CCR2-dependent monocyte-derived cells restrict SARS-CoV-2 infection

• Published in: bioRxiv
• Main Authors: Vanderheiden, Abigail, Thomas, Jeronay, Soung, Allison L, Davis-Gardner, Meredith E, Floyd, Katharine, Jin, Fengzhi, Cowan, David A, Pellegrini, Kathryn, Creanga, Adrian, Pegu, Amarendra, Derrien-Colemyn, Alexandrine, Shi, Pei-Yong, Grakoui, Arash, Klein, Robyn S, Bosinger, Steven E, Kohlmeier, Jacob E, Menachery, Vineet D, Suthar, Mehul S
• Format: Journal Article Paper
• Language: English
• Published: United States Cold Spring Harbor Laboratory 04.05.2021
• Edition: 1.1
• Subjects: Immunology
• ISSN: 2692-8205; 2692-8205
• DOI: 10.1101/2021.05.03.442538

SARS-CoV-2 has caused a historic pandemic of respiratory disease (COVID-19) and current evidence suggests 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-dependent infiltration of monocytes restricts viral burden in the lung. We find that a recently developed mouse-adapted MA-SARS-CoV-2 strain, as well as the emerging B. 1.351 variant, trigger an inflammatory response in the lung characterized by expression of pro-inflammatory cytokines and interferon-stimulated genes. scRNA-seq analysis of lung homogenates identified a hyper-inflammatory monocyte profile. 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. We utilize this model to demonstrate that mechanistically, CCR2 signaling promotes infiltration of classical monocytes into the lung and 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 CCR2-monocyte axis that is critical for promoting viral control and restricting inflammation within the respiratory tract during SARS-CoV-2 infection.