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Baudin, Maria
Publications (7 of 7) Show all publications
Baudin, M., Jumaa, A. M., Jomma, H. J. E., Karsany, M. S., Bucht, G., Näslund, J., . . . Mohamed, N. (2016). Association of Rift Valley fever virus infection with miscarriage in Sudanese women: a cross-sectional study. The Lancet Global Health, 4(11), e864-e871
Open this publication in new window or tab >>Association of Rift Valley fever virus infection with miscarriage in Sudanese women: a cross-sectional study
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2016 (English)In: The Lancet Global Health, E-ISSN 2214-109X, Vol. 4, no 11, p. e864-e871Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Rift Valley fever virus is an emerging mosquito-borne virus that causes infections in animals and human beings in Africa and the Arabian Peninsula. Outbreaks of Rift Valley fever lead to mass abortions in livestock, but such abortions have not been identified in human bezings. Our aim was to investigate the cause of miscarriages in febrile pregnant women in an area endemic for Rift Valley fever.

METHODS: Pregnant women with fever of unknown origin who attended the governmental hospital of Port Sudan, Sudan, between June 30, 2011, and Nov 17, 2012, were sampled at admission and included in this cross-sectional study. Medical records were retrieved and haematological tests were done on patient samples. Presence of viral RNA as well as antibodies against a variety of viruses were analysed. Any association of viral infections, symptoms, and laboratory parameters to pregnancy outcome was investigated using Pearson's χ(2) test.

FINDINGS: Of 130 pregnant women with febrile disease, 28 were infected with Rift Valley fever virus and 31 with chikungunya virus, with typical clinical and laboratory findings for the infection in question. 15 (54%) of 28 women with an acute Rift Valley fever virus infection had miscarriages compared with 12 (12%) of 102 women negative for Rift Valley fever virus (p<0·0001). In a multiple logistic regression analysis, adjusting for age, haemorrhagic disease, and chikungunya virus infection, an acute Rift Valley fever virus infection was an independent predictor of having a miscarriage (odds ratio 7·4, 95% CI 2·7-20·1; p<0·0001).

INTERPRETATION: This study is the first to show an association between infection with Rift Valley fever virus and miscarriage in pregnant women. Further studies are warranted to investigate the possible mechanisms. Our findings have implications for implementation of preventive measures, and evidence-based information to the public in endemic countries should be strongly recommended during Rift Valley fever outbreaks.

FUNDING: Schlumberger Faculty for the Future, CRDF Global (31141), the Swedish International Development Cooperation Agency, the County Council of Västerbotten, and the Faculty of Medicine, Umeå University.

Keywords
Rift Valley fever, Rift Valley fever virus, infectious diseases, virology, miscarriage, Sudan, maternal health
National Category
Infectious Medicine
Research subject
Infectious Diseases; Medical Virology; Obstetrics and Gynaecology
Identifiers
urn:nbn:se:umu:diva-126472 (URN)10.1016/S2214-109X(16)30176-0 (DOI)000386811200028 ()27692776 (PubMedID)
Available from: 2016-10-07 Created: 2016-10-07 Last updated: 2018-06-09Bibliographically approved
Islam, M. K. K., Baudin, M., Eriksson, J., Öberg, C., Habjan, M., Weber, F., . . . Evander, M. (2016). High-Throughput Screening Using a Whole-Cell Virus Replication Reporter Gene Assay to Identify Inhibitory Compounds against Rift Valley Fever Virus Infection. Journal of Biomolecular Screening, 21(4), 354-362
Open this publication in new window or tab >>High-Throughput Screening Using a Whole-Cell Virus Replication Reporter Gene Assay to Identify Inhibitory Compounds against Rift Valley Fever Virus Infection
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2016 (English)In: Journal of Biomolecular Screening, ISSN 1087-0571, E-ISSN 1552-454X, Vol. 21, no 4, p. 354-362Article in journal (Refereed) Published
Abstract [en]

Rift Valley fever virus (RVFV) is an emerging virus that causes serious illness in humans and livestock. There are no approved vaccines or treatments for humans. The purpose of the study was to identify inhibitory compounds of RVFV infection without any preconceived idea of the mechanism of action. A whole-cell-based high-throughput drug screening assay was developed to screen 28,437 small chemical compounds targeting RVFV infection. To accomplish both speed and robustness, a replication-competent NSs-deleted RVFV expressing a fluorescent reporter gene was developed. Inhibition of fluorescence intensity was quantified by spectrophotometry and related to virus infection in human lung epithelial cells (A549). Cell toxicity was assessed by the Resazurin cell viability assay. After primary screening, 641 compounds were identified that inhibited RVFV infection by 80%, with 50% cell viability at 50 mu M concentration. These compounds were subjected to a second screening regarding dose-response profiles, and 63 compounds with 60% inhibition of RVFV infection at 3.12 mu M compound concentration and 50% cell viability at 25 mu M were considered hits. Of these, six compounds with high inhibitory activity were identified. In conclusion, the high-throughput assay could efficiently and safely identify several promising compounds that inhibited RVFV infection.

