Early cell-autonomous and niche-mediated epithelial response to influenza infection in primary alveolar organoids

Amber Elitz; Sharlene Fernandes; Kathleen C.S. Cook; Helen I Warheit-Niemi; Barbara Zhao; Andrea Toth; Amanda L. Zacharias; William J. Zacharias

doi:10.1172/jci.insight.201739

Early cell-autonomous and niche-mediated epithelial response to influenza infection in primary alveolar organoids

Amber Elitz,¹ Sharlene Fernandes,¹ Kathleen C.S. Cook,¹ Helen I Warheit-Niemi,¹ Barbara Zhao,¹ Andrea Toth,¹ Amanda L. Zacharias,¹ and William J. Zacharias²

Published July 2, 2026 - More info

View PDF

Abstract

Influenza A virus (IAV) infection is a major cause of morbidity and mortality for patients worldwide. Alveolar type 2 (AT2) cells are the preferential target of IAV as part of the pathogenesis of viral pneumonia and acute respiratory distress syndrome (ARDS). Early IAV infection of alveolar cells has been challenging to model both in vitro and in vivo. To address this challenge, we used a combination of murine and human primary alveolar organoids to define methods for robust IAV infection and evaluated cell-autonomous consequences of IAV using a temporal series of multiome paired single nuclei RNA and ATAC sequencing assays. Infected AT2 cells demonstrated conserved changes defined by early loss of surfactant secretion, decreased lipid biogenesis, a rapid burst of antiviral response, and late viral-mediated suppression. Surprisingly, uninfected AT2 cells underwent substantial transcriptional and epigenomic changes in IAV-treated cultures, leading to transition to damage-associated cell states within hours via a process driven by the inflammatory milieu of murine organoids. Together, these data provide new methods for high-fidelity modeling of IAV infection in alveolar cells and defined a conserved AT2 cell response signature to IAV with implications for ARDS pathogenesis.

Early cell-autonomous and niche-mediated epithelial response to influenza infection in primary alveolar organoids

Amber Elitz,¹ Sharlene Fernandes,¹ Kathleen C.S. Cook,¹ Helen I Warheit-Niemi,¹ Barbara Zhao,¹ Andrea Toth,¹ Amanda L. Zacharias,¹ and William J. Zacharias²

Article tools

Metrics

Go to

Early cell-autonomous and niche-mediated epithelial response to influenza infection in primary alveolar organoids

Amber Elitz,1 Sharlene Fernandes,1 Kathleen C.S. Cook,1 Helen I Warheit-Niemi,1 Barbara Zhao,1 Andrea Toth,1 Amanda L. Zacharias,1 and William J. Zacharias2

Article tools

Metrics

Go to

Sign up for email alerts

Amber Elitz,¹ Sharlene Fernandes,¹ Kathleen C.S. Cook,¹ Helen I Warheit-Niemi,¹ Barbara Zhao,¹ Andrea Toth,¹ Amanda L. Zacharias,¹ and William J. Zacharias²