Neutrophil- and B cell-mediated host defense against viral and fungal respiratory infections
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2024-03-21
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Infections of the lung continue to be a worldwide annual problem affecting millions of people. Fighting acute respiratory infections requires rapid and collaborative responses involving diverse immune cells. An interesting and unexplained clinical problem that sparked this thesis was the clinical observation that influenza A, a common respiratory virus, increases susceptibility to secondary infections with environmental fungi such as Aspergillus fumigatus (Af). By establishing a mouse model of viral-fungal co-infection and using clinical human samples, I discovered an essential collaboration between an underappreciated innate B lymphocyte, called B1a, which produced natural antibodies against Af, which tagged the fungi for elimination by neutrophils. Following influenza A infections, B1a cells died of apoptosis leading to diminished natural anti-Af antibodies and negating the ability of neutrophils to target and eliminate Af. Disruption of this axis explained susceptibility in viral- and steroid-associated infections. Delving deeper into the requirements of immune cell resistance to influenza and Af as individual infections, I discovered unique roles for neutrophils during influenza and innate B cells in aspergillosis. While there is ample research investigating neutrophils and their roles during infections with extracellular pathogens, it remained unclear how the neutrophil pool is affected following viral infections and subsequent functional outcomes. Additionally, it has been recently proposed that an interferon-responsive neutrophil state with unknown functions emerges following viral infections. In isolated viral infection, I found neutrophils adapt to an anti-viral phenotype which is spatially regulated, requires type I interferon licensing and sympathetic drive. On the other hand, using a genetically engineered mouse, we studied the specific roles of innate B1a cells during Aspergillus infection and found that this rare antibody producing cells was essential for host resistance against isolated Af infection. Moreover, I discovered key molecular requirements of the B1a cells that allow them to traffic and recruit properly in the lung, and I discovered that these cells can be amplified to improve host defense against Af. Altogether, this body of work uncovers neutrophils’ effects following isolated viral infection and during co-infection and demonstrates the tight interconnectedness between neutrophils and B lymphocytes which are critical for anti-fungal immunity.
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Sarden, N. (2024). Neutrophil- and B cell-mediated host defense against viral and fungal respiratory infections (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.