Parasitic helminths are among the most pervasive pathogens of the animal kingdom. To complete their life cycle, these intestinal worms migrate through host tissues causing significant damage in their wake. As a result, infection can lead to malnutrition, anemia and increased susceptibility to co-infection. Despite repeated deworming treatment, individuals living in endemic regions remain highly susceptible to re-infection by helminths, but rarely succumb to excessive tissue damage. The chronicity of infection and inability to resist numerous species of parasitic helminths that have co-evolved with their hosts over millenia suggests that mammals have developed mechanisms to tolerate this infectious disease. Distinct from resistance where the goal is to destroy and eliminate the pathogen, disease tolerance is an active process whereby immune and structural cells restrict tissue damage to maintain host fitness without directly affecting pathogen burden. Although disease tolerance is evolutionary conserved and has been well-described in plant systems, only recently has this mode of host defense, in its strictest sense, begun to be explored in mammals. In this review, we will examine the inter- and intracellular networks that support disease tolerance during enteric stages of parasitic helminth infection and why this alternative host defense strategy may have evolved to endure the presence of non-replicating pathogens and maintain the essential functions of the intestine
