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Effect of interferon-alpha and cell differentiation on Puumala virus infection in human monocyte/macrophages
M Temonen1, H Lankinen, O Vapalahti
1Department of Virology, Haartman Institute, Helsinki University, Finland.
Abstract:
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.
Insights
Puumala virus (PUU) infection is poorly understood. Mature macrophages increase susceptibility to PUU, suggesting a role in viral spread during nephropathia epidemica.
Area of Science:
- Virology
- Immunology
- Cell Biology
Background:
- Hantavirus infections, including Puumala virus (PUU) causing nephropathia epidemica, have poorly understood pathogenesis.
- Monocytes and macrophages are key immune cells involved in viral infections.
Purpose of the Study:
- To investigate the role of interferon alpha (IFN-alpha) and cell differentiation in Puumala virus (PUU) infection of human monocyte/macrophages.
- To understand the susceptibility of different immune cell states to PUU infection.
Main Methods:
- Studied PUU infection in primary human monocyte/macrophages.
- Assessed the impact of IFN-alpha pretreatment and cell differentiation on PUU replication.
- Utilized U-937 and THP-1 cell lines to investigate MxA protein and differentiation effects.
Main Results:
- PUU infection showed low-level replication in monocyte/macrophages with delayed nucleocapsid protein accumulation.
- PUU induced low levels of IFN-alpha, which exhibited an inhibitory effect on virus production.
- IFN-alpha pretreatment dose-dependently inhibited PUU N accumulation and infectious virus yield.
- MxA protein did not confer resistance to PUU infection.
- Cell differentiation significantly increased susceptibility to PUU infection.
Conclusions:
- Puumala virus is a poor inducer of IFN-alpha, but the induced IFN-alpha can inhibit viral replication.
- MxA protein is not a key factor in conferring resistance to PUU.
- Differentiated macrophages become more susceptible to PUU, suggesting a potential role in viral dissemination in vivo.