TRAITS OF PATHOGENS

Frank pathogens cause disease in some proportion of normal hosts and opportunists cause disease only in those with compromised defenses; an opportunist in one host may be a frank pathogen in another. A frank pathogen’s long-term survival usually depends upon replication in and transmission among members of one or more host species, but opportunists are not bounded by these restrictions.

In either case, the vital events are adherence, entry, avoidance of host defenses, multiplication and spread, and damage to the host. Not all pathogens are equipped for all of these steps. Clostridium tetani does not adhere or enter on its own, but often overcomes these deficits by riding into tissue on foreign objects. Arcanobacterium pyogenes usually lives a quiet, unobtrusive life on mucous membranes, but given a bit of coaxing (in the form of ruminal acidosis, primary viral or bacterial infection, or injury) it can produce life-threatening infections. Zygomycetes are no threat to the normal rumen, but they invade and do massive damage in cattle with compromised rumen function. Herein lies also the most important difference between pathogens and commensals: the former can access privileged niches that are normally unavailable to the latter. Pathogens most often gain entry to these sites by relying on their own devices but are sometimes found to be in complicity with the host cell. Opportunistic infections occur when commensals or other nonadapted organisms are provided an advantage in the form of compromised host defenses. It is likely that nearly any microbe, given sufficient help in clearing host-imposed barriers, can cause infection. The common theme is microbial use of available tools and resources to derive a living from the host.

Pathogen entry to an intact host is fraught with challenges (for the pathogen). Crossing of unbroken keratinized epithelium by bacterial pathogens is relatively rare, although “successful” interactions of this type are common among fungi. Encounters with mucosal epithelium are often an extreme change in environment for a pathogen, which needs the specific machinery to deal with unfamiliar pH, osmolarity, redox potential, and other factors. Some pathogens must eventually deal with the intracellular environment, and these organisms cope by way of multiple sets of virulence genes in sometimes-overlapping systems.

Finding and occupying a niche is the next challenge. Multitudes of commensal bacteria, fungi, and protozoa derive their living from residence in or on hosts, and, not surprisingly, make no effort to welcome interlopers. Some opportunistic pathogens cannot succeed in this endeavor without outside assistance, as with Clostridium difficile infectionin humans subjected to systemic antimicrobial therapy (Figure 1-1).

FIGURE 1-1 Clostridium difficile, a pathogen of humans and domestic animals, also infects hamsters and other rodents, causing rapidly fatal, antibiotic-associated typhlocolitis. Main photo is of infected hamster at necropsy; inset shows excised hamster gut.

(Courtesy J. Glenn Songer.)

Having gained a foothold, the pathogen (whether frank or opportunistic) must defend itself, mainly by avoiding, bypassing, or subverting host defenses. The innate and induced components of the immune system, in the form of phagocytes and humoral components, are, by design, hostile to invading microbes. Microbial strategies for dealing with these issues are diverse, inventive, multifaceted, and often elegant.

Having negotiated some sort of understanding with the host immune defenses, the pathogen (if it is to truly earn its stripes) must set about damaging the host. Succeeding chapters relate in some detail myriad methods by which microbial pathogens accomplish this end. Generally speaking, damage is mediated either without production of toxins (as in generation of a self-destructive immune response) or with toxin production, of which there are many examples. An organism that does not consistently cause host damage is unlikely to be a frank pathogen.

ORIGIN AND EVOLUTION OF VIRULENCE

Bacteria are estimated to have emerged as life forms between 3.5 and 3.8 billion years ago and have adapted to numerous microenvironments over the intervening years. Interesting findings of recent studies suggest that evolution may have produced pathogens long before animals were available as hosts. The principal selective factors affecting microbes seem to have been protozoal predation and environmental stresses in the form of drying and oxidation. Organisms able to cope with both may in fact have been unknowingly assembling the rudiments of a system for survival in animal hosts. They have been left to follow Darwinian principles toward increased overall fitness.

At one time, dogma held that commensal organisms in association with hosts lost the ability to carry out key processes, thus coming to depend on the host to provide essentials for growth and survival. With increased dependence, some organisms “defected,” replicating at the host’s expense, using host cell machinery and in some cases causing what we recognize as disease. Adaptation of bacteria to the physiologically stable environments of host cells may result in reductive evolution, with loss of genes not essential for this lifestyle. Genomes experiencing reductive evolution often contain large numbers of pseudogenes, as in Mycobacterium leprae. Other examples include the absence or inactivation in Yersinia pestis of genes of its progenitor Yersinia pseudotuberculosis. Large chromosomal regions present in most Escherichia coli strains are deleted from enteroinvasive E. coli and Shigella strains. Loss of cadA is virulence associated in Shigella and enteroinvasive E. coli, in that cadaverine (a product of a CadA-catalyzed reaction) inhibits the enterotoxin activity of these organisms. Despite these supportive data, this “gain of virulence by loss of independence” hypothesis it not completely satisfying in explaining virulence evolution; some commensal organisms (e.g., Corynebacterium diphtheriae and perhaps saprophytic neisseriae) gain attributes that make them pathogenic.

