Structural Insights into Immune Evasion Mechanisms of Respiratory Syncytial Virus (RSV) and Highly Pathogenic Avian Influenza (HPAI) Restricted; Files & ToC
Salas, Eliseo (Fall 2025)
Abstract
Lower respiratory viruses cause hundreds of thousands of hospitalizations each year in the US and represent a major burden on both the health and economic sectors. The individuals predominantly affected by these infections are children under the age of two, older adults, and the immunocompromised, who are at the greatest risk with prolonged infections resulting in morbidity. Efforts have been made to understand how viruses differ in their mode of infectivity and how recurring viral pathogens overcome the body’s natural defenses. Two prominent recurring viral pathogens are the respiratory syncytial virus (RSV) and influenza virus (IAV), which can overcome the immune system in highly specialized ways. This dissertation aims to characterize the molecular interactions disrupted by these viruses during viral infection using structural biology techniques. In the case of RSV, all viral cytoplasmic proteins were recombinantly purified. The interaction between RSV nonstructural protein 2 (NS2) and melanoma differentiation-associated gene 5 (MDA5) was explored using in vitro pulldown assays and X-ray crystallography. The results from these experiments suggest that the N-terminus of NS2 plays a crucial role in recognizing and binding to MDA5 to a greater extent than previously believed. For the study of the influenza virus, the surface glycoprotein hemagglutinin (HA) derived from a highly pathogenic avian influenza (HPAI) virus H5N1 strain was recombinantly purified. HA is responsible for viral attachment, and preventing its normal function via antibody binding has proven an effective approach for developing novel passive antibody therapies. A humanized mouse model, engineered to produce human-like antibodies, was used to generate a library of antibodies targeting HA at various stages of infection. Biochemical assays were performed to curate and narrow down the number of antibody candidates. The top antibodies were complexed with HA and characterized by negative-stain electron microscopy (nsEM) and cryogenic electron microscopy (cryoEM). Together, these studies identified three highly potent antibodies that target HA by binding adjacent to the receptor binding site and preventing viral entry. Altogether, these findings provide further insight into how viral proteins function when interacting with the immune system, which can help us develop novel therapeutics against these two persistent pathogens.
Table of Contents
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File download under embargo until 12 January 2032 | 2025-11-26 14:17:27 -0500 | File download under embargo until 12 January 2032 |
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