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Thunberg, Therese
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Publications (7 of 7) Show all publications
Rankin, G., Byström, J. W., Gustafsson, R., Hansson, M., Thunberg, T., Ahlm, C. & Connolly, A.-M. F. (2019). MMP9 Associates with Endothelial Glycocalyx Degradation During Haemorrhagic Fever with Renal Syndrome. Paper presented at 3rd Joint Meeting of the European-Society-for-Microcirculation (ESM) and the European-Vascular-Biology-Organization (EVBO), Maastricht, Netherlands, April, 2019.. Journal of Vascular Research, 56, 35-35
Open this publication in new window or tab >>MMP9 Associates with Endothelial Glycocalyx Degradation During Haemorrhagic Fever with Renal Syndrome
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2019 (English)In: Journal of Vascular Research, ISSN 1018-1172, E-ISSN 1423-0135, Vol. 56, p. 35-35Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Introduction: Haemorrhagic fever with renal syndrome (HFRS) is characterized by fever, hypotension, vascular leakage, thrombocytopenia and renal failure. HFRS in Sweden is caused by the Puumala hantavirus and is spread by viral-infested droppings from bank voles. The health care system has little to offer these patients since there is no antiviral treatment and as of yet there is no vaccine prophylaxis available. We previously showed that a marker of endothelial glycocalyx degradation (Syndecan-1) was associated with disease severity and disseminated intravascular coagulation during HFRS (Connolly-Andersen et al., 2014, Open Forum Infect Dis.).

Methods: We analysed the levels of other endothelial glycocalyx degradation markers (heparan sulfate, soluble thrombomodulin, albumin), a potential “sheddase”: Matrix Metalloproinase 9 (MMP9) and neutrophil activation/tissue damage (neutrophil gelatinase-associated lipocalin, NGAL) in patient plasma from 44 HFRS patients collected consecutively following disease onset. We used the generalized estimating equation to analyse the association between endothelial glycocalyx degradation, MMP9 levels, neutrophil activation/tissue damage and HFRS disease outcome (need for oxygen, transfusion with blood components, need for intensive care unit (ICU) treatment and renal damage).

Results: 44 HFRS patients were included in this study (29 females (66%)); need for oxygen: 11 (25%); transfusion with blood components: 3 (7%) and stay at ICU: 2 (5%)). The levels of MMP9 were significantly associated with all markers of endothelial glycocalyx degradation. Neutrophil activation/tissue damage (NGAL) was also significantly associated with MMP9 and endothelial glycocalyx degradation markers (apart from albumin (p = 0.053). In addition degradation of endothelial glycocalyx associated with HFRS disease outcome.

Conclusion: Degradation of the endothelial glycocalyx could be a potential mechanism of HFRS pathogenesis, and potentially MMP9 could contribute to degradation of the endothelial glycocalyx

Place, publisher, year, edition, pages
S. Karger, 2019
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-158767 (URN)10.1159/000499516 (DOI)000463529300074 ()
Conference
3rd Joint Meeting of the European-Society-for-Microcirculation (ESM) and the European-Vascular-Biology-Organization (EVBO), Maastricht, Netherlands, April, 2019.
Note

Supplement 1, meeting abstract 73.

Available from: 2019-05-08 Created: 2019-05-08 Last updated: 2019-05-08
Connolly-Andersen, A.-M., Thunberg, T. & Ahlm, C. (2014). Endothelial activation and repair during hantavirus infection: association with disease outcome. Open forum infectious diseases, 1(1), Article ID ofu027.
Open this publication in new window or tab >>Endothelial activation and repair during hantavirus infection: association with disease outcome
2014 (English)In: Open forum infectious diseases, ISSN 2328-8957, Vol. 1, no 1, article id ofu027Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Endothelial activation and dysfunction play a central role in the pathogenesis of sepsis and viral hemorrhagic fevers. Hantaviral disease is a viral hemorrhagic fever and is characterized by capillary dysfunction, although the underlying mechanisms for hantaviral disease are not fully elucidated.

METHODS: The temporal course of endothelial activation and repair were analyzed during Puumala hantavirus infection and associated with disease outcome and a marker for hypoxia, insulin-like growth factor binding protein 1 (IGFBP-1). The following endothelial activation markers were studied: endothelial glycocalyx degradation (syndecan-1) and leukocyte adhesion molecules (soluble vascular cellular adhesion molecule 1, intercellular adhesion molecule 1, and endothelial selectin). Cytokines associated with vascular repair were also analyzed (vascular endothelial growth factor, erythropoietin, angiopoietin, and stromal cell-derived factor 1).

RESULTS: Most of the markers we studied were highest during the earliest phase of hantaviral disease and associated with clinical and laboratory surrogate markers for disease outcome. In particular, the marker for glycocalyx degradation, syndecan-1, was significantly associated with levels of thrombocytes, albumin, IGFBP-1, decreased blood pressure, and disease severity.

CONCLUSIONS: Hantaviral disease outcome was associated with endothelial dysfunction. Consequently, the endothelium warrants further investigation when designing future medical interventions.

Keywords
travel health advice, illness during travel, risk behaviour during travel, risk groups in travel medicine, compliance with travel health advice
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-100520 (URN)10.1093/ofid/ofu027 (DOI)25734100 (PubMedID)
Available from: 2015-03-04 Created: 2015-03-04 Last updated: 2018-06-07Bibliographically approved
Pettersson, L., Thunberg, T., Rocklöv, J., Klingström, J., Evander, M. & Ahlm, C. (2014). Viral load and humoral immune response in association with disease severity in Puumala hantavirus-infected patients-implications for treatment. Clinical Microbiology and Infection, 20(3), 235-241
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
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2014 (English)In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 20, no 3, p. 235-241Article 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
Keywords
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: 2018-06-08Bibliographically approved
Thunberg, T. (2013). Study of pathogenesis and immune response in human Puumala virus infection. (Doctoral dissertation). Umeå: Umeå universitet
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. p. 60
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1577
Keywords
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: 2018-06-08Bibliographically approved
Lindgren, T., Ahlm, C., Mohamed, N., Evander, M., Ljunggren, H.-G. & Björkström, N. K. (2011). Longitudinal analysis of the human T cell response during acute hantavirus infection. Journal of Virology, 85(19), 10252-10260
Open this publication in new window or tab >>Longitudinal analysis of the human T cell response during acute hantavirus infection
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2011 (English)In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 85, no 19, p. 10252-10260Article 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: 2018-06-08Bibliographically approved
Björkström, N. K., Lindgren, T., Stoltz, M., Fauriat, C., Braun, M., Evander, M., . . . Ljunggren, H.-G. (2011). Rapid expansion and long-term persistence of elevated NK cell numbers in humans infected with hantavirus. Journal of Experimental Medicine, 208(1), 13-21
Open this publication in new window or tab >>Rapid expansion and long-term persistence of elevated NK cell numbers in humans infected with hantavirus
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2011 (English)In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 208, no 1, p. 13-21Article 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
Keywords
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: 2018-06-08Bibliographically approved
Klingström, J., Lindgren, T. & Ahlm, C. (2008). Sex-dependent differences in plasma cytokine responses to hantavirus infection. Clinical and Vaccine Immunology, 15(5), 885-887
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, p. 885-887Article 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: 2018-06-08Bibliographically approved
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