Abstract
Hantavirus infections may cause severe and sometime life-threatening lung failure. The pathogenesis is not fully known and there is an urgent need for effective treatment. We aimed to investigate the association between pulmonary viral load and immune responses, and their relation to disease severity. Bronchoscopy with sampling of bronchoalveolar lavage (BAL) fluid was performed in 17 patients with acute Puumala hantavirus infection and 16 healthy volunteers acting as controls. Lymphocyte subsets, granzyme concentrations, and viral load were determined by flow cytometry, enzyme-linked immunosorbent assay (ELISA), and quantitative reverse transcription polymerase chain reaction (RT-PCR), respectively. Analyses of BAL fluid revealed significantly higher numbers of activated CD8+ T cells and natural killer (NK) cells, as well as higher concentrations of the cytotoxins granzymes A and B in hantavirus-infected patients, compared to controls. In patients, Puumala hantavirus RNA was detected in 88 % of BAL cell samples and correlated inversely to the T cell response. The magnitude of the pulmonary cytotoxic lymphocyte response correlated to the severity of disease and systemic organ dysfunction, in terms of need for supplemental oxygen treatment, hypotension, and laboratory data indicating renal failure, cardiac dysfunction, vascular leakage, and cell damage. Regulatory T cell numbers were significantly lower in patients compared to controls, and may reflect inadequate immune regulation during hantavirus infection. Hantavirus infection elicits a pronounced cytotoxic lymphocyte response in the lungs. The magnitude of the immune response was associated with disease severity. These results give insights into the pathogenesis and possibilities for new treatments.
Highlights
Hantaviruses are rodent-borne viruses causing disease worldwide
We have demonstrated that hantavirus infection induces an activated cytotoxic effector immune response in the lungs
The magnitude of the immune response was associated with need for oxygen treatment, indicating poor gas exchange, as well as several systemic markers for disease severity
Summary
Hantaviruses are rodent-borne viruses causing disease worldwide. Infections with American hantaviruses (e.g., Andes and Sin Nombre virus) may lead to hantavirus cardiopulmonary syndrome, presenting with severe cardiopulmonary failure and high mortality, while infections with Asian or European hantaviruses are known to cause hemorrhagic fever with renal syndrome, characterized by coagulopathy and acute renal insufficiency [1,2,3,4]. The dichotomy of hantavirus syndromes is not clear cut, as patients infected with European Puumala virus (PUUV) commonly present with lung involvement, indicated by lower respiratory tract symptoms and impaired pulmonary gas diffusion capacity [5,6,7]. The presence of virus in the lungs during hantavirus infection has only been evaluated in post-mortem samples from patients infected with American hantaviruses or in small case series of
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