Author ORCID Identifier

https://orcid.org/0000-0003-4110-9101

Date of Award

Winter 1-31-2023

Document Type

Thesis (Ph.D.)

Department or Program

Microbiology and Immunology

First Advisor

Robert Cramer

Second Advisor

Joshua Obar

Third Advisor

James Bliska

Abstract

The human lung is not sterile but a complex environment with various microorganisms. Besides commensals in the lung, hundreds to thousands of individual microbiomes enter the lung every day but without causing the symptom. Host innate immunity plays an important role in maintaining homeostasis of the lung environment and as the first defense line against pathogens. Aspergillus fumigatus (A. fumigatus) is a saprophytic filamentous fungus that can cause human disease in immune compromised patients. However, with functional innate immunity, immune cells can quickly recognize pathogen associated molecular patterns (PAMPs) from A. fumigatus through pattern recognition receptors (PRRs). The activation of PRRs can activate innate immunity and facilitate inflammatory responses through cytokine and chemokine production. As the initiation of inflammation, the recruited innate immune cells can eliminate A. fumigatus through phagocytosis and kill them in the mature phagolysosome with ROS-dependent and independent mechanisms.

In this dissertation, we will cover the regulation of antifungal immunity in two specific directions: (1) investigate the immune modulation on innate immunity in the post-viral environment and the cause of viral-fungal superinfection. (2) characterize a potential fungal binding receptor and examine its role in antifungal immunity. In the first project, we demonstrated a novel mechanism within specific cell types that can contribute to defective fungal clearance and lead to high mortality in Influenza A Virus- A. fumigatus superinfection. For the second part, we used our newly generated mutant mice line and biochemistry approach to study the potential role of fungal surface binding protein in host immunity. These results further demonstrate the importance of antifungal immunity and upstream immune modulation in preventing the initiation of invasive aspergillosis.

Original Citation

Chapter 2 is published as the reference:

Ko-Wei Liu, Madeleine S. Grau, Jane T. Jones, Xi Wang, Elisa M. Vesely, Matthew R. James, Cecilia Gutierrez-Perez, Robert

A. Cramer*, Joshua J. Obar*. 2022. Post-Influenza Environment Reduces Aspergillus Conidia Clearance and Facilitates Invasive Aspergillosis In Vivo; mBio 2022 Nov 15; 0285422. doi: 10.1128/mbio.02854-22.

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