Drivers of Heightened Innate Immunity in Airway Epithelium

Date of Award

Fall 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Immunobiology

First Advisor

Foxman, Ellen

Abstract

Following the emergence of SARS-CoV-2 in 2019, significant research efforts have been focused on understanding how human respiratory viruses and viral coinfections affect clinical outcomes. Recent studies suggest that respiratory viruses can interfere with one another by inducing protective host responses and pre-activating antiviral innate immunity. However, the occurrence and mechanisms of viral interference remain understudied. Here, we investigated drivers of protective antiviral responses and mechanisms of viral interference using nasopharyngeal swabs and models of human respiratory epithelium.First, a series of studies investigating nasopharyngeal immune responses in SARS-CoV-2 infection found heightened interferon and pro-inflammatory responses in young children. In the absence of pre-existing adaptive immunity in the population, heightened innate immune responses were predicted to lead to more effective control of SARS-CoV-2 infection, but the underlying drivers of heightened innate immunity were unclear. Here, we show that children experienced high rates of respiratory viruses and bacterial pathobionts which drive distinct heightened nasal innate immunophenotypes. Next, we used an organoid model of human airway epithelium to study mechanisms of virus-induced protection. Our study focused on the duration of heightened epithelial interferon responses induced by rhinovirus (RV), the most common respiratory virus. We discovered that heightened epithelial interferon responses last for at least two weeks, providing continued protection against SARS-CoV-2 and influenza viruses. We show that long-term antiviral protection is maintained through persistent activation of the JAK/STAT signaling pathway and intracellular type III interferon protein which together drive a sustained interferon-stimulated gene (ISG) signature. In conclusion, our results define key drivers of heightened nasal innate immune responses in children and show novel mechanisms of persisting epithelial interferon signatures induced by RV infection.

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