Inflammatory monocytes mediate control of acute alphavirus infection in mice

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 ly6chimonocytes 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 ly6chimonocytes 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. © 2017 haist et al.