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.