UC San Diego

Metabolism is central to maintaining health and homeostasis during all challenges a mammal may face. This is true for infections as well and the field of immunometabolism has emerged for determining how metabolism influences the immune system during disease. Lipids are a major source of carbon and energy for cells while having been found to influence immune cells in a variety of systems. Here we explore novel roles for triglycerides through the interactions of adaptive immune and adipose tissue along with fatty acid utilization in myeloid cells. This dissertation describes original work demonstrating how adaptive immune system leads to sickness-induced anorexia and fat wasting. We found that fat wasting was dependent on lipolysis and that this fat wasting had no impact on inflammation within the adipose tissue. Further, we found that the fat wasting and sickness-induced anorexia are likely linked and CD4+ T cells are necessary to mediate both processes. Surprisingly, these metabolic perturbations do not have any tangible benefit to the host and preventing them did not change parasitemia or survival. Indeed, we found that CD4+ T cells were entirely dispensable in the infection, with mice lacking these immune cells surviving as long as wild type mice with similar parasitemia. Only B cells seemed necessary for mediating survival and parasitemia in wild type mice and CD8+ T cells were detrimental to survival. When looking specifically at lipid utilization in myeloid cells rather than lipid availability, we found beta oxidation in myeloid cells is detrimental to survival. There were no differences between knockout mice and wild type mice in parasitemia, indicating that immunopathology caused by the myeloid cells likely contributes to death and knocking out beta oxidation may alleviate the immunopathology. We found a slight rescue in anemia in the knockout mice, which is a major contributor for host death during a T. brucei infection. Thus, we have found novel roles for the adaptive immune system in mediating fat wasting and surprisingly this increase in lipid availability led to no difference in health while also finding a novel role for beta oxidation in myeloid cells for decreasing tolerance in the host. This work expands upon our understanding of how lipids availability is influenced by immune cells and how lipid utilization impacts health during a disease.