Tacaribe Virus but Not Junin Virus Infection Induces Cytokine Release from Primary Human Monocytes and Macrophages

Abstract

The mechanisms underlying the development of disease during arenavirus infection are poorly understood. However, common to all hemorrhagic fever diseases is the involvement of macrophages as primary target cells, suggesting that the immune response in these cells may be of paramount importance during infection. Thus, in order to identify features of the immune response that contribute to arenavirus pathogenesis, we have examined the growth kinetics and cytokine profiles of two closely related New World arenaviruses, the apathogenic Tacaribe virus (TCRV) and the hemorrhagic fever-causing Junin virus (JUNV), in primary human monocytes and macrophages. Both viruses grew robustly in VeroE6 cells; however, TCRV titres were decreased by approximately 10 fold compared to JUNV in both monocytes and macrophages. Infection of both monocytes and macrophages with TCRV also resulted in the release of high levels of IL-6, IL-10 and TNF-α, while levels of IFN-α, IFN-β and IL-12 were not affected. However, we could show that the presence of these cytokines had no direct effect on growth of either TCRV of JUNV in macrophages. Further analysis also showed that while the production of IL-6 and IL-10 are dependent on viral replication, production of TNF-α also occurs after exposure to UV-inactivated TCRV particles and is thus independent of productive virus infection. Surprisingly, JUNV infection did not have an effect on any of the cytokines examined indicating that, in contrast to other viral hemorrhagic fever viruses, macrophage-derived cytokine production is unlikely to play an active role in contributing to the cytokine dysregulation observed in JUNV infected patients. Rather, these results suggest that an early, controlled immune response by infected macrophages may be critical for the successful control of infection of apathogenic viruses and prevention of subsequent disease, including systemic cytokine dysregulation.

The New World arenavirus Tacaribe virus induces caspase-dependent apoptosis in infected cells

“…Several lines of evidence suggested that TCRV might be impaired in its ability to suppress apoptosis induction compared with JUNV (Groseth et al, 2011;Wolff et al, 2013a), leading us to investigate whether TCRV infection indeed induces appreciable levels of apoptosis in infected cells, and, if so, by what mechanisms. Vero E6 cells, which represent a highly permissive system for arenavirus infection and are defective in IFN secretion, were inoculated with TCRV at an m.o.i.…”

“…Stock preparations of TCRV with a titre of 1.5|10 6 p.f.u. ml 21 were inactivated as previously described (Carter et al, 1973;Elliott et al, 1982;Groseth et al, 2011) by irradiation at 254 nm using a UV lamp (CAMAG) for 1 h. Inactivated samples were analysed by plaque assay as described previously (Wolff et al, 2013a), to ensure complete inactivation (data not shown).…”

“…Using this approach, we have previously identified differences in the induction of cytokine responses to infection with TCRV or JUNV in macrophages, as well as differences in their influence on host cell apoptosis (Groseth et al, 2011;Wolff et al, 2013a). Other known differences that also might play a role for the virulence include receptor usage (Abraham et al, 2009), as well as the ability to engage in IFN antagonism (Xing et al, 2015).…”

“…Other known differences that also might play a role for the virulence include receptor usage (Abraham et al, 2009), as well as the ability to engage in IFN antagonism (Xing et al, 2015). Previous studies have shown that TCRV lacks a novel NP-mediated anti-apoptotic function that was described for JUNV (Wolff et al, 2013a), and together with the observation that TCRV infection also induces severe cytopathic effects (CPEs) during infection in cell culture (Groseth et al, 2011), this suggests that cell death might be due at least in part to apoptotic responses. However, the extent to which apoptosis is in fact being induced during infection, as well as the biological role and significance of any induction of apoptotic pathways during TCRV infection, remained unclear.…”

Molecular-Biological Peculiarities of Arenavirus Reproduction in Sensitive Cells

“…вирусы ласса и мопейя способны инфициро-вать первичные макрофаги человека и дендритные клетки, но патогенный для человека вирус ласса не активирует эти клетки в процессе инфицирования, а непатогенный вирус мопейя активирует эти клет-ки, что проявляется в повышении уровня экспрес-сии маркеров сD86, сD80 и α-интерферона [17]. аналогичным образом первичные макрофаги чело-века показывают более высокий уровень продукции интерлейкина-6, интерлейкина-10 и α-интерферона при инфицировании вирусом такарибе по сравнению с инфицированием патогенным для человека вирусом хунин [7]. показано, что Z-белок всех известных па-тогенных аренавирусов, в отличие от непатогенных, способен ингибировать активацию макрофагов [27].…”