COVID-19 and influenza infections mediate distinct pulmonary cellular and transcriptomic changes
Chenxiao Wang, Mst Shamima Khatun, Zhe Zhang, Michaela J. Allen, Zheng Chen, Calder Ellsworth, Joshua M. Currey, Guixiang Dai, Di Tian, Konrad Bach, Xiao‐Ming Yin, Vicki Traina‐Dorge, Jay Rappaport, Nicholas J. Maness, Robert V. Blair, Jay K. Kolls, Derek Pociask, Xuebin Qin
Abstract
SARS-CoV-2 infection can cause persistent respiratory sequelae. However, the underlying mechanisms remain unclear. Here we report that sub-lethally infected K18-human ACE2 mice show patchy pneumonia associated with histiocytic inflammation and collagen deposition at 21 and 45 days post infection (DPI). Transcriptomic analyses revealed that compared to influenza-infected mice, SARS-CoV-2-infected mice had reduced interferon-gamma/alpha responses at 4 DPI and failed to induce keratin 5 (Krt5) at 6 DPI in lung, a marker of nascent pulmonary progenitor cells. Histologically, influenza- but not SARS-CoV-2-infected mice showed extensive Krt5+ "pods" structure co-stained with stem cell markers Trp63/NGFR proliferated in the pulmonary consolidation area at both 7 and 14 DPI, with regression at 21 DPI. These Krt5+ "pods" structures were not observed in the lungs of SARS-CoV-2-infected humans or nonhuman primates. These results suggest that SARS-CoV-2 infection fails to induce nascent Krt5+ cell proliferation in consolidated regions, leading to incomplete repair of the injured lung.