Leptin signaling regulates physiological damage and host-pathogen cooperation

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.