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Pathogenesis of hantavirus infections is poorly understood. Puumala virus (PUU) is the etiologic agent of nephropathia epidemica, a form of hemorrhagic fever with renal syndrome common in Europe. We have studied PUU infection in primary human monocyte/macrophages and specifically the role of interferon alpha (IFN-alpha) and cell differentiation in it. PUU infection proceeded at a low level in monocyte/macrophages, and nucleocapsid (N) protein accumulation started 2 days postinfection. IFN-induced antiviral MxA protein was detected 3 days postinfection, suggesting IFN-alpha production in culture. IFN-alpha titers remained low, proposing that PUU is a poor IFN inducer. However, the PUU-induced IFN had an inhibitory effect on virus production as was shown by the effect of anti-IFN-alpha. Pretreatment of cells with IFN-alpha caused a dose-dependent inhibition of PUU N accumulation and reduced the yield of infectious virus. Monocytic U-937 cells overexpressing MxA protein were susceptible to PUU, suggesting that, unlike in some other negative strand RNA virus infections, MxA does not mediate resistance to PUU infection. Differentiation of monocyte/macrophages in culture and treatment of THP-1 promonocytic cells with phorbol 12-myristate 13-acetate made the cells more susceptible to PUU. The increased susceptibility of mature macrophages to PUU suggests that after differentiation to tissue macrophages they might function in the spread of the virus during PUU infection.

SUMMARYIncreased capillary permeability is a central feature of the severe forms of haemorrhagic fever with renal syndrome (HFRS) and occurs also, though less frequently, in nephropathia epidemica (NE), one of the milder forms of this syndrome, caused by Puumala virus. We therefore searched for antiendothelial cell antibodies (AECA) in patients with NE and in those with other presumed or serologically proven acute viral illnesses. By enzyme immunoassay, using human umbilical vein endothelial cells (HUVEC) as the substrate, IgG class AECA were detected significantly more frequently in patients with NE and with influenza A than in Red Cross blood donors. A lesser degree of reactivity could be shown with a human alveolar cell carcinoma line and with human and mouse embryonic fibroblasts. Pretreatment of HUVEC with interferon-gamma (IFN-y), but not with IL-I or tumour necrosis factor-alpha (TNF-a), increased their ability to bind IgG of sera from patients with NE and acute febrile illnesses. We conclude that, although AECA can be demonstrated in NE, they occur also in other acute viral illnesses and, unless cytopathic by a mechanism not shared by the AECA of these other illnesses, are unlikely to be causally related to the capillary leak in HFRS.