Junin Virus Triggers Macrophage Activation and Modulates Polarization According to Viral Strain Pathogenicity

MARÍA F. FERRER; PABLO THOMAS; AÍDA O. LÓPEZ ORTIZ; ANDREA E. ERRASTI; NANCY CHARO; EUGENIO A. CARRERA SILVA ; RICARDO M. GÓMEZ

Prime Archives in Immunology

Vide Leaf

Lugar: Hyderabad; Año: 2020; p. 1 - 27

The New World arenavirus Junin (JUNV) is the etiological agentof Argentine hemorrhagic fever (AHF). Previous studies ofhuman macrophage infection by the Old-World arenavirusesMopeia and Lassa showed that while the non-pathogenic Mopeiavirus replicates and activates human macrophages, thepathogenic Lassa virus replicates but fails to activate humanmacrophages. Less is known in regard to the impact of NewWorld arenavirus infection on the human macrophage immuneresponse. Macrophage activation is critical for controllinginfections but could also be usurped favoring immune evasion.Therefore, it is crucial to understand how the JUNV infectionmodulates macrophage plasticity to clarify its role in AHFpathogenesis. With this aim in mind, we compared infection withthe attenuated Candid 1 (C#1) or the pathogenic P strains of theJUNV virus in human macrophage cultures. The results showedthat both JUNV strains similarly replicated and inducedmorphological changes as early as 1 day post-infection.However, both strains differentially induced the expression ofCD71, the receptor for cell entry, the activation and maturationmolecules CD80, CD86 and HLA-DR and selectively modulatedcytokine production. Higher levels of TNF-α, IL-10 and IL-12were detected with C#1 strain, while the P strain induced onlyhigher levels of IL-6. We also found that C#1 strain infectionskewed macrophage polarization to M1, whereas the P strainshifted the response to an M2 phenotype. Interestingly, theMERTK receptor, that negatively regulates the immuneresponse, was down-regulated by C#1 strain and up-regulated byP strain infection. Similarly, the target genes of MERTKactivation, the cytokine suppressors SOCS1 and SOCS3, werealso increased after P strain infection, in addition to IRF-1, thatregulates type I IFN levels, which were higher with C#1compared with P strain infection. Together, this differentialactivation/polarization pattern of macrophages elicited by Pstrain suggests a more evasive immune response and may haveimportant implications in the pathogenesis of AHF andunderpinning the development of new potential therapeuticstrategies.