UC Irvine

Infection tolerance is the ability to minimize damage caused by pathogens or the host's response to them. A prime example of such resilience is the white-footed deermouse, or P. leucopus, a reservoir of agents of zoonoses like Lyme disease, anaplasmosis, or Powassan virus encephalitis. Despite being persistently infected with pathogens, deermice can strike a delicate balance, keeping the pathogens in check while avoiding maladaptive host response that could lead to inflammation-induced damage. This unique resilience makes deermice an excellent animal model for understanding infection tolerance: they don't get sick and remain fit for their populations' proliferation. As a result, they live longer than most other rodents of the same size. A deeper understanding of how deermice moderate inflammation and other damaging host responses, including sepsis, could explain why some patients with certain infections experience more prolonged or severe disease courses. These individuals may lack the capacity that deermice possess to avoid sickness. Identifying and characterizing factors of infection tolerance in deermice that reduce inflammation elicited by microbes or their toxins may thus lead to more effective therapies. In this dissertation, I describe the microbiome of P. leucopus from a closed colony using metagenomics and compare it to that of M. musculus and a natural population of P. leucopus. Our findings reveal that deermice have a higher number of lactobacilli in their gastrointestinal microbiota. We also discovered new species of lactobacilli that are specific to deermice. As the microbiome influences the immune system, I employ sequencing and immunology techniques to examine tolerance in immune-related tissues of P. leucopus. Immunity evolved to protect the host from pathogens, but inflammatory molecules can cause pathology, chronic conditions, and accelerated aging. The second part of the study explains some of the mechanisms for striking tolerance without developing pathology through inflammation in P. leucopus while infected with Borrelia hermsii or SARS-CoV-2. This study suggests that P. leucopus responds to pathogens by recruiting and activating leucocytes during the initial stage of infection while regulating the activity of these cells with anti-inflammatory cytokines. This model of infection tolerance was evaluated and characterized compared to M. musculus by the early response to endotoxins and bacterial infection. Each rodent species responded by activating a different immune response route. While P. leucopus displayed an alternatively activated macrophage profile and reduced transcription of endogenous retroviruses, as well as consistently moderate pathogenesis, M. musculus displayed classically activated macrophages and higher expression of endogenous retroviral proteins. We are the first to report infection of P. leucopus with SARS-CoV-2 and describe the host response in the brain.