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Rapid expansion and long-term persistence of elevated NK cell numbers in humans infected with hantavirus
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
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2011 (English)In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 208, no 1, 13-21 p.Article in journal (Refereed) Published
Abstract [en]

Natural killer (NK) cells are known to mount a rapid response to several virus infections. In experimental models of acute viral infection, this response has been characterized by prompt NK cell activation and expansion followed by rapid contraction. In contrast to experimental model systems, much less is known about NK cell responses to acute viral infections in humans. We demonstrate that NK cells can rapidly expand and persist at highly elevated levels for >60 d after human hantavirus infection. A large part of the expanding NK cells expressed the activating receptor NKG2C and were functional in terms of expressing a licensing inhibitory killer cell immunoglobulin-like receptor (KIR) and ability to respond to target cell stimulation. These results demonstrate that NK cells can expand and remain elevated in numbers for a prolonged period of time in humans after a virus infection. In time, this response extends far beyond what is considered normal for an innate immune response.

Place, publisher, year, edition, pages
Rockefeller University Press, 2011. Vol. 208, no 1, 13-21 p.
Keyword [en]
natural killer cells, human cytomegalovirus infection, immunodeficiency syndrome AIDS, Barr virus infection, target cells, T-cells, class-I, mediated cytotoxicity, hemorrhagic fever, adaptive immunity
National Category
Infectious Medicine
Identifiers
URN: urn:nbn:se:umu:diva-41728DOI: 10.1084/jem.20100762ISI: 000286309300002PubMedID: 21173105OAI: oai:DiVA.org:umu-41728DiVA: diva2:407674
Available from: 2011-03-31 Created: 2011-03-31 Last updated: 2017-12-11Bibliographically 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.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1577
Keyword
Hantavirus, puumala virus, immune response, viral load, NK cells, T cells, cytokines, disease severity
National Category
Basic Medicine
Research subject
Infectious Diseases
Identifiers
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)
Opponent
Supervisors
Available from: 2013-08-30 Created: 2013-07-11 Last updated: 2013-09-03Bibliographically approved

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