Pathogen-Mediated Inhibition of Anorexia Promotes Host Survival and Transmission

Abstract

Summary Sickness-induced anorexia is a conserved behavior induced during infections. Here, we report that an intestinal pathogen, Salmonella Typhimurium, inhibits anorexia by manipulating the gut-brain axis. Inhibition of inflammasome activation by the S. Typhimurium effector, SlrP, prevented anorexia caused by IL-1β mediated signaling to the hypothalamus via the vagus nerve. Rather than compromising host defenses, pathogen-mediated inhibition of anorexia increased host survival. SlrP-mediated inhibition of anorexia prevented invasion and systemic infection by wild-type S. Typhimurium, reducing virulence while increasing transmission to new hosts, suggesting there are trade-offs between transmission and virulence. These results clarify the complex and contextual role of anorexia in host defense and suggest that microbes have evolved mechanisms to modulate sickness-induced behaviors to promote health of their host and their transmission at the expense of virulence.

Cooperative Metabolic Adaptations in the Host Can Favor Asymptomatic Infection and Select for Attenuated Virulence in an Enteric Pathogen

“…With our study, we suggest that one function of acute IR during disease is to increase the availability of glucose to resident microbes of the host to tame their virulence. This is supported by recent studies showing that feeding during infection dampens pathogen virulence during Salmonella intestinal infection and that the host fucosylation response during LPS-induced anorexia prevents the virulent behavior of the resident microbiota during sickness (Pickard et al, 2014; Rao et al, 2017). …”

“…By not achieving high levels of growth within the host, the host becomes a healthy reservoir for the pathogen facilitating increased transmission to new hosts, that become asymptomatic, persistent shedders and ultimately may result in pathogen strains with greater fitness than the parental strain. Trade-offs between virulence and transmission have been reported previously (Mackinnon et al, 2008; Paul et al, 2004; Rao et al, 2017). It will be important to perform population studies in the future to determine whether the attenuated strains are more fit, define the mechanism of attenuation and determine if these strains can revert back to their original phenotype and become virulent to the host again.…”

“…Pathogens are equipped with virulence factors enabling the pathogen to achieve specialized niches where they can replicate and be transmitted to new hosts, ultimately resulting in disease. While virulence factors are adaptation factors to promote pathogen fitness, their expression must be tightly regulated to achieve the optimal balance between pathology and fitness, as too much pathology could ultimately compromise both the host and the pathogen (Ayres, 2016; Rao et al, 2017). For pathogens that asymptomatically and persistently infect hosts, it appears a new equilibrium has been reached between the host and the pathogen in which pathogen fitness is achieved, without the need for employing virulence factors, and resulting in an otherwise healthy host.…”

Metabolic Instruction of Immunity

“…A recent report by Rao and colleagues suggests that Salmonella typhimurium inhibits infection-induced anorexia upon oral infection by antagonizing caspase-1 activity downstream of inflammasome activation to decrease IL-1β signaling to the hypothalamus via the vagus nerve (Rao et al, 2017). Disrupting this adaptation in Salmonella by genetic deletion of its ubiquitin ligase SlrP resulted in modulation of the gut-brain axis.…”

Manipulating Glucose Metabolism during Different Stages of Viral Pathogenesis Can Have either Detrimental or Beneficial Effects

“…In fact, targeting metabolic events represents a logical approach to pathogen control since many cause major changes in metabolism not only in cells they infect, but also impact on the function of distant uninfected organs such as the liver, kidney, cardiovascular system and even the brain (16). Some of the general physiological consequences of systemic infections has been highlighted by recent studies (16, 17). However, the general topic of how virus infections, particularly those that cause local infections, influences physiological responses is still poorly understood.…”