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Longitudinal analysis of the human T cell response during acute hantavirus infection
(Clas Ahlm)
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. (Clas Ahlm ; Arcum)
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. (Ahlm o Evander)
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. (Magnus Evander ; Arcum)
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2011 (English)In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 85, no 19, 10252-10260 p.Article in journal (Refereed) Published
Abstract [en]

Longitudinal studies of T cell immune responses during viral infections in humans are essential for our understanding of how effector T cell responses develop, clear infection, and provide long-lasting immunity. Here, following an outbreak of a Puumala hantavirus infection in the human population, we longitudinally analyzed the primary CD8 T cell response in infected individuals from the first onset of clinical symptoms until viral clearance. A vigorous CD8 T cell response was observed early following the onset of clinical symptoms, determined by the presence of high numbers of Ki67(+)CD38(+)HLA-DR(+) effector CD8 T cells. This response encompassed up to 50% of total blood CD8 T cells, and it subsequently contracted in parallel with a decrease in viral load. Expression levels of perforin and granzyme B were high throughout the initial T cell response and likewise normalized following viral clearance. When monitoring regulatory components, no induction of regulatory CD4 or CD8 T cells was observed in the patients during the infection. However, CD8 as well as CD4 T cells exhibited a distinct expression profile of inhibitory PD-1 and CTLA-4 molecules. The present results provide insight into the development of the T cell response in humans, from the very onset of clinical symptoms following a viral infection to resolution of the disease.

Place, publisher, year, edition, pages
Baltimore: American Society for Microbiology , 2011. Vol. 85, no 19, 10252-10260 p.
National Category
Clinical Medicine
URN: urn:nbn:se:umu:diva-48993DOI: 10.1128/JVI.05548-11PubMedID: 21795350OAI: diva2:452553
Available from: 2011-10-31 Created: 2011-10-31 Last updated: 2016-05-24Bibliographically approved
In thesis
1. Study of pathogenesis and immune response in human Puumala virus infection
Open this publication in new window or tab >>Study of pathogenesis and immune response in human Puumala virus infection
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Hantaviruses can cause two severe human diseases: hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS). Hantaviruses are spread to humans mainly through inhalation of infectious virions, secreted from infected rodents. The human diseases are characterized by an increased capillary leakage syndrome. Hantaviruses are known to infect endothelial cells, but they are non-cytopathogenic. The mechanism behind human disease is not well understood, but an overactive immune response is implicated in the pathogenesis. The aim of my thesis has been to investigate parts of innate and adaptive immune responses in Puumala virus-infected patients.

In paper I we found a sex difference in the cytokine profile during acute infection. Females had significantly higher plasma levels of IL-9, FGF-2, GM-CSF and lower levels of IL-8 and IP-10 compared to males. These differences may affect the activation and function of the immune response.

In paper II we studied the phenotype and kinetics of NK cells. We observed that CD56dim NK cells were elevated during acute infection and that these, predominantly NKG2C+ NK cells, remained elevated for at least two months after symptom debut. Our novel finding of a prolonged NK cell response, implicates that NK cells may possess adaptive immunity features. 

In paper III we observed a vigorous cytotoxic T cell (CTL) response during acute infection, which contracted in parallel with decrease in viral load. The CTL response was not balanced by an increase in regulatory T cells. The T cells expressed inhibitory immunoregulatory receptors, known to dampen intrinsic T cell activity. 

In paper IV, we found that a low IgG response in patients was significantly associated with more severe disease, while the viral load did not affect the outcome. Our findings support the use of passive immunization as a treatment alternative for hantavirus-infected patients.

In conclusion, my thesis contributes to an increased knowledge about the immune response in hantavirus-infected patients. The findings, combined with future studies, will hopefully lead to a better understanding of the pathogenesis and possible treatment alternatives.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2013. 60 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1577
Hantavirus, puumala virus, immune response, viral load, NK cells, T cells, cytokines, disease severity
National Category
Basic Medicine
Research subject
Infectious Diseases
urn:nbn:se:umu:diva-76706 (URN)978-91-7459-681-6 (ISBN)
Public defence
2013-09-20, E04, byggnad 6E, Norrlands Universitetssjukhus, Umeå, 09:00 (English)
Available from: 2013-08-30 Created: 2013-07-11 Last updated: 2013-09-03Bibliographically approved

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