Lack of pathogenic involvement of CCL4 and its receptor CCR5 in arthritogenic alphavirus disease
Muddassar Hameed1,2, Norman A Solomon1,2, James Weger-Lucarelli1,2,3
1Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, United States.
Abstract:
Arthritogenic alphaviruses, including chikungunya (CHIKV), Mayaro (MAYV), Ross River (RRV), and O'nyong nyong virus (ONNV), are emerging and reemerging viruses that cause disease characterized by fever, rash, and incapacitating muscle and joint pain and inflammation. Alphavirus infection induces robust immune responses, leading to the upregulation of several cytokines and chemokines, including chemokine C ligand 4 (CCL4). CCL4 is a chemoattractant for immune cells such as T cells, natural killer cells, monocytes/macrophages, and dendritic cells, recruiting these cells to the site of infection, stimulating the release of proinflammatory mediators, and inducing T cell differentiation. CCL4 has been found at high levels in both the acute and chronic phases of chikungunya disease; however, the role of CCL4 in arthritogenic alphavirus disease development remains unexplored. Here, we tested the effect of CCL4 on MAYV infection in mice through antibody neutralization and treatment with recombinant mouse CCL4. We observed no differences in mice depleted of CCL4 or treated with recombinant CCL4 in terms of disease progression such as weight loss and footpad swelling or the development of viremia. CCL4 uses the G protein-coupled receptor C-C chemokine receptor type 5 (CCR5). To determine whether CCR5 deficiency would alter disease outcomes or virus replication in mice, we inoculated CCR5 knockout (CCR5--) mice with MAYV and observed no effect on disease development and immune cell profile of blood and footpads between CCR5-/- and wild type mice. These studies failed to identify a clear role for CCL4 or its receptor CCR5 in MAYV infection.
Insights
Chemokine CCL4 and its receptor CCR5 do not significantly impact Mayaro virus (MAYV) infection progression or severity in mice. These findings suggest CCL4 and CCR5 are not primary drivers of alphavirus-induced joint inflammation.
Area of Science:
- Virology and Immunology
- Molecular and Cellular Biology
Background:
- Arthritogenic alphaviruses like chikungunya (CHIKV) and Mayaro virus (MAYV) cause debilitating joint pain and inflammation.
- Alphavirus infections trigger immune responses, including the upregulation of chemokine C ligand 4 (CCL4), a known immune cell chemoattractant.
- While CCL4 is elevated in chikungunya, its specific role in arthritogenic alphavirus disease pathogenesis remains unclear.
Purpose of the Study:
- To investigate the role of chemokine CCL4 in Mayaro virus (MAYV) infection.
- To determine the impact of CCL4 neutralization and recombinant CCL4 treatment on MAYV disease progression in mice.
- To assess the influence of C-C chemokine receptor type 5 (CCR5), the receptor for CCL4, on MAYV infection outcomes.
Main Methods:
- MAYV-infected mice were treated with antibodies to neutralize CCL4 or with recombinant mouse CCL4.
- Disease progression was monitored via weight loss and footpad swelling; viremia was also assessed.
- MAYV infection was studied in CCR5 knockout mice compared to wild-type controls.
Main Results:
- CCL4 depletion or administration did not alter MAYV disease progression, including weight loss, footpad swelling, or viremia.
- CCR5 knockout mice exhibited no significant differences in disease development or immune cell profiles compared to wild-type mice after MAYV infection.
- These findings indicate that neither CCL4 nor its receptor CCR5 play a critical role in MAYV pathogenesis in this mouse model.
Conclusions:
- Chemokine CCL4 and its receptor CCR5 are not essential for the development of Mayaro virus-induced disease in mice.
- The study did not identify a clear role for the CCL4/CCR5 axis in the pathogenesis of MAYV infection.
- Further research may be needed to elucidate other immune mediators involved in alphavirus-induced arthritis.
