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Hantaan Virus Nucleocapsid Protein Binds to Importin alpha Proteins and Inhibits Tumor Necrosis Factor Alpha-Induced Activation of Nuclear Factor Kappa B
ARMY MEDICAL RESEARCH INST OF INFECTIOUS DISEASES FORT DETRICK MD
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Hantaviruses such as Hantaan virus HTNV and Andes virus cause two human diseases, hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome, respectively. For both, disease pathogenesis is thought to be immunologically mediated and there have been numerous reports of patients with elevated levels of proinflammatory and inflammatory cytokines, including tumor necrosis factor alpha TNF-alpha, in their sera. Multiple viruses have developed evasion strategies to circumvent the host cell inflammatory process, with one of the most prevalent being the disruption of nuclear factor kappa B NF-kB activation. We hypothesized that hantaviruses might also moderate host inflammation by interfering with this pathway. We report here that the nucleocapsid N protein of HTNV was able to inhibit TNF-alpha-induced activation of NF-kB, as measured by a reporter assay, and the activation of endogenous p65, an NF-B subunit. Surprisingly, there was no defect in the degradation of the inhibitor of NF-kB IkB protein, nor was there any alteration in the level of p65 expression in HTNV N-expressing cells. However, immunofluorescence antibody staining demonstrated that cells expressing HTNV N protein and a green fluorescent protein-p65 fusion had limited p65 nuclear translocation. Furthermore, we were able to detect an interaction between HTNV N protein and importin , a nuclear import molecule responsible for shuttling NF-kB to the nucleus. Collectively, our data suggest that HTNV N protein can sequester NF-kB in the cytoplasm, thus inhibiting NF-kB activity. These findings, which were obtained using cells transfected with cDNA representing the HTNV N gene, were confirmed using HTNV-infected cells.
APPROVED FOR PUBLIC RELEASE