by successful pathogens to avoid immune detection.

Their Ultimate Purpose

The ability to multiply is a characteristic of all living organisms since, ultimately, reproduction and survival is its goal. Whether the pathogen’s habitat in the relevant host is intracellular or extracellular, mucosal or submucosal, within the bloodstream or within another privileged anatomic site, pathogens have evolved a distinct set of biochemical tactics to achieve this goal. The ultimate success of a pathogen, indeed, of any microorganism, is measured by the degree to which it can multiply and to the extent that it succeeds is to the demise of the host. More info? Read