Place, publisher, year, edition, pages
Sage Publications, 2016
Keywords
high-throughput screening, antiviral, cell-based assay, recombinant virus, Rift Valley fever
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-119642 (URN)10.1177/1087057115625184 (DOI)000372883200004 ()26762502 (PubMedID)
Available from: 2016-05-18 Created: 2016-04-25 Last updated: 2018-09-14Bibliographically approved
Bergstedt Oscarsson, K., Brorstad, A., Baudin, M., Lindberg, A., Forssén, A., Evander, M., . . . Ahlm, C. (2016). Human Puumala hantavirus infection in northern Sweden: increased seroprevalence and association to risk and health factors. BMC Infectious Diseases, 16, Article ID 566.
Open this publication in new window or tab >>Human Puumala hantavirus infection in northern Sweden: increased seroprevalence and association to risk and health factors
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2016 (English)In: BMC Infectious Diseases, ISSN 1471-2334, E-ISSN 1471-2334, Vol. 16, article id 566Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The rodent borne Puumala hantavirus (PUUV) causes haemorrhagic fever with renal syndrome in central and northern Europe. The number of cases has increased and northern Sweden has experienced large outbreaks in 1998 and 2006-2007 which raised questions regarding the level of immunity in the human population.

METHODS: A randomly selected population aged between 25 and 74 years from northern Sweden were invited during 2009 to participate in a WHO project for monitoring of trends and determinants in cardiovascular disease. Health and risk factors were evaluated and sera from 1,600 participants were available for analysis for specific PUUV IgG antibodies using a recombinant PUUV nucleocapsid protein ELISA.

RESULTS: The overall seroprevalence in the investigated population was 13.4 %, which is a 50 % increase compared to a similar study only two decades previously. The prevalence of PUUV IgG increased with age, and among 65-75 years it was 22 %. More men (15.3 %) than women (11.4 %) were seropositive (p < 0.05). The identified risk factors were smoking (OR = 1.67), living in rural areas (OR = 1.92), and owning farmland or forest (OR = 2.44). No associations were found between previous PUUV exposure and chronic lung disease, diabetes, hypertension, renal dysfunction, stroke or myocardial infarction.

CONCLUSIONS: PUUV is a common infection in northern Sweden and there is a high life time risk to acquire PUUV infection in endemic areas. Certain risk factors as living in rural areas and smoking were identified. Groups with increased risk should be targeted for future vaccination when available, and should also be informed about appropriate protection from rodent secreta.

Keywords
Emerging infection, Hantavirus, Haemhorrhagic fever with renal syndrome, Puumala, seroepidemiology, Risk factors
National Category
Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-127441 (URN)10.1186/s12879-016-1879-2 (DOI)000385447000001 ()27737653 (PubMedID)
Available from: 2016-11-12 Created: 2016-11-12 Last updated: 2018-06-09Bibliographically approved
Baudin, M. (2016). Rift Valley fever: consequences of virus-host interactions. (Doctoral dissertation). Umeå: Umeå universitet
Open this publication in new window or tab >>Rift Valley fever: consequences of virus-host interactions
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Rift Valley fever virus (RVFV) is a mosquito-borne virus which has the ability to infect a large variety of animals including humans in Africa and Arabian Peninsula. The abortion rate among these animals are close to 100%, and young animals develop severe disease which often are lethal.

In humans, Rift Valley fever (RVF) presents in most cases as a mild illness with influenza-like symptoms. However, in about 8% of the cases it progresses into a more severe disease with a high case fatality rate. Since there is such a high abortion rate among infected animals, a link between human miscarriage and RVFV has been suggested, but never proven.

We could in paper I for the first time show an association between acute RVFV infection and miscarriage in humans. We observed an increase in pregnant women arriving at the Port Sudan Hospital with fever of unknown origin, and several of the patients experienced miscarriage. When we analysed their blood samples for several viral diseases we found that many had an acute RVFV infection and of these, 54% experienced a miscarriage. The odds of having a miscarriage was 7 times higher for RVFV patients compared to the RVFV negative women of which only 12% miscarried. These results indicated that RVFV infection could be a contributing factor to miscarriage.

