Sensing and Responding to Stress Stimuli in Caenorhabditis elegans: Implications for Aging and Immunity
Animals have evolved sophisticated mechanisms to perceive stress or even anticipate it before it has caused damage. Ideally, stress responses are controlled to ensure that they are specific and not excessive lest they cause collateral damage to the host. Here I describe my work in Caenorhabditis elegans examining the initiation and consequences of stress responses. In chapters 2 and 3, I examine the mechanisms of initiation of C.elegans immune responses to Pseudomonas aeruginosa, focusing on pathogen recognition. In chapters 4 and 5 I describe a project that was initiated within the realm of host-pathogen interactions, but evolved to focus on age as a context determining the outcome of both biotic and abiotic stress responses.
Despite extensive knowledge of conserved signaling pathways in the C.elegans immune response, a question that has remained elusive is whether C.elegans can directly recognize pathogens, or if alternatively, they detect cellular damage caused by infection. I have shown that the immune response to P. aeruginosa can be dissociated from colonization and that potential damage from secreted molecules cannot induce a marker of the early immune response; in contrast, a non-pathogenic Pseudomonad can. This suggests that the response can be initiated at least in part by structural features of the bacteria. Furthermore, I have identified a family of genes in C.elegans encoding LysM domain proteins which are known to participate in recognition of microbial envelope components. Genetic and functional analyses suggest a potential role for family members in pathogen recognition in C. elegans.
In the second half of this dissertation, I show that while the C.elegans JNK homolog KGB-1 is stress-protective during development, its activation in adults compromises stress resistance as well as general lifespan. I go on to show that this phenomenon is mediated in part by KGB-1's age-dependent antagonistic modulation of the conserved FOXO transcription factor, DAF-16. Genome-wide analysis of the KGB-1 transcriptome revealed that KGB-1 regulates several genes in an age-specific manner, and pointed to another conserved transcription factor, FOS-1 as a mediator of KGB-1's effects. Interestingly, the phenomenon of the same protein having opposite effects dependent on age is reminiscent of the Antagonistic Pleiotropy theory for the evolution of aging. Our results shed light on molecular mechanisms underlying this long-standing theory.