The CCR2 inflammatory pathway is a target for improving severe disease and pulmonary inflammation in experimental COVID-19.

Authors

Yvette Kazungu, Shrilakshmi Hegde, Parul Sharma, Amy Marriott, Andrew Steven, Jesus Reine, Jessica Dagley, Matthias Mack, Anja Kipar, James P Stewart, Joseph D Turner

Published in

Virulence. Volume 17. Issue 1. Pages 2690741. Epub Jul 15, 2026.

Abstract

SARS-CoV2 can induce an acute respiratory distress syndrome (ARDS), provoked by a dysregulated hyper-inflammatory pulmonary immune response. Here, we used the keratinocyte-18 humanized angiotensin converting enzyme-2 (K18-hACE2) mouse model of SARS-CoV2, where expression of the CoV2 spike protein receptor, hACE-2, is restricted to epithelia, to characterize inflammatory pulmonary immune responses post-intranasal infections with the delta isolate SARS-CoV2(∆) B.1.617.2. Immune-profiling by focused transcript analysis, inflammatory protein array, and multi-color flow cytometry, confirmed that clinically relevant markers of COVID-19 (IL-6, GM-CSF, neutrophils, inflammatory monocytes) were significantly elevated in lungs of mice at day 5 post-infection and that remdesivir antiviral active metabolite (GS441524) treatment significantly modified SARS-CoV2∆ viral loads and pulmonary inflammation. Chemokine ligands of CCR2 (CCL2/7/8) were among the top 5% upregulated pulmonary transcripts in a focused human infection response array to SARS-CoV2∆. CCL2 was confirmed as elevated in protein assays in SARS-CoV2∆ infected lungs. To address the functional relevance of the CCR2 pathway of inflammatory cell recruitment to the lungs mediating disease, mice were administered with anti-CCR2 antibody daily at the point of infection for up to 6 d. Anti-CCR2 treated mice showed significant improved welfare scores, were protected from weight loss, modified myeloid pneumonitis, and displayed significantly blunted cytokine and chemokine response in the lungs, despite not affecting pulmonary viral loads. Our data supports therapeutic benefit of modifying CCR2-dependent cell recruitment in the treatment of viral-induced ARDS.

PMID:
42455170
Bibliographic data and abstract were imported from PubMed on 15 Jul 2026.

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