Accidental virulence, cryptic pathogenesis, martians, lost hosts, and the pathogenicity of environmental microbes.

Why do only certain microbes have the capacity to be virulent, and why are certain microbes virulent only in certain hosts? These fundamental questions have shaped and directed the thinking of microbiologists and the field of microbial pathogenesis since the germ theory of disease was proposed in the late 19th century. The germ theory gave rise to the prevailing view that there are fundamental differences between pathogenic and nonpathogenic microbes. This view, which regards virulence as a microbial characteristic, is supported by the observation that certain microbes require specific factors, such as toxins and capsules, for animal virulence. However, almost since it was first put forth that pathogens and nonpathogens are fundamentally different, there have been exceptions and challenges to this view. The demonstration that animal and/or in vitro passage can alter virulence illustrated that virulence is not necessarily a stable or invariant trait. Then, the 20th-century emergence of commensal microbes that were previously considered to be avirulent, such as Candida albicans (7) and Staphylococcus epidermidis (40), as clinically relevant pathogens provided clear evidence that virulence can be a function of the immune status of the host. For microbes that cause disease at one time but not another, the determinant of disease is often a change in the host that alters the host-microbe interaction. Hence, while virulence is a microbial property, it is expressed only in a susceptible host (4). Given that the outcome of microbial infection is often a function of the immune status of the host and that a susceptible host is required for microbial virulence, it makes sense to categorize microbial pathogens based on how they are acquired. There are two basic types of acquisition. One type encompasses microbes that are acquired from other living hosts, including those of the same or different species, e.g., insects or protozoa. The other type encompasses microbes that are acquired from the environment, though it may contain the remains of formerly living species, such as decaying vegetation. Microbes acquired from other hosts are adapted for host survival. Their virulence often stems from an altered hostmicrobe relationship in which the immune response cannot control microbial proliferation. Among human eukaryotic pathogens, Candida albicans, Pneumocystis spp., and the dermatophytes are each host acquired. The diseases caused by these microbes usually occur when an alteration in the host-microbe relationship, such as that induced by antibiotics, immunosuppression, or changes in their niche, results in a larger fungal burden. However, a large inoculum could also have the capacity to cause disease in healthy hosts, as illustrated by the dramatic example of self-experimentation in which a physician imbibed a C. albicans suspension that resulted in candidemia and candiduria (22). A similar example of self-experimentation led to the association of Helicobacter pylori, another human commensal microbe, with peptic ulcer disease. In contrast, microbes acquired from the environment have no obvious requirement for residence in an animal host to survive or replicate. For example, and in contrast to the requirements of many parasites, there is no evidence that environmentally acquired pathogenic fungi, such as Cryptococcus neoformans and Histoplasma capsulatum, require residence in a living animal host. Although we acknowledge that some environmental fungi, such as H. capsulatum and Coccidioides spp., can be recovered from small animals, such as wild bats (37) and small rodents (9), respectively, their presence in such hosts does not appear to be a necessity for survival. Microbes acquired from the environment often cause disease in situations in which the host is exposed to a large microbial inoculum. For example, histoplasmosis and coccidioidomycosis in healthy hosts can follow cave visits (23) and archeological excavations (31), respectively. Nonetheless, the diseases caused by most environmentally acquired fungi occur predominantly in hosts with preexisting immune impairment and/or those that acquire large inocula. For example, coccidioidomycosis can develop in healthy individuals after exposure to a large inoculum and is generally self limited. However, in hosts with impaired immunity, coccidioidomycosis is a chronic, often lethal disease. In general, microbes acquired directly from the environment are not communicable to other hosts. Nevertheless, occasional person-to-person transmission of cryptococcosis has been reported as a consequence of needlestick accidents (18), showing that in unusual circumstances microbes acquired directly from the environment can be passed from host to host. * Corresponding author. Mailing address: Department of Microbiology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. Phone: (718) 430-3665. Fax: (718) 430-8968. E-mail: [email protected]. Published ahead of print on 19 October 2007.