Damage control in host-pathogen interactions.

W hen facing a problem, we would ideally like to be able to eliminate its source. If that is not feasible, we focus our efforts on damage control, by attempting to minimize the consequences of the problem at hand. Likewise, host defense from infections can employ two distinct strategies of protection: one aims to reduce or eliminate the invading pathogen, whereas the other reduces the damage to the host inflicted by a given pathogen burden. The two strategies are referred to as resistance and tolerance, respectively (1). Resistance mechanisms are generally mediated by the immune system. Mechanisms of tolerance (not to be confused with immunological tolerance) are far less well understood, particularly in animal hosts (2). The report by Seixas et al. (3) in this issue of PNAS describes a mechanism of host tolerance used during infection with Plasmodium parasites. This study provides one of the first insights into molecular mechanisms of infection tolerance in mammals and is likely to be applicable, at least in principle, to a broad range of infectious diseases. Resistance and tolerance have long been recognized as distinct host defense strategies used by plants to deal with their pests. The distinction between the two strategies is fundamentally important, because they rely on discrete molecular mechanisms and entail different consequences for the evolutionary dynamics of host–pathogen interactions (4). Surprisingly, the concepts of resistance and tolerance are seldom applied to studies of animal immunity, where research has traditionally focused almost exclusively on mechanisms of resistance. Consequently, very little is known about the underlying mechanisms of tolerance and their utility for host protection. Tolerance mechanisms do exist in animals, however, as documented by the few studies reported to date: Råberg et al. (5) described a variation in tolerance to Plasmodium infection in several inbred mouse strains, which was probably the first clear description of tolerance in animals, and Schneider and colleagues (6–9) in a series of elegant studies dissected the contributions of resistance and tolerance to Drosophila defense from infections. Together, these studies have indicated the existence of powerful but poorly understood defense mechanisms that contribute to host survival from infections. Clearly, this line of research will have to be continued and significantly expanded to reveal what is likely to be a plethora of mechanisms that contribute to host tolerance to infections. Some basic conceptual aspects of host tolerance have been discussed in detail in recent excellent reviews (1, 2, 10). To provide a context for the discussion of the new report by Seixas et al. (3), a couple of points need to be made. First, the symptoms of infectious diseases can be either due to direct damage to the host inflicted by the pathogen, or due to immunopathology—the collateral damage to the host tissues caused by the immune response. Accordingly, tolerance mechanisms may be broadly divided into mechanisms that protect the host tissues from direct pathogeninduced damage, for example, caused by microbial toxins, and the mechanisms that limit immunopathology. The latter in turn can be subdivided into immunoregulatory mechanisms, which control the intensity and duration of the immune and inflammatory responses, and the mechanisms that render tissues more resistant to inflammatory damage. Second, the relative contribution of the two types of mechanisms most likely depends on the replication, transmission, and host adaptation strategies of microorganisms. An extreme example illustrating this point is the nature of host–commensal interactions. Here, the host tolerates microbial colonization of enormous proportions without any adverse effects (in fact, with a number of essential benefits). In large part, this is due to potent immunoregulatory mechanisms that maintain a host–commensal homeostasis at the sites of colonization, such as the colon. If the normal immunoregulatory state is disrupted, however, the ensuing problems are due almost entirely to the inappropriate immune and inflammatory responses triggered by the commensal microbes. Most pathogenic infections will elicit both types of tissue damage, and therefore the host may commonly employ both types of tolerance mechanisms. The case in point is infection with Plasmodium, the causative agent of malaria. This protozoan parasite can cause direct damage to the host through hemolysis and anemia, and indirect damage attributable to immunopathology. The latter is responsible for some forms of severe malaria, including cerebral malaria, which is caused by the disruption of the blood–brain barrier followed by the often lethal inflammatory response in the brain (11). During the blood stage of infection, Plasmodium invades red blood cells (RBCs), where it degrades hemoglobin, resulting in the release of free heme. Because free heme is toxic to the host and to the parasite, both try to convert it to more innocuous chemical forms. Plasmodium converts heme into a polymer called hemozoin, which is nontoxic to the parasite. This conversion can be blocked by chloroquine, which