There are many viruses known to cause viral hemorrhagic fevers in humans. The mechanisms causing hemorrhage are likely to vary among viruses. Some viruses, such as Marburg virus, are directly cytopathic to infected endothelial cells, suggesting infection of endothelial cells alone can cause hemorrhage. On the other hand, there are viruses which infect endothelial cells without causing any cytopathic effects, suggesting the involvement of host immune responses in developing hemorrhage. Typical examples of these include viruses of the hantavirus species. We hypothesize that impairment of endothelial cell's defense mechanisms against cytotoxic CD8+ T cells is the mechanism of capillary leakage in hantavirus pulmonary syndrome and hemorrhagic fever with renal syndrome, which may be common to other viral hemorrhagic fevers. CD8+ T cells may be a potential target for therapy of some viral hemorrhagic fevers.

BACKGROUND: Respiratory infection with the neurovirulent vaccinia virus (VV) strain Western Reserve (WR) results in an acute infection of the lung followed by dissemination of the virus to other organs and causes lethality in mice. The mechanisms of lethality are not well-understood. In this study, we analyzed virus replication and host immune responses after intranasal infection with lethal and non-lethal doses of VV using the WR strain and the less virulent Wyeth strain. RESULTS: The WR strain replicated more vigorously in the lung and in the brain than the Wyeth strain. There were, however, no differences between the virus titers in the brains of mice infected with the higher lethal dose and the lower non-lethal dose of WR strain, suggesting that the amount of virus replication in the brain is unlikely to be the sole determining factor of lethality. The WR strain grew better in primary mouse lung cells than the Wyeth strain. Lethal infection with WR strain was associated with a reduced number of lymphocytes and an altered phenotype of the T cells in the lung compared to non-lethal infections with the WR or Wyeth strains. Severe thymus atrophy with a reduction of CD4 and CD8 double positive T cells was also observed in the lethal infection. CONCLUSION: These results suggest that the lethality induced by intranasal infection with a high dose of the WR strain is caused by the higher replication of virus in lung cells and immune suppression during the early phase of the infection, resulting in uncontrolled virus replication in the lung.

Hantavirus infection causes two human diseases, hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. The typical feature of these diseases is increased permeability in microvascular beds in the kidneys and the lungs, respectively. The mechanism of capillary leakage, however, is not understood. Some evidence suggests that hantavirus disease pathogenesis is immunologically mediated by cytotoxic T lymphocytes and other immune cells in target organs producing inflammatory cytokines. In this study we examined the roles of virus-specific cytotoxic T lymphocytes in increased permeability of human endothelial cells infected with hantavirus. We used a human CD8(+) hantavirus-specific cytotoxic T lymphocyte line, 1A-E2, specific for the HLA-A24-restricted epitope in Sin Nombre and Puumala virus G2 protein, and the human endothelial cell line, EA.hy926 that expresses HLA-A24 molecule. The cytotoxic T lymphocyte line recognized and lysed target cells infected with Sin Nombre virus, and in transwell permeability assays increased permeability of EA.hy926 cell monolayer infected with Sin Nombre virus or recombinant adenovirus expressing the Sin Nombre virus G2 protein. These results suggest that cytotoxic T lymphocyte activity contribute to capillary leakage observed in patients with hantavirus pulmonary syndrome or hemorrhagic fever with renal syndrome.

The efficiency of prime-boost vaccinations on the induction of T-cell responses to Sin Nombre virus nucleocapsid protein expressed by recombinant vaccinia virus, replication-deficient adenovirus, and plasmid DNA in mice was quantitated by the number of epitope-specific interferon-gamma-producing T cells and cytotoxic T-lymphocyte activity induced. In prime-boost immunizations, all combinations that included the recombinant adenovirus induced a much higher number of epitope-specific interferon-gamma-producing T cells than did other combinations. A single immunization of the recombinant adenovirus was able to induce similarly high levels of epitope-specific interferon-gamma-producing cells, despite the fact that the recombinant adenovirus produces less amount of the Sin Nombre virus nucleocapsid protein.