Novel Core Gene Signature Associated with Inflammation-to-Metaplasia Transition in Influenza A Virus-Infected Lungs

Respiratory infections caused by RNA viruses are a major contributor to respiratory disease due to their ability to cause annual epidemics with profound public health implications. Influenza A virus (IAV) infection can affect a variety of host signaling pathways that initiate tissue regeneration with hyperplastic and/or dysplastic changes in the lungs. Although these changes are involved in lung recovery after IAV infection, in some cases, they can lead to serious respiratory failure. Despite being ubiquitously observed, there are limited data on the regulation of long-term recovery from IAV infection leading to normal or dysplastic repair represented by inflammation-to-metaplasia transition in mice or humans. To address this knowledge gap, we used integrative bioinformatics analysis with further verification in vivo to elucidate the dynamic molecular changes in IAV-infected murine lung tissue and identified the core genes (<i>Birc5</i>, <i>Cdca3</i>, <i>Plk1</i>, <i>Tpx2</i>, <i>Prc1. Rrm2</i>, <i>Nusap1</i>, <i>Spag5</i>, <i>Top2a</i>, <i>Mcm5</i>) and transcription factors (<i>E2F1</i>, <i>E2F4</i>, <i>NF-YA</i>, <i>NF-YB</i>, <i>NF-YC</i>) involved in persistent lung injury and regeneration processes, which may serve as gene signatures reflecting the long-term effects of IAV proliferation on the lung. Further analysis of the identified core genes revealed their involvement not only in IAV infection but also in COVID-19 and lung neoplasm development, suggesting their potential role as biomarkers of severe lung disease and its complications represented by abnormal epithelial proliferation and oncotransformation.