Innate immunity and endoplasmic reticulum homeostasis
The interaction between microbes and their animal and plant hosts have shaped the evolution and physiology of multicellular organisms. Resistance to infection represents the sum of both mounting an antimicrobial innate immune response to infection as well as the ability to survive, or tolerate, the potentially damaging consequences of host immunity. We previously defined a conserved p38 mitogen-activated protein kinase (MAPK) pathway that is required for innate immunity in C. elegans (Kim et al., 2002). Immune signaling through the p38 MAPK pathway is Toll-independent in C. elegans, but requires the upstream activity of SARM/TIR-1, a conserved Toll-Interleukin-1 Receptor (TIR) domain adaptor protein in response to pathogenic bacteria (Liberati et al., 2004). We identified a conserved CREB/ATF family transcription factor, ATF-7, as a pivotal regulator of p38 MAPK-mediated innate immunity (Shivers et al., 2010).
In addition, we have been interested in the integrative physiology of innate immunity and cellular stress responses during infection of the host (Kim et al., 2004). We have observed that infection results in the physiological induction of the Unfolded Protein Response (UPR), which functions to maintain endoplasmic reticulum (ER) homeostasis. We have shown that the conserved IRE-1-XBP-1 pathway of the UPR is required for host tolerance to infection (Richardson et al., 2010 and 2011). Our studies suggest that an ancient, essential physiological role for the UPR is to protect the host during the activation of innate immunity to microbial pathogens. We are actively working to define the molecular relationships between immune activation, tissue damage, and the function of the UPR under both physiological and pathological conditions.
Genetic and neuronal basis of behavioral responses to microbes
Diverse behaviors in C. elegans, including aspects of feeding, reproduction, and development, are all influenced by the presence of bacterial food in the laboratory. More recently, C. elegans has been observed to exhibit protective avoidance behaviors in the presence of pathogenic bacteria. We are interested in how the nervous system recognizes and responds to microbes with changes in behavior. We observed that the aforementioned TIR-1-dependent signaling pathway has a dual role in the nervous system, mediating pathogen avoidance behavior (Shivers et al., 2009), suggestive of an ancient commonality in signaling mechanisms between two principal modes of host defense in C. elegans, innate immunity and behavioral avoidance.
Our interest in the genetic and neuronal basis of pathogen avoidance developed from our studies of genetic variation in susceptibility of different C. elegans strains to infection by pathogenic bacteria. A quantitative trait locus analysis of the difference in pathogen susceptibility between the laboratory wild type strain of C. elegans from Bristol, England, and a wild isolate from Hawaii was carried out in collaboration with Leonid Kruglyak’s laboratory (Reddy et al., 2009). Our study showed that a previously defined polymorphism in the neuropeptide receptor NPR-1 is a key determinant of pathogen resistance through the modulation of behavioral avoidance (Reddy et al., 2009; Reddy et al., 2011). We subsequently investigated naturally occurring genetic variation in pathogen avoidance behavior among wild isolates of C. elegans, identifying causative natural polymorphisms in a conserved neuronal E3 ubiquitin ligase HECW-1 (Chang et al., 2011). We continue to study both natural genetic variation among wild strains as well as mutants isolated from standard forward genetic approaches in the laboratory to understand how the C. elegans nervous system detects and responds to its microbial environment. We anticipate such studies will provide insights into the neuroendocrine signals involved in physiological communication between the nervous system and immune and other tissues during interactions with the microbial environment.
How interactions with microbes influence organismal aging and longevity.
A number of observations underscore how the species and composition of the bacterial food provided to C. elegans may influence organismal longevity. We have been exploring the intersection of our studies of microbes, innate immunity, neuroendocrine signaling, and their influence on organismal aging and longevity. Immunosenescence is a widely observed but poorly understood decline in immune function associated with age. We have defined a molecular basis for innate immunosenescence in C. elegans, observing that a marked decline in p38 MAPK signaling is associated with the aging of C. elegans (Youngman et al., 2011). We have observed that p38 MAPK signaling also contributes to the dramatic extension in longevity observed in C. elegans mutants defective in insulin signaling (Troemel et al., 2006). We are actively investigating how the diverse effects of microbes on host innate immunity, ER homeostasis, and neuroendocrine signaling can influence aging and longevity in C. elegans.
