CCR2 Signaling Restricts SARS-CoV-2 Infection

• Authors: Abigail Vanderheiden, Emory University; Jeronay Thomas, Emory University; Allison L Soung, Washington Univ; Meredith E Davis-Gardner, Emory University; Katharine Floyd, Emory University; Fengzhi Jin, Emory University; David A Cowan, Emory University; Kathryn Pellegrini, Emory University; Adrian Creanga, National Institute of Allergy and Infectious Diseases, NIH, Bethesda; Amarendra Pegu, National Institute of Allergy and Infectious Diseases, NIH, Bethesda; Alexandrine Derrien-Colemyn, National Institute of Allergy and Infectious Diseases, NIH, Bethesda; Pei-Yong Shi, The University of Texas Medical Branch; Arash Grakoui, Emory University; Robyn S Klein, Washington University in St. Louis; Steven Bosinger, Emory University; Jacob Kohlmeier, Emory University; Vineet D Menachery, University of Texas Medical Branch; Mehul Suthar, Emory University
• Journal Title: MBIO
• Volume: Volume 12, Number 6
• Publisher: AMER SOC MICROBIOLOGY | 2021-11-01, Pages e0274921-e0274921
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1128/mBio.02749-21
• Subjects: Biology, Microbiology; Health Sciences, Immunology; Health Sciences, Pathology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Microbiology; lung inflammation; monocytes; SARS-CoV-2; innate immunity; mouse model; DENDRITIC CELLS; BONE-MARROW; MACROPHAGES; MONOCYTES; INFLAMMATION; SUBSETS; MILD; LIFE

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.