Disease Tolerance as an Inherent Component of Immunity

Abstract

Pathogenic organisms exert a negative impact on host health, revealed by the clinical signs of infectious diseases. Immunity limits the severity of infectious diseases through resistance mechanisms that sense and target pathogens for containment, killing, or expulsion. These resistance mechanisms are viewed as the prevailing function of immunity. Under pathophysiologic conditions, however, immunity arises in response to infections that carry health and fitness costs to the host. Therefore, additional defense mechanisms are required to limit these costs, before immunity becomes operational as well as thereafter to avoid immunopathology. These are tissue damage control mechanisms that adjust the metabolic output of host tissues to different forms of stress and damage associated with infection. Disease tolerance is the term used to define this defense strategy, which does not exert a direct impact on pathogens but is essential to limit the health and fitness costs of infection. Under this argument, we propose that disease tolerance is an inherent component of immunity.

Achieving symptom relief in patients with Myalgic encephalomyelitis by targeting the neuro-immune interface and inducing disease tolerance

“…We believe that one unifying concept could be the failure in upregulating disease tolerance mechanisms in the event of an infection or virus reactivation and this is what we propose herein. Such disease tolerance mechanisms are important in limiting the reduction in host fitness as a consequence of the infection directly or as a consequence of the elicited immune defenses (41). Our data of upregulated disease tolerance pathways upon INMEST treatment support the hypothesis that ME is a result of a failure to upregulate disease tolerance mechanism when faced with infection and thereby leading to a deterioration of physiological functions (Fig.…”

“…Given the evidence of chronic immune activation in ME and the multifaceted symptoms in ME we considered possible unifying mechanisms that could explain the variable presentation of this mysterious illness. Disease tolerance is an overall term describing a range of stress-response pathways that limit tissue damage caused by invading pathogens or indirectly by host immune responses (41). We hypothesized that ME could be due to a failure of upregulating such disease tolerance mechanisms in response to infection.…”

A trade-off between resistance to infection and reproduction in primate evolution

“…In strong support of this notion, humans are more susceptible to develop septic shock when challenged by bacterial lipopolysaccharide (LPS), as compared to other mammalian lineages (Chen et al, 2019). Whether this can be explained by intrinsic characteristics of human immunity and/or the capacity to establish disease tolerance to infection (Martins et al, 2019;Medzhitov et al, 2012), is unclear. This is consistent however with the idea that, similar to GGTA1, humans carry other loss-offunction mutations associated with enhanced immune resistance to bacterial infection (Olson, 1999;Wang et al, 2006).…”

Inducible mechanisms of disease tolerance provide an alternative strategy of acquired immunity to malaria

“…Tolerance mechanisms of host defense do not have a direct impact on pathogen load and instead act to minimise tissue damage caused by the pathogen -and the immune response targeting it. They also function to protect vital homeostatic processes, such as energy metabolism, under conditions of infection-induced stress (Martins et al, 2019). We have taken tremendous steps to understand acquired resistance mechanisms that can eliminate pathogens and provide sterile immunity.…”