Host-Microbe Interactions and Aging in C. elegans

Research in our lab seeks to understand the fundamentals of host-microbe interactions in the context of the whole organism. Much of our current interest is focused on the gut microbiota, but we are also interested in how gut commensals affect host immunity and host-pathogen interactions. Our level of investigation spans the range between molecular mechanisms, ecological constraints and impact on evolution. To achieve all this, we are using the nematode Caenorhabditis elegans, a powerful model organism for genetic studies, as a host model. Research in our lab includes three major directions: a) Shaping the structure and function of the Gut microbiota; b) Regulatory mechanisms of innate immune responses; and c) the role of antagonistic pleiotropy in aging.

 

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Host factors shaping the gut microbiota and microbial contributions

We have established C. elegans a new model to study host-microbiota interactions. Bringing with it unrivaled genetic tractability, C. elegans provides the ability to use genetically-homogenous populations to average-out inter-individual variation and thus to discern shared patterns in the establishment and shaping of the gut microbiota. We are using ‘deep sequencing’ complemented with isolation of specific gut residents to understand community level processes and interactions, as well as individual contributions. C. elegans has been grown in the lab for several decades with E. coli as its sole source of food. While this greatly simplifies cultivating and working with C. elegans it left us with no knowledge about the worm interactions with microbes in its natural environment. Characterization of the worm gut microbiota thus offers us novel insights into its natural history. Using C. elegans as a model we are characterizing host factors that shape the gut microbiota, and further using the worm to interrogate contributions of gut microbe to their host - from immunity to evolution. 

Antagonistic Pleiotropy and Aging

Pleiotropic effects of protein activity, in which one protein affects multiple traits, are a common theme in biology. Pleiotropic effects manifested at different ages are at the basis of the Antagonistic Pleiotropy theory for the evolution of aging. This theory proposes that since selection pressure declines with age, gene variants with late-life deleterious effects could still be positively-selected if they have early-life beneficial effects (Williams, 1957). Examples of antagonistic pleiotropy have been described (and debated), but mechanistic understanding of this phenomenon is still lacking. Our work in C. elegans identified a novel example of what appears to be antagonistic pleiotropy in a central stress-protective mechanism. We found that the c-Jun N-terminal kinase (JNK)-homolog KGB-1, which protects C. elegans from heavy metals and protein folding stress during development, compromises stress resistance and lifespan when activated in young adults. Much of this depend on age-dependent antagonistic regulation of the longevity-associated transcription factor DAF-16/FOXO. To understand what changes with age in the way KGB-1 functions, and what it tells us about aging, we explore KGB-1's tissue specific contributions and its interactions with downstream mediators. 

KGB-1 is not the only protein that demonstrates antagonistic pleiotropy. However, antagonsitic pleiotropy could also be presented by some of our beneficial gut microbes. Our studies of the C. elegans microbiome lead us to explore this possibility.

Regulatory mechanisms of innate immune responses

Immune responses of C. elegans to various pathogens have been characterized by our lab and by others. While it is yet unknown how these are initiated, or how the worm recognizes different pathogens, work in our lab focuses on delineating the regulatory programs orchestrating these responses.