BREAKING! American Scientists Study Discover That CCR2 Signaling Inhibits SARS-CoV-2 Infection!

SARS-CoV-2 Research: American Scientist from Emory University, University of Texas and Washington University School of Medicine have in a new study discovered that CCR2 signaling inhibits SARS-CoV-2 infection!

 
Current evidence suggests that COVID-19 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.
 
In this study, the research team characterized a mouse model of SARS-CoV-2 infection and found that early CCR2 signaling restricts the viral burden in the lung. The study findings showed 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.
 
Utilizing intravital antibody labeling, the study team demonstrates 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.
 
The study team utilized 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.
 
Corresponding author Dr Mehul S. Suthar from the Center for Childhood Infections and Vaccines of Children’s Healthcare of Atlanta, Department of Pediatrics, Emory University told Thailand Medical News, “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.”
 
The study findings 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.
 
The study findings were published in the peer reviewed journal: mBIO. https://journals.asm.org/doi/full/10.1128/mBio.02749-21
 
It has been found that the innate immune response against SARS-CoV-2 involves limited production of interferon (IFN), and inflammatory cytokines such as interleukin-6 (IL-6]), IL-1β, tumor necrosis fact or-alpha (TNF-α), and IL-8 by alveolar macrophages or respiratory epithelial cells.
 
Past studies involving the analysis of bronchoalveolar lavage (BAL) fluids of SARS-CoV-2-infected individuals reported a correlation between the innate immune response and vigorous infiltration of neutrophils, dendritic cells (DCs), and monocytes into the lung airways.
 
Medical researchers have categorized monocytes in the lung parenchyma into subpopulations based on their expression of Ly6C. Previous studies have indicated that Ly6C-high classical monocytes are pro-inflammatory, whereas Ly6C-low non-classical monocytes are involved with healing wounds.In homeostatic conditions, Ly6C-low monocytes are dominant.
 
Comparatively, during acute infection, Ly6C-high monocytes infiltrate the lungs in a CCR2-dependent manner.
 
Many earlier studies have also shown that classical Ly6C-high monocytes can differentiate into monocyte-derived dendritic cells (moDCs). An increase in the level moDCs occurs during viral respiratory infection or antigen presentation.
 
Many researchers and scientists have pointed out a gap in research regarding the role of monocytes in providing protection against SARS-CoV-2 infection.
 
This new study addresses this gap by studying the role of monocytes in protecting individuals from SARS-CoV-2 by using a mouse-adapted SARS-CoV-2 (MA-SARS-CoV-2) strain and the human variant B.1.351.
 
Furthermore, the study team has identified a CCR2-monocyte axis that is essential for controlling the virus and inhibiting inflammation within the respiratory tract during COVID-19 infection.
 
Another past study had identified a strong and reproducible connection between inflammatory cytokine levels and severe SARS-CoV-2 infection in humans.
 
As with the results of the aforementioned study, the current study revealed that the SARS-CoV-2-infected mice possessed a proinflammatory cytokine profile. To this end, the lungs of infected mice contained chemoattractants for monocytes (Ccl2) and T-cells (Cxcl10), pyrogens (Il6 and Tnf), matrix metalloproteinases (Mmp14), interferon-stimulated genes (ISGs) (Irf7 and Isg15), and alarmins (S100a8).
 
The study team interestingly also found that the expression of the inflammatory gene in the lung of MA-SARS-CoV-2 mice was dependent on the viral load.
 
In this context, the study team observed that cytokine transcripts studied by quantitative polymerase chain reaction (qPCR) were positively correlated with viral RNA.
 
This study finding collaborates with a previous study using human subjects that described the relationship between SARS-CoV-2 viral load with IL-6 levels and an increased risk of death.
 
The study team showed a substantial increase in the numbers of S100a8+ granulocytes in the lung parenchyma. Similarly, this finding is in line with studies associated with the analysis of the lung tissue or BAL fluids obtained from COVID-19 patients.
 
This current study findings report an increased level of inflammatory cytokines and neutrophils in Ccr2−/− mice, which might be owing to elevated viral load in the lungs. This finding indicates that the MA-SARS-CoV-2 burden might be directly linked with cytokine expression and infiltration of neutrophils into the lungs.
 
Past studies have shown that CCR2 expression is a determining factor of inflammatory Ly6C-high blood monocytes.
 
The study findings reported that although CCR2 did not contribute to an increase in the numbers of circulating monocytes, it plays an important role in promoting the infiltration of activated monocytes into the lung parenchyma during COVID-19.
 
The study team also observed that inflammatory monocytes express a variety of chemokine receptors, like CXCR3.
 
Importantly, this study highlighted the importance of CCR2 in promoting the recruitment and differentiation of monocytes into transitional macrophages and the rise in moDC during MA-SARS-CoV-2 infection.
 
However, despite the researchers of the current study focusing on the role of CCR2 only in monocyte-derived cells, it is also expressed in other types of cells such as natural killer cells and T-cells. In the future, more research on CCR2 signaling in other cell types and its role in both innate and adaptive immune responses is required.
 
The study team revealed that as compared to other respiratory viruses like influenza, where CCR2 is associated with mortality and inflammation, in the context of COVID-19 infection, CCR2 limited viral burden and weight loss of infected mice. In the lung parenchyma, CCR2 promoted the infiltration of monocyte-derived cells.
 
The study team characterized a mouse model and highlighted that early CCR2-dependent infiltration of monocytes in the lungs is essential for controlling the viral load. This can also inhibit cytokine production during the early stages of MA-SARS-CoV-2 infection.
 
Hence, taking into account the role of monocyte-derived cells in inhibiting COVID-19 in the lungs and priming adaptive immune responses, it could be effectively used in developing future therapies and vaccines.
 
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