Overview
We are interested in understanding the molecular interaction between microbes and the simple animal host Caenorhabditis elegans. Our lab studies evolutionarily conserved pathways of innate immunity and the genetic determinants of C. elegans neurobehavioral responses to pathogenic bacteria. Our work focuses on the interplay between innate immunity and host organism physiology, including how basic cellular homoestatic processes, such as the response to endoplasmic reticulum stress, are influenced by infection and immunity of the host.

Innate immunity in C. elegans
Convergent genetic investigations in Drosophila and mice established that key signaling pathways of mammalian innate immunity are conserved in the immune responses of invertebrate organisms. We have established that C. elegans also responds to infection with pathogenic bacteria with the activation of a conserved p38 mitogen-activated protein kinase pathway, which regulates the expression of secreted immune effectors such as C-type lectins and antimicrobial peptides (Kim et al., 2002; Kim et al., 2004; Troemel et al., 2006). We and others have established that the p38 MAPK pathway functions downstream of a conserved Toll-Interleukin-1 Receptor (TIR) domain protein, TIR-1. Recently, we defined a conserved CREB/ATF transcription factor, ATF-7, as playing a pivotal role in the activation of the C. elegans immune response (Shivers et al., 2010). We anticipate that the ongoing investigation of innate immunity in C. elegans will reveal ancient features of host defense that may illuminate basic mechanisms of innate immunity in evolutionarily diverse species.

Integrative physiology of innate immunity and stress responses
The detection and compensatory response to the accumulation of unfolded proteins in the endoplasmic reticulum (ER), termed the Unfolded Protein Response (UPR), represents a conserved cellular homeostatic mechanism with important roles in normal development and in the pathogenesis of disease. A pivotal mediator of the UPR, the transcription factor XBP-1, is required for the differentiation of the highly secretory plasma cells of the mammalian adaptive immune system, but recent work also points to important receiprocal interactions between the UPR and other aspects of immunity and inflammation. Building on our characterization of the innate immune system in C. elegans, we have been able to define an essential role for XBP-1 in protecting the host during activation of innate immunity (Richardson et al., 2010). Our findings support the idea that the ubiquitous microbiota of multicellular organisms represents a physiologically relevant inducer of ER stress. Our current work is defining how physiological induction of immunity and ER stress influences organismal physiology.

We have also initiated the study of how immunity influences stress responses at the cellular and organismal levels by analyzing the interaction between immunity and aging. The increased susceptibility to infection with advancing age has been observed in diverse species, including humans, but the molecular mechanisms remain poorly understood. We have begun to define the dynamic activities of immune signaling pathways over the course of the aging process, and how infection and innate immunity can influence organismal longevity.

Neuroendocrine physiology in response to bacteria
C. elegans exhibits diverse behaviors in response to bacteria provided as a nutrient source, such as feeding, reproductive egg-laying, and changes in locomotion. Remarkably, the Avery and Bargmann groups have shown that C. elegans can discriminate between nutritional, beneficial bacteria, and bacteria that represent poor nutritional sources or are pathogenic. With a relatively simple, defined nervous system of 302 neurons, C. elegans represents a tractable experimental system in which to define how the nervous system processes environmental, immune, and metabolic cues to promote protective behavioral responses.

We have shown that the aforementioned TIR-1 protein acts in a MAPK-activating module in distinct tissue-specific pathways to modulate responses to bacteria. TIR-1 acts in the intestinal cells to mediate cell autonomous innate immune responses to infection, as well as in the chemosensory nervous system to mediate serotonin-dependent aversive learning responses to infection with pathogenic bacteria (Shivers et. al., 2009). These data suggest the co-option of ancestral immune signaling pathways in the evolution of physiological responses to microbes.

In addition, we have shown that a polymorphism in the npr-1 gene, encoding a neuronally-expressed G protein-coupled receptor, is a critical determinant of C. elegans survival during infection with pathogenic bacteria. Bacteria induce NPR-1-dependent behaviors that result in enhanced avoidance of pathogenic bacteria, accounting for the role of NPR-1 in modulating pathogen resistance (Reddy et al., 2009). We continue to investigate natural variation in strains of C. elegans to define polymorphisms involved in influencing behavioral avoidance responses.

We are also investigating the genetic determinants of the human opportunistic pathogen, Pseudomonas aeruginosa, that are recognized by the C. elegans host, as well as the mechanisms that P. aeruginosa utilizes to evade host recognition.