Another aspect of dogma was that a well-adapted parasite is a benign parasite. Pathogens were believed to evolve uniformly toward a benign coexistence, or mutualism, allowing more effective reproduction in association with a host. Lewis Thomas said, of C. diphtheriae relating to human hosts, “It is certainly a strange relationship, without any of the straightforward predator-prey aspects that we used to assume for infectious disease. It is hard to see what the diphtheria bacillus has to gain in life from the capacity to produce such a toxin. Corynebacteria live well enough in the surface of human respiratory membranes, and the production of a necrotic pseudomembrane carries the risk of killing off the host and ending the relationship. It does not, in short, make much sense, and appears more like a biological mix-up than an evolutionary advantage.”

The theory behind this statement was widely accepted throughout most of the twentieth century, and has merit in some superficial ways. Ruminants are beautiful examples of beneficial symbiotic relations between host and microbe. Bacteria and protozoa are provided a relatively safe environment with a continuous food supply, whereas the host benefits from microbial transformation of its cellulose-based food intake into ruminant-utilizable nutrients. The skin and gastrointestinal tract also provide residence for microbes that on the whole live harmoniously with their hosts.

However, this theory fails to take into account the basic Darwinian principle of natural selection. Natural selection suggests not peaceful coexistence but competition, in which the genetically superior traits of the stronger, more fit individuals accumulate at the expense of the less fit. Genetically superior pathogens exploit host resources more efficiently and pass on those traits to future generations.

Evolution of microbial virulence is influenced by many factors. One is the selective pressure of the host’s defense mechanisms. Rate of pathogen reproduction is equally important. Perhaps most important of all is transmissibility; especially in the case of immobilization and death, the ultimate host disbenefits, and natural selection favors more transmissible genotypes.

Mathematic models describe the dynamics of pathogen transmission in a host population and suggest that the basic reproductive number is pivotal in pathogen transmission. Where host reproduction is continuous and pathogens are transmitted directly from one host to another, the basic reproductive number is:

where b is the rate of disease transmission, N is the number of susceptible hosts, a is the rate of pathogen-independent mortality, and n is the rate of recovery of the infected host. This basic reproductive number illustrates the mechanisms by which selection for virulence operates. Selection in the pathogen population favors a high R0, achieved by a high rate of transmission, b, or with low rates of pathogen-induced host mortality, a, or recovery, n. If b, a, and n are independent, selection for high R0 will result in the evolution of highly transmissible, benign parasites, an outcome consistent with earlier evolutionary theory. However, if parameters that determine R0 are associated with one another, evolutionary endpoints can include evolution toward virulence or toward avirulence. For example, if b increases more than linearly with a, selection favors a pathogen that kills every infected host.

Generation time in the host can dramatically affect the level of virulence; a genotype that reproduces slowly, but immobilizes or kills the host quickly, may not survive. A pathogen that reproduces rapidly and is transmitted may leave many offspring to die with the host but will nonetheless have a fitness advantage. If, however, disease produced by a rapidly reproducing pathogen severely hinders transmission, Darwinian principles might augur toward genotypes with slower reproduction and at least some degree of transmissibility. In general, slowly reproducing pathogens are more likely to cohabit with other slow reproducers because they will fare less well in company with rapidly reproducing pathogens.

Examination of five millennia of human history and patterns of management of domestic animals suggests that what we recognize today as infectious diseases are mainly products of populations large enough to sustain host-to-host pathogen transfer. Pathogens exist in hosts on a fine line between needs for transmission and longevity. Increased transmission contributes to fitness but requires increased growth, which depletes host resources, causes host damage or death, and subsequently pathogen death. Pathogens that optimize this process may be favored by natural selection.

Microbial virulence is on average strongly dependent upon efficient transmission; adding a low infectious dose further increases the efficiency. “Dead-end” hosts are not uncommon, but this is likely not a fully evolved virulence strategy. For example, Leptospira interrogans serovar icterohaemorrhagiae is commonly found in feral rodents, in which it causes relatively minor pathology (Figure 1-2). However, humans and other species infected by contact with rodent-contaminated environments are likely to develop severe, frequently fatal, disease. Transmission from rodent to rodent and rodent to environment is common, but infected humans (for example) are unlikely to transmit the infection. Another example is provided by the relationship of Neisseria meningitidis to human hosts; this organism is a commensal of the human nasopharynx, but can enter the cerebrospinal fluid and produce meningitis. Transmission from the nasopharynx is common, but organisms sequestered in cerebrospinal fluid are not available to other hosts. The host with meningitis is thus a dead-end host.

FIGURE 1-2 Pathogenic leptospira may be host adapted or nonadapted and the resulting diseases are less or more severe, respectively.

(Courtesy Al Ritchie, deceased.)