Although GWAS have implicated chemokine receptors in affecting disease severity, the role of chemokines in COVID-19 pathogenesis has not been defined. To bridge this gap, we surveyed expression of 14 chemokine receptors on blood leukocytes from 19 hospitalized COVID-19 patients vs. healthy controls. Among many differences between patients and controls, we found that CCR2, which we have shown mediates lymphocyte transendothelial migration, was down on patient MAIT cells and pDCs, whose numbers in blood are depressed in COVID-19. If a chemokine receptor mediates extravasation, lower levels of the receptor on blood cells could result from efficient, and thereby preferential migration of leukocytes expressing higher levels of the receptor into infected tissue. In support of this mechanism, we found enrichment of CCR2 highcells among MAIT cells migrating to the CCR2 ligand, CCL2, in vitro. To test if CCR2 mediates leukocyte extravasation in COVID-19 we infected transgenic K18-hACE2 Ccr2 reporter mice that were Ccr2 +/RFP(Ccr2 sufficient) or Ccr2 RFP/RFP(Ccr2 deficient) with SARS-CoV-2 intranasally and analyzed pDCs. Blood pDCs were RFP +and their numbers were decreased in Ccr2 RFP/RFPmice at baseline. Over seven days after infection with SARS-CoV-2 (LD 50), pDCs increased and then decreased in the blood, while increasingly progressively in lungs in both Ccr2 +/RFPand Ccr2 RFP/RFPmice. However, absolute numbers of lung pDCs and ratios of lung/blood pDCs were markedly diminished, as was survival, in Ccr2 RFP/RFPmice. We propose that increased mortality in Ccr2-deficient mice may be due in part to inadequate numbers of lung pDCs, leading to local deficiencies in type 1 and III interferons, which are critical for defense against SARS-CoV-2.

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