Ly6C+ monocytes in the skin promote systemic alphavirus dissemination

Holmes, Autumn C.; Lucas, Cormac J.; Brisse, Morgan E.; Ware, Brian C.; Hickman, Heather D.; Morrison, Thomas E.; Diamond, Michael S.

doi:10.1016/j.celrep.2024.113876

Cited by 6 publications

References 58 publications

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Innate and adaptive immune responses that control lymph-borne viruses in the draining lymph node

Melo-Silva,

Sigal

2024

Cell Mol Immunol

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The interstitial fluids in tissues are constantly drained into the lymph nodes (LNs) as lymph through afferent lymphatic vessels and from LNs into the blood through efferent lymphatics. LNs are strategically positioned and have the appropriate cellular composition to serve as sites of adaptive immune initiation against invading pathogens. However, for lymph-borne viruses, which disseminate from the entry site to other tissues through the lymphatic system, immune cells in the draining LN (dLN) also play critical roles in curbing systemic viral dissemination during primary and secondary infections. Lymph-borne viruses in tissues can be transported to dLNs as free virions in the lymph or within infected cells. Regardless of the entry mechanism, infected myeloid antigen-presenting cells, including various subtypes of dendritic cells, inflammatory monocytes, and macrophages, play a critical role in initiating the innate immune response within the dLN. This innate immune response involves cellular crosstalk between infected and bystander innate immune cells that ultimately produce type I interferons (IFN-Is) and other cytokines and recruit inflammatory monocytes and natural killer (NK) cells. IFN-I and NK cell cytotoxicity can restrict systemic viral spread during primary infections and prevent serious disease. Additionally, the memory CD8+ T-cells that reside or rapidly migrate to the dLN can contribute to disease prevention during secondary viral infections. This review explores the intricate innate immune responses orchestrated within dLNs that contain primary viral infections and the role of memory CD8+ T-cells following secondary infection or CD8+ T-cell vaccination.

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Innate and adaptive immune responses that control lymph-borne viruses in the draining lymph node

Melo-Silva,

Sigal

2024

Cell Mol Immunol

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Activating FcγRs on monocytes are necessary for optimal Mayaro virus clearance

Dunagan,

Dábilla,

McNinch

et al. 2024

Preprint

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Mayaro virus (MAYV) is an emerging arbovirus. Previous studies have shown antibody Fc effector functions are critical for optimal monoclonal antibody-mediated protection against alphaviruses; however, the requirement of Fc gamma receptors (FcγRs) for protection during natural infection has not been evaluated. Here, we showed mice lacking activating FcγRs (FcRγ-/-) developed prolonged clinical disease with more virus in joint-associated tissues. Viral clearance was associated with anti-MAYV cell surface binding rather than neutralizing antibodies. Lack of Fc-FcγR engagement increased the number of monocytes through chronic timepoints. Single cell RNA sequencing showed elevated levels of pro-inflammatory monocytes in joint-associated tissue with increased MAYV RNA present in FcRγ-/- monocytes and macrophages. Transfer of FcRγ-/- monocytes into wild type animals was sufficient to increase virus in joint-associated tissue. Overall, this study suggests that engagement of antibody Fc with activating FcγRs promotes protective responses during MAYV infection and prevents monocytes from being potential targets of infection.

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Lack of pathogenic involvement of CCL4 and its receptor CCR5 in arthritogenic alphavirus disease

Hameed,

Solomon,

Weger-Lucarelli

2024

Preprint

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Arthritogenic alphaviruses, including chikungunya virus (CHIKV), Mayaro virus (MAYV), Ross River virus (RRV), and O’nyong nyong virus (ONNV) are emerging and reemerging viruses that cause disease characterized by fever, rash, and incapacitating joint swelling. Alphavirus infection induces robust immune responses in infected hosts, 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 depletion 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.

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Ly6C+ monocytes in the skin promote systemic alphavirus dissemination

Cited by 6 publications

References 58 publications

Innate and adaptive immune responses that control lymph-borne viruses in the draining lymph node

Innate and adaptive immune responses that control lymph-borne viruses in the draining lymph node

Activating FcγRs on monocytes are necessary for optimal Mayaro virus clearance

Lack of pathogenic involvement of CCL4 and its receptor CCR5 in arthritogenic alphavirus disease

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