CCR2 Signaling Restricts SARS-CoV-2 Infection
| Autor: | Steven E. Bosinger, Fengzhi Jin, Pei Yong Shi, Jacob E. Kohlmeier, Jeronay Thomas, Vineet D. Menachery, Abigail Vanderheiden, Robyn S. Klein, David A Cowan, Kathryn L. Pellegrini, Meredith E. Davis-Gardner, Arash Grakoui, Allison Soung, Katharine Floyd, Mehul S. Suthar |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Receptors
CCR2 medicine.medical_treatment viruses mouse model Pneumonia Viral Inflammation Biology Virus Replication Microbiology Proinflammatory cytokine Mice Virology medicine Animals Lung innate immunity Innate immune system SARS-CoV-2 Respiratory disease lung inflammation COVID-19 Viral Load respiratory system medicine.disease Immunity Innate QR1-502 respiratory tract diseases Mice Inbred C57BL Disease Models Animal Cytokine medicine.anatomical_structure Immunology Cytokines Female medicine.symptom monocytes Viral load Respiratory tract Signal Transduction Research Article |
| Zdroj: | mBio, Vol 12, Iss 6 (2021) mBio |
| ISSN: | 2150-7511 |
| Popis: | 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. IMPORTANCE SARS-CoV-2 has caused a historic pandemic of respiratory disease (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-dependent infiltration of monocytes restricts the viral burden in the lung. We find that SARS-CoV-2 triggers an inflammatory response in the lung characterized by the expression of proinflammatory cytokines and interferon-stimulated genes. Using RNA sequencing and flow cytometry approaches, we demonstrate that 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. Mechanistically, CCR2 signaling promoted 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 that the CCR2 pathway is critical for promoting viral control and restricting inflammation within the respiratory tract during SARS-CoV-2 infection. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|