HOW TO SURVIVE AN INFECTION: LESSONS FROM THE FLY
Sotelo Troha, Katia
How an organism is able to combat infection and survive has been a central and longstanding question in the field of infection biology. To fight infection, a host activates a combination of immune and physiological responses. While detection of microbial presence is sufficient to stimulate the immune response, some physiological responses to infection occur as a consequence of microbial growth and virulence, and can therefore be very specific to the particular microbe the host interacts with. Despite recent advances, our knowledge of the different processes that are activated or repressed in response to infection, and of how such responses contribute to organismal survival, remains limited. To identify new biological processes required to survive infection, we used RNA-seq to profile the D. melanogaster response to infection with 10 different bacterial pathogens. We found that each bacterium triggers a unique transcriptional response. However, we also identified a core set of 252 genes that are differentially expressed in response to the majority of bacteria tested. Among these, we determined that the transcription factor CrebA is a novel regulator of infection tolerance that acts to promote host survival during infection. Knock-down of CrebA significantly increased mortality from microbial infection without any concomitant change in bacterial number. Upon infection, CrebA is upregulated by both the Toll and Imd pathways in the fat body, where it is required to induce the expression of secretory pathway genes. Loss of CrebA during infection triggered endoplasmic reticulum (ER) stress and activated the unfolded protein response (UPR), which contributed to infection-induced mortality. Altogether, our study reveals essential features of the response to bacterial infection and elucidates the function of a novel regulator of infection tolerance that promotes survival to infection. The second research project of this dissertation assesses the role of a different biological process, hemolymph (extracellular fluid analogous to blood) filtration, in the host response to infection. Nephrocytes are podocyte-like cells that regulate hemolymph composition by filtration. Flies deficient for Klf15, a transcription factor required for nephrocyte development and function, are viable but lack nephrocytes. Surprisingly, we found that Klf15 mutants display constitutively elevated Toll pathway activity, and as a consequence, are more resistant to microbial infection. Our analysis revealed that nephrocytes uptake Lys-type peptidoglycan from systemic circulation and degrade it inside lysosomes. Without nephrocyte function, microbiota-derived peptidoglycan accumulates in circulation, triggering Toll pathway activation even in the absence of infection. These results unveil a role for hemolymph filtration in the maintenance of immune tolerance to microbiota. Although our study was not able to address whether nephrocytes filter Lys-type peptidoglycan from circulation in the context of a systemic bacterial infection, we found a novel and important physiological connection between hemolymph filtration and the immune system, and learned that disruption of this process actually increases survival to infection.
Lee, Siu Sylvia; Russell, David G.; Buchon, Nicolas S.; Han, Chun
Immunology and Infectious Disease
Ph. D., Immunology and Infectious Disease
Doctor of Philosophy
dissertation or thesis