Damage control in host–pathogen interactions

Abstract

When 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 … 1E-mail: ruslan.medzhitov{at}yale.edu