J Virol . Cellular Heterogeneity and Molecular Reprogramming of the Host Response during Influenza Acute Lung Injury

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J Virol


. 2022 Oct 26;e0124622.
doi: 10.1128/jvi.01246-22. Online ahead of print.
Cellular Heterogeneity and Molecular Reprogramming of the Host Response during Influenza Acute Lung Injury


Kai Guo ¹ , Dan Justin Kalenda Yombo ^{# 2} , Taylor Schmit ^{# 2} , Zhihan Wang ² , Zahrasadat Navaeiseddighi ³ , Venkatachelem Sathish ⁴ , Ramkumar Mathur ⁵ , Min Wu ² , Bony De Kumar ² , Junguk Hur ² , Nadeem Khan ^{2 3}



Affiliations

• PMID: 36286482
• DOI: 10.1128/jvi.01246-22

Abstract

An exuberant host response contributes to influenza A virus (IAV) (or influenza)-mediated lung injury. However, despite significant information on the host response to IAV, the cellular framework and molecular interactions that dictate the development of acute injury in IAV-infected lungs remain incompletely understood. We performed an unbiased single-cell RNA sequencing (scRNAseq) analysis to examine the cellular heterogeneity and regulation of host responses in the IAV model of acute lung injury. At the cellular level, IAV infection promoted the overwhelming recruitment of monocytes that exhibited the cell differentiation trajectory to monocyte-derived macrophages. Together, monocytes and monocyte-derived myeloid cells constituted over 50% of the total immune cells in IAV-infected lungs. In contrast, IAV infection resulted in a significant loss of nonhematopoietic cells. Molecularly, our data show the multidimensional cell-cell communication dynamics of interferon and chemokine signaling between immune and nonimmune cells and the cell-specific molecular pathways regulating the host responses during IAV-induced lung injury. Our data provide a foundation for further exploring the mechanistic association of the IAV host response with acute lung injury. IMPORTANCE A dysregulated host response develops acute lung injury during IAV infection. However, the pathological immune mechanism(s) associated with acute lung injury during IAV infection is yet to be elucidated. In this study, we performed scRNAseq to examine the dynamics of host responses during the peak of IAV-mediated lung injury. At the cellular level, our data reveal significant myelopoiesis predominated by monocytes and macrophages and the simultaneous disruption of the nonhematopoietic cell framework, crucial for regulating inflammation and barrier integrity in IAV-infected lungs. Molecularly, we observed a complex cellular network involving cell-cell communications and a number of unique regulons dictating the outcome of interferon and chemokine responses during peak lung injury. Our data present a unique atlas of cellular changes and the regulation of global and cell-specific host responses during IAV infection. We expect that this information will open new avenues to identify targets for therapeutic intervention against IAV lung injury.

Keywords: acute lung injury; cellular heterogeneity; influenza; molecular reprogramming; single-cell RNA-seq.