C. elegans host defense pathways protect against microbiota cryptic virulence

Abstract

Abstract Animals are colonized by diverse communities that provide essential functions to the superorganism. At homeostasis, such microbiota communities are thought to benefit the healthy host. In contrast, dysbiosis can be both pathogenic and a consequence of disease. Establishing causal relationships among microbiota composition, host immune status, and disease is essential for fundamental understanding of many diseases and for their therapeutic targeting. Here we took a reductionist approach to address the potential for normal microbiota bacteria to cause disease in the immunodeficient host (i.e., the cryptic virulence of pathobionts) using C. elegans. C. elegans are known to rely on several host defense pathways to counteract intestinal infections. Although these pathways are known to play pivotal roles in defense against various human pathogenic bacteria, it is not clear what roles these pathways play for interactions with the native microbiota. To address this gap in knowledge, we determined the functional significance of p38, Wnt, and TFEB pathways in terms of gene expression and host survival of monocolonization by individual members of the C. elegans microbiota. We find that distinct host defense pathways are necessary for normal survival of animals colonized with distinct microbiota members. Our results suggest that specific microbiota members trigger specific host defense pathways, which are necessary for the host to defend against their cryptic virulence. The new insights provide the necessary foundation to characterize the molecular mechanisms by which microbiota members trigger host defense pathways specifically, including potentially novel bacterial metabolites with useful therapeutic properties in mammals. Supported by gran from NIH (R01GM101056-10) Supported by grant from NIH (Innate Immunity Training Grant (T32 AI095213))