Chang, H.C., Paek, J., Kim, D.H. (2011) Natural Polymorphisms in C. elegans HECW-1 E3 Ligase Affect Pathogen Avoidance Behaviour. Nature 480, 525-529.
Kim, D.H., Feinbaum, R., Alloing, G., Emerson, F.E., Garsin, D.A., Inoue, H., Tanaka-Hino, M., Hisamoto, N., Matsumoto, K., Tan, M.W., Ausubel, F.M. (2002) A Conserved p38 MAP Kinase Pathway in Caenorhabditis elegans Innate Immunity. Science 297, 623-626.
Kim, D.H., Liberati, N.T., Mizuno, T., Inoue, H., Hisamoto, N., Matsumoto, K., Ausubel, F.M. (2004) Integration of Caenorhabditis elegans MAPK Pathways Mediating Immunity and Stress Resistance by MEK-1 MAPK Kinase and VHP-1 MAPK Phosphatase. Proc Natl Acad Sci USA 101, 10990-10994.
Liberati, N.T., Fitzgerald, K.A., Kim, D.H., Feinbaum, R., Golenbock, D.T., Ausubel, F.M. (2004) Requirement for a Conserved Toll/Interleukin-1 Resistance Domain Protein in the Caenorhabditis elegans Immune Response. Proc Natl Acad Sci USA 101, 6593-6598.
Reddy, K.C., Andersen, E.C., Kruglyak, L., Kim, D.H. (2009) A Polymorphism in npr-1 Is a Behavioral Determinant of Pathogen Susceptibility in C. elegans. Science 323, 382-384.
Reddy, K.C., Hunter, R.C., Bhatla, N., Newman, D.K., Kim, D.H. (2011) Caenorhabditis elegans NPR-1-Mediated Behaviors Are Suppressed in the Presence of Mucoid Bacteria. Proc Natl Acad Sci USA 108, 12887-12892.
Richardson, C.E., Kooistra, T., Kim, D.H. (2010) An Essential Role for XBP-1 in Host Protection against Immune Activation in C. elegans. Nature 463, 1092-1095.
Richardson, C.E., Kinkel, S., Kim, D.H. (2011) Physiological IRE-1-XBP-1 and PEK-1 Signaling in Endoplasmic Reticulum Homeostasis in C. elegans. PLoS Genetics 7, e1002391.
Shivers, R.P., Kooistra, T., Chu, S.W., Pagano, D.A., Kim, D.H. (2009) Tissue-Specific Activities of an Immune Signaling Module Regulate Physiological Responses to Pathogenic and Nutritional Bacteria in C. elegans. Cell Host Microbe 6, 321-330.
Shivers, R.P., Pagano, D.J., Kooistra, T., Richardson C.E., Reddy, K.C., Whitney, J.K., Kamanzi, O., Matsumoto, K., Hisamoto, N., Kim, D.H. (2010) Phosphorylation of the Conserved Transcription Factor ATF-7 by PMK-1 p38 MAPK Regulates Innate Immunity in Caenorhabditis elegans. PLoS Genetics 6:e1000892.
Troemel, E.R., Chu, S.W., Reinke, V., Lee, S.S., Ausubel, F.M., Kim, D.H. (2006) p38 MAPK Regulates Expression of Immune Response Genes and Contributes to Longevity in C. elegans. PLoS Genetics 2: e183.
Youngman, M.J., Rogers, Z.N., Kim, D.H. (2011) A Decline in p38 MAPK Signaling Underlies Immunosenescence in Caenorhabditis elegans. PLoS Genetics 7, e1002082.