Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Study of pathogenesis and immune response in human Puumala virus infection
Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
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 [en]
Hantavirus, puumala virus, immune response, viral load, NK cells, T cells, cytokines, disease severity
National Category
Basic Medicine
Research subject
Infectious Diseases
Identifiers
URN: urn:nbn:se:umu:diva-76706ISBN: 978-91-7459-681-6 (print)OAI: oai:DiVA.org:umu-76706DiVA: diva2:636724
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
List of papers
1. Sex-dependent differences in plasma cytokine responses to hantavirus infection
Open this publication in new window or tab >>Sex-dependent differences in plasma cytokine responses to hantavirus infection
2008 (English)In: Clinical and Vaccine Immunology, ISSN 1556-6811, E-ISSN 1556-679X, Vol. 15, no 5, 885-887 p.Article in journal (Refereed) Published
Abstract [en]

There are often sex differences in susceptibility to infectious diseases and in level of mortality after infection. These differences probably stem from sex-related abilities to mount proper or unwanted immune responses against an infectious agent. We report that hantavirus-infected female patients show significantly higher plasma levels of interleukin-9 (IL-9), fibroblast growth factor 2, and granulocyte-macrophage colony-stimulating factor and lower levels of IL-8 and gamma interferon-induced protein 10 than male patients. The results demonstrate that a virus infection can induce sex-dependent differences in acute immune responses in humans. This finding may, at least partly, explain the observed sex differences in susceptibility to infectious diseases and in mortality following infection.

National Category
Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-23368 (URN)10.1128/CVI.00035-08 (DOI)18353922 (PubMedID)
Available from: 2009-06-13 Created: 2009-06-13 Last updated: 2017-10-31Bibliographically approved
2. Rapid expansion and long-term persistence of elevated NK cell numbers in humans infected with hantavirus
Open this publication in new window or tab >>Rapid expansion and long-term persistence of elevated NK cell numbers in humans infected with hantavirus
Show others...
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
Keyword
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:nbn:se:umu:diva-41728 (URN)10.1084/jem.20100762 (DOI)000286309300002 ()21173105 (PubMedID)
Available from: 2011-03-31 Created: 2011-03-31 Last updated: 2017-12-11Bibliographically approved
3. Longitudinal analysis of the human T cell response during acute hantavirus infection
Open this publication in new window or tab >>Longitudinal analysis of the human T cell response during acute hantavirus infection
Show others...
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
National Category
Clinical Medicine
Identifiers
urn:nbn:se:umu:diva-48993 (URN)10.1128/JVI.05548-11 (DOI)21795350 (PubMedID)
Available from: 2011-10-31 Created: 2011-10-31 Last updated: 2017-12-08Bibliographically approved
4. Viral load and humoral immune response in association with disease severity in Puumala hantavirus-infected patients-implications for treatment
Open this publication in new window or tab >>Viral load and humoral immune response in association with disease severity in Puumala hantavirus-infected patients-implications for treatment
Show others...
2014 (English)In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 20, no 3, 235-241 p.Article in journal (Refereed) Published
Abstract [en]

Hantaviruses are the causative agents of haemorrhagic fever with renal syndrome (HFRS) in Eurasia and of hantavirus cardiopulmonary syndrome (HCPS) in the Americas. The case fatality rate varies between different hantaviruses and can be up to 40%. At present, there is no specific treatment available. The hantavirus pathogenesis is not well understood, but most likely, both virus-mediated and host-mediated mechanisms are involved. The aim of the present study was to investigate the association among Puumala hantavirus (PUUV) viral RNA load, humoral immune response and disease severity in patients with HFRS. We performed a study of 105 PUUV-infected patients that were followed during the acute phase of disease and for up to 1-3 months later. Fifteen of the 105 patients (14%) were classified as having moderate/severe disease. A low PUUV-specific IgG response (p <0.05) and also a higher white blood cell count (p <0.001) were significantly associated with more severe disease. The PUUV RNA was detected in a majority of patient plasma samples up to 9 days after disease onset; however, PUUV RNA load or longevity of viraemia were not significantly associated with disease severity. We conclude that a low specific IgG response was associated with disease severity in patients with HFRS, whereas PUUV RNA load did not seem to affect the severity of HFRS. Our results raise the possibility of passive immunotherapy as a useful treatment for hantavirus-infected patients.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2014
Keyword
age, disease severity, hantavirus, haemorrhagic fever with renal syndrome, humoral immune response, immunoglobulins, neutrophil, Puumala virus, viral load, white blood cell count
National Category
Microbiology in the medical area Infectious Medicine
Research subject
Microbiology
Identifiers
urn:nbn:se:umu:diva-74938 (URN)10.1111/1469-0691.12259 (DOI)000331024400018 ()23742660 (PubMedID)
Available from: 2013-07-02 Created: 2013-07-02 Last updated: 2017-12-06Bibliographically approved

Open Access in DiVA

fulltext(2450 kB)738 downloads
File information
File name FULLTEXT02.pdfFile size 2450 kBChecksum SHA-512
add574c1dd719c25c1f2bed4fdd9b361a4fd3340aa1d7f8060c3aded22a0589265068e3022ca8af3fe4e63c4a419e4093138b2cc5ed38aa1021dfedfd0840bfd
Type fulltextMimetype application/pdf

Authority records BETA

Thunberg, Therese

Search in DiVA

By author/editor
Thunberg, Therese
By organisation
Department of Clinical Microbiology
Basic Medicine

Search outside of DiVA

GoogleGoogle Scholar
Total: 738 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 707 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf