Journal Article

Inflammatory monocytes mediate control of acute alphavirus infection in mice

Haist, Kelsey C., Morrison, Thomas E., Davenport, Bennett J., Burrack, Kristina S.

2017

Overview

Chikungunya virus (CHIKV) and Ross River virus (RRV) are mosquito-transmitted alphaviruses that cause debilitating acute and chronic musculoskeletal disease. Monocytes are implicated in the pathogenesis of these infections; however, their specific roles are not well defined. To investigate the role of inflammatory Ly6ChiCCR2+ monocytes in alphavirus pathogenesis, we used CCR2-DTR transgenic mice, enabling depletion of these cells by administration of diptheria toxin (DT). DT-treated CCR2-DTR mice displayed more severe disease following CHIKV and RRV infection and had fewer Ly6Chi monocytes and NK cells in circulation and muscle tissue compared with DT-treated WT mice. Furthermore, depletion of CCR2+ or Gr1+ cells, but not NK cells or neutrophils alone, restored virulence and increased viral loads in mice infected with an RRV strain encoding attenuating mutations in nsP1 to levels detected in monocyte-depleted mice infected with fully virulent RRV. Disease severity and viral loads also were increased in DT-treated CCR2-DTR+;Rag1-/- mice infected with the nsP1 mutant virus, confirming that these effects are independent of adaptive immunity. Monocytes and macrophages sorted from muscle tissue of RRV-infected mice were viral RNA positive and had elevated expression of Irf7, and co-culture of Ly6Chi monocytes with RRV-infected cells resulted in induction of type I IFN gene expression in monocytes that was Irf3;Irf7 and Mavs-dependent. Consistent with these data, viral loads of the attenuated nsP1 mutant virus were equivalent to those of WT RRV in Mavs-/- mice. Finally, reconstitution of Irf3-/-;Irf7-/- mice with CCR2-DTR bone marrow rescued mice from severe infection, and this effect was reversed by depletion of CCR2+ cells, indicating that CCR2+ hematopoietic cells are capable of inducing an antiviral response. Collectively, these data suggest that MAVS-dependent production of type I IFN by monocytes is critical for control of acute alphavirus infection and that determinants in nsP1, the viral RNA capping protein, counteract this response.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adaptive immunity / Alphavirus / Aquatic insects / Biology and Life Sciences / Bone marrow / CCR2 protein / Cell culture / Cell cycle / Chikungunya virus / Depletion / Development and progression / Epidemics / Funding / Gene expression / Health services / Immunity / Immunology / Infections / Infectious diseases / Inflammation / Interferon / Interferon regulatory factor 3 / Interferon regulatory factor 7 / Killer cells / Leukocytes (neutrophilic) / Macrophages / Medicine / Medicine and Health Sciences / Mice / Monocyte chemoattractant protein 1 / Monocytes / Mosquitoes / Muscles / Musculoskeletal diseases / Mutation / Neutrophils / Pathogenesis / Physiological aspects / Proteins / Public health / RAG1 protein / Research and Analysis Methods / Ribonucleic acid / RNA / RNA virus infections / Toxins / Transgenic mice / Vector-borne diseases / Viral infections / Virology / Virulence / Viruses