Essential role of the CCL2–CCR2 axis in Mayaro virus-induced disease

Author:

Santos Franciele Martins1ORCID,Costa Victor Rodrigues de Melo1,Araújo Simone de2,Sousa Carla Daiane Ferreira de3,Moreira Thaiane Pinto3,Gonçalves Matheus Rodrigues1,Santos Anna Clara Paiva Menezes dos3,Ferreira Heloísa Athayde Seabra2,Costa Pedro Augusto Carvalho2,Barrioni Breno Rocha4,Bargi-Souza Paula2ORCID,Pereira Marivalda de Magalhães4,Nogueira Maurício Lacerda5,Souza Danielle da Glória3ORCID,Guimarães Pedro Pires Goulart2,Teixeira Mauro Martins6,Queiroz-Junior Celso Martins1ORCID,Costa Vivian Vasconcelos1ORCID

Affiliation:

1. Department of Morphology, Drug Research and Development Center, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil

2. Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil

3. Department of Microbiology, Host Microorganism Interaction Laboratory, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil

4. Department of Metallurgical and Materials Engineering, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil

5. Virology Research Laboratory, São José do Rio Preto School of Medicine (FAMERP), São José do Rio Preto, São Paulo, Brazil

6. Department of Biochemistry and Immunology, Drug Research and Development Center, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil

Abstract

ABSTRACT Mayaro virus (MAYV) is an emerging arbovirus member of the Togaviridae family and Alphavirus genus. MAYV infection causes an acute febrile illness accompanied by persistent polyarthralgia and myalgia. Understanding the mechanisms involved in arthritis caused by alphaviruses is necessary to develop specific therapies. In this work, we investigated the role of the CCL2/CCR2 axis in the pathogenesis of MAYV-induced disease. For this, wild-type (WT) C57BL/6J and CCR2 −/− mice were infected with MAYV subcutaneously and evaluated for disease development. MAYV infection induced an acute inflammatory disease in WT mice. The immune response profile was characterized by an increase in the production of inflammatory mediators, such as IL-6, TNF, and CCL2. Higher levels of CCL2 at the local and systemic levels were followed by the significant recruitment of CCR2 + macrophages and a cellular response orchestrated by these cells. CCR2 −/− mice showed an increase in CXCL-1 levels, followed by a replacement of the macrophage inflammatory infiltrate by neutrophils. Additionally, the absence of the CCR2 receptor protected mice from bone loss induced by MAYV. Accordingly, the silencing of CCL2 chemokine expression in vivo and the pharmacological blockade of CCR2 promoted a partial improvement in disease. Cell culture data support the mechanism underlying the bone pathology of MAYV, in which MAYV infection promotes a pro-osteoclastogenic microenvironment mediated by CCL2, IL-6, and TNF, which induces the migration and differentiation of osteoclast precursor cells. Overall, these data contribute to the understanding of the pathophysiology of MAYV infection and the identification future of specific therapeutic targets in MAYV-induced disease. IMPORTANCE This work demonstrates the role of the CCL2/CCR2 axis in MAYV-induced disease. The infection of wild-type (WT) C57BL/6J and CCR2 −/− mice was associated with high levels of CCL2, an important chemoattractant involved in the recruitment of macrophages, the main precursor of osteoclasts. In the absence of the CCR2 receptor, there is a mitigation of macrophage migration to the target organs of infection and protection of these mice against bone loss induced by MAYV infection. Much evidence has shown that host immune response factors contribute significantly to the tissue damage associated with alphavirus infections. Thus, this work highlights molecular and cellular targets involved in the pathogenesis of arthritis triggered by MAYV and identifies novel therapeutic possibilities directed to the host inflammatory response unleashed by MAYV.

Funder

Conselho Nacional de Desenvolvimento Científico e Tecnológico

Fundação de Amparo à Pesquisa do Estado de Minas Gerais

L’Oréal-UNESCO-ABC ‘Para Mulheres na Ciência’

International Society of Neurochemistry

Centers for Research on Emerging Infectious Diseases

Publisher

American Society for Microbiology

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