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.
Highlights
The Arenaviridae constitute a large family of bi-segmented singlestranded RNA viruses, with 25 species currently being recognized [1,2,3,4] and new members being discovered approximately once every 3 years [5]
In order to determine if a similar mechanism might contribute to arenavirus pathogenesis, we have examined the infection and subsequent cytokine production in human monocytes and macrophages by two closely related arenaviruses: the apathogenic Tacaribe virus (TCRV) and the hemorrhagic fever-causing Junin virus (JUNV)
We found that both viruses infected primary monocyte and macrophage cultures; only, in the case of TCRV was infection accompanied by the production of cytokines
Summary
The Arenaviridae constitute a large family of bi-segmented singlestranded RNA viruses, with 25 species currently being recognized [1,2,3,4] and new members being discovered approximately once every 3 years [5]. The most clinically significant in terms of disease burden is Junin virus (JUNV), which is the causative agent of Argentine hemorrhagic fever (AHF) Since it was first identified in the 1950s JUNV infection has typically been responsible for 300–1000 cases of AHF per year. Infection is most commonly seen among agricultural workers and occurs seasonally in the humid pampas of the provinces of Buenos Aires, Santa Fe, Cordoba, and La Pampa in Argentina, with infection believed to occur through cutaneous or mucosal contact to contaminated blood, feces or urine from infected rodents, often in the form of aerosols [9] The majority of these infections with JUNV result in clinical disease [9], which can be divided into three distinct phases: prodromal, neurological– hemorrhagic, and convalescent [7]. 20–30% of AHF cases progress to the neurologic– hemorrhagic phase of disease characterized by severe hemorrhagic or neurological manifestations and shock [9]
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