Genetic analysis of innate immunity using C. elegans

Increasing evidence suggests that the intestine plays an important role in sensing not only the presence
of pathogens but also changes in the microbiota, which ultimately result in changes in the regulation of
immune pathways and behaviors by communicating with neurons. However, the complexity of the
nervous and immune systems of mammals makes it difficult to dissect the mechanisms by which the
neural-gut axis communicates using bidirectional signals to control intestinal immunity. Studies in the
nematode Caenorhabditis elegans show that bacterial colonization of the intestine results in the
activation of the expression of innate immune genes in the gut and the activation of a neuroendocrine
signal that controls pathogen avoidance. The germline also plays a key role in the neural-gut axis not
only by transmitting the immunological memory to the next generation but also by communicating
pathogenic cues that travel from the gut to the nervous system to control innate immunity. The long-term
goal of this proposal is to elucidate the mechanism by which the neural-germline-gut axis communicates
to sense pathogens and/or infection-induced physiological changes to control innate immunity at the
whole animal level. Thus, we will explore the general hypothesis that the neural-germline-gut axis plays
a critical role in the organismal response against bacterial pathogens by helping the nervous system
integrate signals from infected sites and different tissues to coordinate the immune response. Specific
genes and neurons will be studied to dissect the neural circuits that regulate immune activation in
response to pathogen exposure and pathogen-induced alterations of the animal’s physiology. A
genetics approach will also be used to identify neurotransmitters and endocrine signals potentially
involved in the neural-immune communication that takes place between neurons and different tissues
and infected sites.
RELEVANCE (See instructions):
The systemic control of innate immunity is critical because inflammation accounts for the major
physiological, metabolic, and pathological responses to infections. We plan to continue our studies to clarify
the role of the nervous system in the regulation of intestinal innate immune responses against bacterial
pathogens. A better understanding of the neural-immune communication could lead to new therapeutic
targets for diseases involving a deficient innate immune system.

Grant Number: 5R37GM070977-24
NIH Institute/Center: NIH
Principal Investigator: Alejandro Aballay