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Orthohantavirus infection triggers differentiation and subsequent polarization of human blood monocytes into macrophages

Orthohantaviruses (HTV) are enveloped RNA viruses, belonging to genus Orthohantavirus. Puumala orthohantavirus (PUUV) is pathogenic causing mild to moderate forms of hemorrhagic fever with renal syndrome (HFRS) in Euroasia, an acute viral disease. Tula orthohantavirus (TULV) is considered apathogenic due to limited evidence of pathogenesis in humans. In Croatia, HFRS is endemic rodent-borne disease of high public health importance. Outbreaks affecting the continental part of the country occur every few years. Monocytes, macrophages and dendritic cells (DC), as innate immune system cells, are target cells for HTV potentially contributing to dissemination of the virus in the body and development of the disease. Cytokines are considered to play role in HFRS immunopathogenesis and possibly may drive different influence on clinical picture. The mechanisms which lead to HFRS development are still very poorly understood and little is known about the host immune response to the orthohantavirus infection. The aim of this in vitro study was to analyze the expression dynamics of selected cell surface molecules on monocytes infected with PUUV or TULV, as well as the secretion patterns of selected cytokines and chemokines, in order to investigate whether HTV infection triggers differentiation of monocytes and subsequent cell polarization. Primary human monocytes were infected in vitro with PUUV or TULV and cultured for seven days post infection. Immunophenotyping was done in three time points using in-house created polychromatic screening panel with antibodies specific for cell surface molecules on monocytes, macrophages and DC. Expression levels of 21 cytokines/chemokines in cell culture supernatants in six time points were determined by multiplex immunoassays with magnetic beads. Differences have been identified between infected and uninfected cells in cell surface molecules expression levels and concentrations of some cytokines and chemokines in supernatants (TNF-a, IL-1RA, IL-6, CCL2, CCL22, CD206). Differences were also found between infections with pathogenic and apathogenic HTV (CXCL8, CXCL10, CD206). Our findings indicate that HTV induce activation and differentiation of primary human monocytes toward macrophages in the time course.

pathogenic, apathogenic, monocytes, macrophages, dendritic cells, immunophenotyping, multiplex immunotest

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