CCR2 Signaling Restricts SARS-CoV-2 Infection

Abigail Vanderheiden, Jeronay Thomas, Allison L. Soung, Meredith E. Davis-Gardner, Katharine Floyd, Fengzhi Jin, David A. Cowan, Kathryn Pellegrini, Pei Yong Shi, Arash Grakoui, Robyn S. Klein, Steven E. Bosinger, Jacob E. Kohlmeier, Vineet D. Menachery, Mehul S. Suthar

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a historic pandemic of respiratory disease (coronavirus disease 2019 [COVID-19]), and current evidence suggests that severe disease is associated with dysregulated immunity within the respiratory tract. However, the innate immune mechanisms that mediate protection during COVID-19 are not well defined. Here, we characterize a mouse model of SARS-CoV-2 infection and find that early CCR2 signaling restricts the viral burden in the lung. We find that a recently developed mouse-adapted SARS-CoV-2 (MA-SARSCoV- 2) strain as well as the emerging B.1.351 variant trigger an inflammatory response in the lung characterized by the expression of proinflammatory cytokines and interferon- stimulated genes. Using intravital antibody labeling, we demonstrate that MASARS- CoV-2 infection leads to increases in circulating monocytes and an influx of CD451 cells into the lung parenchyma that is dominated by monocyte-derived cells. Single-cell RNA sequencing (scRNA-Seq) analysis of lung homogenates identified a hyperinflammatory monocyte profile. We utilize this model to demonstrate that mechanistically, CCR2 signaling promotes the infiltration of classical monocytes into the lung and the expansion of monocyte-derived cells. Parenchymal monocyte-derived cells appear to play a protective role against MA-SARS-CoV-2, as mice lacking CCR2 showed higher viral loads in the lungs, increased lung viral dissemination, and elevated inflammatory cytokine responses. These studies have identified a potential CCR2-monocyte axis that is critical for promoting viral control and restricting inflammation within the respiratory tract during SARS-CoV-2 infection.

Original languageEnglish (US)
Article numbere02749-21
JournalmBio
Volume12
Issue number6
DOIs
StatePublished - Dec 1 2021

Keywords

  • Innate immunity
  • Lung inflammation
  • Monocytes
  • Mouse model
  • SARS-CoV-2

ASJC Scopus subject areas

  • Microbiology
  • Virology

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