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Cytotoxic immune responses in the lungs correlate to disease severity in patients with hantavirus infection
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
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2016 (English)In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 35, no 4, p. 713-721Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2016. Vol. 35, no 4, p. 713-721
Keywords [en]
hantavirus, hemorrhagic fever with renal syndrome, bronchoalveolar lavage, granzymes, viral load, cytotoxic T-lymphocytes, regulatory T-cells
National Category
Infectious Medicine
Research subject
Infectious Diseases
Identifiers
URN: urn:nbn:se:umu:diva-99100DOI: 10.1007/s10096-016-2592-1ISI: 000373300000023PubMedID: 26873376OAI: oai:DiVA.org:umu-99100DiVA, id: diva2:785861
Note

Originally included in thesis in manuscript form

Available from: 2015-02-04 Created: 2015-02-04 Last updated: 2018-09-17Bibliographically approved
In thesis
1. Cardiopulmonary involvement in Puumala hantavirus infection
Open this publication in new window or tab >>Cardiopulmonary involvement in Puumala hantavirus infection
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Puumala hantavirus (PUUV) causes hemorrhagic fever with renal syndrome in Europe. After inhalation of virus shed by bank voles, the virus systemically targets the vascular endothelium leading to vascular dysfunction and leakage. Many patients with PUUV infection experience cardiopulmonary manifestations but the underlying mechanisms have not been determined.

The aims of the studies presented were to describe cardiopulmonary manifestations, investigate pathogenetic mechanisms including presence of virus in the lungs and the local immune response in PUUV infection.

The results showed cardiopulmonary involvement of varying severity in almost all studied patients. High-resolution computed tomography frequently revealed vascular leakage into the lungs or pleural cavities. Pulmonary function tests generally showed reduced gas diffusing capacity, evidenced in patients as dyspnea, poor oxygenation and frequent need of oxygen treatment. Among patients who were not fully recovered at 3 months follow-up, remaining decreased gas diffusing capacity was highly common.

Echocardiography revealed mainly right heart dysfunction which was related to manifestations within the lungs, in terms of increased estimated pulmonary vascular resistance, mild to moderate pulmonary hypertension, and reduced right ventricular systolic function in patients with more pronounced lung involvement, as indicated by need of oxygen treatment.

Analyses on bronchoalveolar lavage (BAL) and bronchial biopsies revealed a highly activated cytotoxic T cell (CTL) response in the lungs. The CTL response was not balanced by the expansion of regulatory T cells and high numbers of CTLs were associated with more severe disease. PUUV RNA was detected in almost all patients’ BAL samples and the viral load was inversely correlated to the number of CTLs.

Three patients presenting with severe and fatal cardiopulmonary distress were also described. Autopsies revealed PUUV protein in vascular endothelium in all investigated organs, including the heart and lungs, along with a massive CTL response mainly in the lungs.

In conclusion, cardiopulmonary involvement of varying severity was present in almost all patients with PUUV infection. Cytotoxic immune responses could contribute to disease development but also help in clearing the infection. Long lasting fatigue after hantavirus infection may be explained by remaining manifestations within the lungs. 

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2015. p. 69
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1698
Keywords
Hemorrhagic fever with renal syndrome, hantavirus, echocardiography, respiratory function tests, computed tomography, bronchoalveolar lavage, biopsy, cytotoxic T cells, disease severity
National Category
Infectious Medicine
Research subject
Infectious Diseases
Identifiers
urn:nbn:se:umu:diva-99103 (URN)978-91-7601-215-4 (ISBN)
Public defence
2015-02-27, E04, byggnad 6E, Norrlands Universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2015-02-06 Created: 2015-02-04 Last updated: 2018-06-07Bibliographically approved

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Rasmuson, JohanPourazar, JamshidMohamed, NahlaLejon, KristinaEvander, MagnusBlomberg, AndersAhlm, Clas

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