Date of Graduation
Master of Science in Biology
influenza a virus, Aspergillus fumigatus, H1N1 pandemic, secondary pneumonia, acute respiratory distress syndrome, co-infection, inflammasome, cytokine, reactive oxygen species, autophagy
Bacteria | Bacterial Infections and Mycoses | Biological Phenomena, Cell Phenomena, and Immunity | Cell Biology | Circulatory and Respiratory Physiology | Comparative and Laboratory Animal Medicine | Fungi | Immunity | Immunology of Infectious Disease | Laboratory and Basic Science Research | Medical Cell Biology | Medical Immunology | Medical Microbiology | Molecular Genetics | Other Immunology and Infectious Disease | Pathogenic Microbiology | Respiratory Tract Diseases | Veterinary Infectious Diseases | Veterinary Microbiology and Immunobiology | Virology | Virus Diseases | Viruses
Bacterial co-infections with influenza A virus (IAV) are extremely serious and life-threatening. However, there exists limited understanding about the importance of fungal infections with IAV. Clinical case reports indicate that fungal co-infections do occur and suggest the IAV pandemic of 2009 had a propensity to predispose patients to secondary fungal infections more than previous IAV strains. IAV-fungal co-infections are marked by high mortality rates of 47 to 61% in previously healthy individuals between the ages of 20 and 60. Yet, the variables involved in this co-infection remain undetermined. I achieved effective recapitulation of this co-infection using a C57Bl/6 murine (mouse) model which resulted in similar morbidity and mortality rates seen in humans. Here, I proposed that an exacerbated immune response during infection with IAV and the opportunistic saprophytic ubiquitous fungal pathogen, Aspergillus fumigatus, induces the development of more severe pneumonia. I explored the possible mechanisms regulating inflammation at the cellular level. To do this, a cellular model was designed using primary mouse bone marrow derived macrophages (BMDMs) infected first with IAV and later co-infected with A. fumigatus. Our in vitro data indicated that IAV and fungal co-infections synergistically enhanced immune cell signaling and pro-inflammatory cytokine production through the caspase-1 containing inflammasomes. Through various immunological techniques, I established that, during co-infection, AIM2 mediated maturation of caspase-1 facilitates the observed increase in production of pro-inflammatory cytokines. Interestingly, enhanced caspase-1 maturation is not due to increased NLRP3 inflammasome priming. NLRP3 expression actually diminishes over the course of infection, which could be explained through increased proteasomal degradation of NLRP3 through dysregulated DAPK1 signaling.
© Meagan Danyelle Rippee-Brooks
Rippee-Brooks, Meagan Danyelle, "Elucidating Immune Signaling of Influenza a Virus and Aspergillus Fumigatus Co-Infections through Pioneered Model Development" (2019). MSU Graduate Theses. 3430.
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