Open AccessCCR2 Signaling Restricts SARS-CoV-2 Infection
Author(s) -
Abigail Vanderheiden,
J. Thomas,
Allison Soung,
Meredith E. Davis-Gardner,
Katharine Floyd,
Fengzhi Jin,
David Cowan,
Kathryn L. Pellegrini,
Adrian Creanga,
Amarendra Pegu,
Alexandrine Derrien-Colemyn,
Pei–Yong Shi,
Arash Grakoui,
Robyn S. Klein,
Steven E. Bosinger,
Jacob E. Kohlmeier,
Vineet D. Menachery,
Mehul S. Suthar
Publication year - 2021
Publication title -
mbio
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.562
H-Index - 121
eISSN - 2161-2129
pISSN - 2150-7511
DOI - 10.1128/mbio.02749-21
Subject(s) - monocyte , immunology , ccr2 , proinflammatory cytokine , immune system , innate immune system , respiratory tract , inflammation , biology , lung , coronavirus , medicine , chemokine , virology , respiratory system , disease , infectious disease (medical specialty) , pathology , covid-19 , anatomy , chemokine receptor
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-SARS-CoV-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 MA-SARS-CoV-2 infection leads to increases in circulating monocytes and an influx of CD45 + 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.