Thesis (M.P.H.)--University of Michigan, 1947.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1961. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 54-57).

Thesis (M.S.)--University of Michigan, 1991.

published_or_final_version / Clinical Psychology / Master / Master of Social Sciences

No description available.

Influenza A virus (IAV) is considered one of the main threats that causes contagious respiratory disease in humans. Each year it threatens the human population with epidemics and pandemics. Limited anti-Influenza drugs are available that target viral proteins. The Influenza virus can mutate rapidly and can quickly develop resistance against available drugs. Therefore, developing novel host-targeted therapeutics effective against different IAVs may be very beneficial. Influenza virus is an intracellular parasite that uses host cell system to favour its replication process and evade host cell defense system. The Influenza A viral nonstructural protein 1(NS1) is a multifunctional protein that is expressed to high levels in infected cells; thus, interacting proteins may be ideal targets for drug development. In this study nine broadly cross-reactive anti-NS1 monoclonal antibodies (mAbs) were generated, characterized and used to co-immunoprecipitate IAV NS1 and its interacting host proteins. 183 proteins were consistently identified in this NS1 interactome study. Importantly, most proteins clustered into different cellular pathways, biological processes and molecular functions, such as mRNA splicing, gene expression, processing of capped intron-containing pre-mRNA and nucleoside, nucleotide and nucleic acid metabolism. Among these, 124 proteins detected in my study represent novel NS1-interacting targets not previously identified. RNAi screening then identified 11 NS1-interacting host factors as vital for IAV replication. From RNAi screening two NS1-interacting candidates, NUMA1 and PRPF19 were chosen for further analysis. IAV production was dramatically reduced in NUMA1 knockdown (KD) cells. Although viral transcription and translation were not inhibited, transport of viral structural proteins to the cytoplasmic membrane was obstructed during maturation steps in NUMA1 KD cells. IAV maturation was also inhibited and new virion production was significantly reduced in PRPF19 KD cells. Overall, a list of novel NS1-interacting host factors were identified utilizing some broadly cross reactive anti-NS1 mAbs in my study, and 11 of them were required for IAV replication. Further research on these new proteins may discover new targets for anti-Influenza drug development. / May 2017

No description available.

Pattern recognition receptors, including members of the NBD and LLR-containing (NLR) family, are key sensors of infection and injury. Early sensing of pathogen invasion and subsequent activation of pro-inflammatory signaling cascades is essential for controlling infection. However, signaling pathways activated upon pathogen recognition can also contribute to inflammation-mediated tissue damage. The studies detailed in Chapters 3 and 4 are primarily concerned with the roles of two NLR family members, Nlrp12 and Nlrc4, during influenza A virus (IAV) infection. While IAV itself is cytopathic, the immune response is responsible for a great deal of the tissue damage during infection in some contexts. NLR family members are involved in both pathogen sensing and modulation of pro-inflammatory signaling, thus they are perfectly situated to shift the balance between pathogen clearance and immunopathology. Nlrp12 has been implicated in regulation of pro-inflammatory signaling through NFκB family members. In Chapter 3 we report that during IAV infection, we find no differences in those pathways, and instead we describe a novel role for Nlrp12 in regulating transcript stability. Previous work has shown that one of the key differences between lethal and sublethal IAV infections is the early and exaggerated recruitment of neutrophils. Previous studies in our laboratory had established a role for Nlrp12 in CXCL1-mediated neutrophil recruitment during respiratory bacterial infections. We therefore hypothesized that Nlrp12-/- mice would be protected from pathogenic neutrophil recruitment during lethal IAV infection due to decreased CXCL1 production. In Chapter 3 we show that indeed, Nlrp12-/- mice have improved survival, decreased pulmonary microvascular permeability, and decreased necrosis and hemorrhage in their airways compared to WT mice. Nlrp12-/- mice also have fewer neutrophils in their lungs, due to decreased production of CXCL1 by neutrophils, DCs and macrophages. Our data showing decreased Cxcl1 transcript stability in R848-treated Nlrp12-/- BMDCs strongly suggest that the reduction in CXCL1 production by DCs in the Nlrp12-/- lungs is a result of decreased Cxcl1 transcript stability. Nlrc4 is a best known as a member of the Nlrc4 inflammasome, which is activated upon sensing of Gram-negative bacterial pathogens. However, a recent study from our laboratory showed an inflammasome-independent role for Nlrc4 in supporting critical anti-tumor T cell responses. Given that T cells are also critical for successful resolution of IAV infection, we hypothesized that during IAV infection, Nlrc4-/- mice would have compromised IAV-specific T cell responses and therefore poorer survival. Indeed, our studies in Chapter 4 show that in IAV-infected Nlrc4-/- mice, the pulmonary IAV-specific CD4 T cell response is significantly diminished and mortality is significantly increased compared to WT mice. During IAV infection, the blunted CD4 T cell response is a result of increased death of the CD4 T cells, perhaps due to increased expression of FasL on CD11c+ cells in the Nlrc4-/- lung environment.

Thesis (M.P.H.)--University of Hong Kong, 2009. / Includes bibliographical references (p. 78-84).

Thesis (M.P.H.)--University of Hong Kong, 2009. / Includes bibliographical references (p. 32-34).