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

FERRER, MARÍA F.; ERRASTI, ANDREA E.; GORGOJO, JUAN; GÓMEZ, RICARDO M.; LÓPEZ ORTIZ, AÍDA O.; ROMANOWSKI, VICTOR; CARRERA SILVA, EUGENIO A.; LÓPEZ ORTIZ, AÍDA O.; ROMANOWSKI, VICTOR; CARRERA SILVA, EUGENIO A.; THOMAS, PABLO; CHARO, NANCY; RODRIGUEZ, MARÍA E.; THOMAS, PABLO; CHARO, NANCY; RODRIGUEZ, MARÍA E.; FERRER, MARÍA F.; ERRASTI, ANDREA E.; GORGOJO, JUAN; GÓMEZ, RICARDO M.

Frontiers in Immunology

International Union of Immunological Societies (IUIS)

Año: 2019 vol. 10

1664-3224

The NewWorld arenavirus Junin (JUNV) is the etiological agent of Argentine hemorrhagicfever (AHF). Previous studies of human macrophage infection by the Old-Worldarenaviruses Mopeia and Lassa showed that while the non-pathogenic Mopeia virusreplicates and activates human macrophages, the pathogenic Lassa virus replicates butfails to activate human macrophages. Less is known in regard to the impact of NewWorld arenavirus infection on the human macrophage immune response. Macrophageactivation is critical for controlling infections but could also be usurped favoring immuneevasion. Therefore, it is crucial to understand how the JUNV infection modulatesmacrophage plasticity to clarify its role in AHF pathogenesis. With this aim in mind, wecompared infection with the attenuated Candid 1 (C#1) or the pathogenic P strains of theJUNV virus in human macrophage cultures. The results showed that both JUNV strainssimilarly replicated and induced morphological changes as early as 1 day post-infection.However, both strains differentially induced the expression of CD71, the receptor for cellentry, the activation and maturation molecules CD80, CD86, and HLA-DR and selectivelymodulated cytokine production. Higher levels of TNF-a, IL-10, and IL-12 were detectedwith C#1 strain, while the P strain induced only higher levels of IL-6. We also found thatC#1 strain infection skewed macrophage polarization to M1, whereas the P strain shiftedthe response to an M2 phenotype. Interestingly, the MERTK receptor, that negativelyregulates the immune response, was down-regulated by C#1 strain and up-regulatedby P strain infection. Similarly, the target genes of MERTK activation, the cytokinesuppressors SOCS1 and SOCS3, were also increased after P strain infection, in additionto IRF-1, that regulates type I IFN levels, which were higher with C#1 compared with Pstrain infection. Together, this differential activation/polarization pattern of macrophageselicited by P strain suggests a more evasive immune response and may have importantimplications in the pathogenesis of AHF and underpinning the development of newpotential therapeutic strategies.