Brain-immune interactions generate pathogen-specific sickness states, 2025, Zuri A. Sullivan et al

[Mij]

Abstract
In nature, animals encounter diverse pathogens that trigger specific peripheral defense programs and elicit sickness behavior, a set of stereotyped physiological and behavioral changes thought to promote host fitness. Most studies to date have relied on one or a few mouse models of infection, limiting insights into pathogen-specific neuroimmune interactions that generate sickness.

We hypothesized that different pathogens might elicit distinct sickness states by engaging different cell types and brain circuits. Using inflammatory models representing bacterial, viral, allergic, parasitic or colitis conditions, we assessed sickness across scales: organismal – behavior and physiology; cellular – brain-wide neural activity; and molecular – single-cell in situ transcriptomics in hypothalamus areas associated with social and homeostatic functions affected during sickness. Remarkably, immune challenges elicited unique repertoires of changes across all scales.

Our findings reveal pathogen-specific sickness states encoded by the brain across scales, thereby broadening our understanding of how infections make us sick.
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[Mij]

Our work points to numerous future directions that will deepen our understanding of the neuroimmune interactions that underlie sickness behavior. Our molecular atlas of immune signals in POA- and PVN-treated mice highlights dozens of candidate immune mediators that may affect the function of defined cell types in these brain areas.

Evaluating these candidates experimentally will likely uncover new molecular and cellular mechanisms that regulate sickness behavior during diverse immune challenges.

Though we sought to be as comprehensive as possible in our selection of non-infectious immune challenges, our work here does not fully capture the landscape of inflammatory and infectious triggers that can influence physiology and behavior. For example, a recent study demonstrating the role of interleukin-6 in cancer cachexia, a debilitating wasting syndrome, points to the importance of studying sickness-like behaviors in non-infectious inflammatory conditions such as cancer, metabolic disease, and aging.

Finally, the proof-of-concept studies here leveraged robust, sterile models of infection and inflammation that can be used under biosafety level 1 conditions and therefore afford great flexibility in the application of downstream analyses and manipulations. However, in future work it will be important to evaluate pathogen-specific sickness states in live pathogen models, which better replicate the physiological conditions under which sickness is generated.

 

[Creekside]

It's good to see research challenging long-held beliefs.