Disease tolerance is a defense strategy essential for survival of infections, limiting physiological damage without killing the pathogen. The disease course and pathology a pathogen may cause can change over the lifespan of a host due to the structural and functional physiological changes that accumulate with age. Since successful disease tolerance responses require the host to engage mechanisms that are compatible with the disease course and pathology caused by an infection, we predicted that this defense strategy would change with age. Animals infected with a lethal dose 50 (LD50) of a pathogen often display distinct health and sickness trajectories due to differences in disease tolerance, and thus can be used to delineate tolerance mechanisms. Using a polymicrobial sepsis model, we found that despite having the same LD50, old and young susceptible mice exhibited distinct disease courses. Young survivors employed a cardioprotective mechanism via FoxO1-mediated regulation of the ubiquitin-proteosome system that was necessary for survival and protection from cardiomegaly. This same mechanism was a driver of sepsis pathogenesis in aged hosts, causing catabolic remodeling of the heart and death. Our findings have implications for the tailoring of therapy to the age of an infected individual and suggest that disease tolerance alleles may exhibit antagonistic pleiotropy.

To combat infections, hosts employ a combination of antagonistic and cooperative defense strategies. The former refers to pathogen killing mediated by resistance mechanisms, while the latter refers to physiological defense mechanisms that promote host health during infection independent of pathogen killing, leading to an apparent cooperation between the host and the pathogen.

To combat infections, hosts employ a combination of antagonistic and cooperative defense strategies. The former refers to pathogen killing mediated by resistance mechanisms, while the latter refers to physiological defense mechanisms that promote host health during infection independent of pathogen killing, leading to an apparent cooperation between the host and the pathogen. Previous work has shown that leptin, a pleiotropic hormone that plays a central role in regulating appetite and energy metabolism, is indispensable for resistance mechanisms, while a role for leptin signaling in cooperative host-pathogen interactions remains unknown. Using a mouse model of Yersinia pseudotuberculosis (Yptb) infection, the causative agent of Far East scarlet-like fever, we unexpectedly found that genetic inhibition of leptin signaling conferred protection from Yptb infection due to increased host-pathogen cooperation rather than greater resistance defenses. The protection against Yptb infection was not due to differences in food consumption, lipolysis or fat mass. Furthermore, we found that the survival advantage was associated with increased liver damage and dysfunction. Our work reveals an additional level of complexity for the role of leptin in infection defense and suggests that in some contexts, in addition to tolerating the pathogen, tolerating organ damage and dysfunction is more beneficial for survival than preventing the damage.