RVFV is an enveloped virus containing the viral glycoproteins n and c (Gn and Gc respectively), where Gn most likely is responsible for the initial cellular contact. The protein DC-SIGN on dendritic cells and the glycosaminoglycan heparan sulfate has been suggested as cellular receptors for RVFV, however other mechanisms are probably also involved in binding and entry. Charge is a driving force for molecular interaction and has been shown to be important for cellular attachment of several viruses, and in paper II we could show that when the charge around the cells was altered, the infection was affected. We also showed that Gn most likely has a positive charge at a physiological pH.

When we added negatively charged molecules to the viral particles before infection, we observed a decreased infection efficiency, which we also observed after removal of carbohydrate structures from the cell surface.

Our results suggested that the cellular interaction partner for initial attachment is a negatively charged carbohydrate. Further investigations into the mechanisms of RVFV cellular interactions has to be undertaken in order to understand, and ultimately prevent, infection and disease.

There is currently no vaccine approved for human use and no specific treatments for RVF, so there is a great need for developing safe effective drugs targeting this virus. We designed a whole-cell based high-throughput screen (HTS) assay which we used to screen libraries of small molecular compounds for anti-RVFV properties. After dose-response and toxicity analysis of the initial hits, we identified six safe and effective inhibitors of RVFV infection that with further testing could become drug candidates for treatment of RVF. This study demonstrated the application of HTS using a whole-cell virus replication reporter gene assay as an effective method to identify novel compounds with potential antiviral activity against RVFV.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2016. p. 58
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1843
Keywords
Rift Valley fever, Rift Valley fever virus, viral haemorrhagic fever, miscarriage, entry, charge, carbohydrates, high-throughput screening, antiviral, cell-based assay
National Category
Infectious Medicine Microbiology in the medical area
Research subject
Medical Virology
Identifiers
urn:nbn:se:umu:diva-126602 (URN)978-91-7601-558-2 (ISBN)
Public defence
2016-11-04, Hörsal D, Unod T9, 9 trappor, Norrlands universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2016-10-14 Created: 2016-10-12 Last updated: 2018-06-09Bibliographically approved
Connolly-Andersen, A.-M., Sundberg, E., Ahlm, C., Hultdin, J., Baudin, M., Larsson, J., . . . Nilsson, S. (2015). Increased Thrombopoiesis and Platelet Activation in Hantavirus-Infected Patients. Journal of Infectious Diseases, 212(7), 1061-1069
Open this publication in new window or tab >>Increased Thrombopoiesis and Platelet Activation in Hantavirus-Infected Patients
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2015 (English)In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 212, no 7, p. 1061-1069Article in journal (Refereed) Published
Abstract [en]

Background. Thrombocytopenia is a common finding during viral hemorrhagic fever, which includes hemorrhagic fever with renal syndrome (HFRS). The 2 main causes for thrombocytopenia are impaired thrombopoiesis and/or increased peripheral destruction of platelets. In addition, there is an increased intravascular coagulation risk during HFRS, which could be due to platelet activation. Methods. Thrombopoiesis was determined by quantification of platelet counts, thrombopoietin, immature platelet fraction, and mean platelet volume during HFRS. The in vivo platelet activation was determined by quantification of soluble P-selectin (sP-selectin) and glycoprotein VI (sGPVI). The function of circulating platelets was determined by ex vivo stimulation followed by flow cytometry analysis of platelet surface-bound fibrinogen and P-selectin exposure. Intravascular coagulation during disease was determined by scoring for disseminated intravascular coagulation (DIC) and recording thromboembolic complications. Results. The levels of thrombopoietin, immature platelet fraction, and mean platelet volume all indicate increased thrombopoiesis during HFRS. Circulating platelets had reduced ex vivo function during disease compared to follow-up. Most interestingly, we observed significantly increased in vivo platelet activation in HFRS patients with intravascular coagulation (DIC and thromboembolic complications) as shown by sP-selectin and sGPVI levels. Conclusions. HFRS patients have increased thrombopoiesis and platelet activation, which contributes to intravascular coagulation.

Place, publisher, year, edition, pages
Oxford University Press, 2015
Keywords
disseminated intravascular coagulation, hantavirus, hemorrhagic fever with renal syndrome, platelets, thrombosis, viral hemorrhagic fever
National Category
Public Health, Global Health, Social Medicine and Epidemiology Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-111492 (URN)10.1093/infdis/jiv161 (DOI)000363191300007 ()25762786 (PubMedID)
Available from: 2015-12-02 Created: 2015-11-13 Last updated: 2018-06-07Bibliographically approved
Bergstedt-Oskarsson, K., Brorstad, A., Baudin, M., Lindberg, A., Forssén, A., Evander, M. & Ahlm, C. (2011). Seroepidemiology, comorbidity and riskfactors for Puumula hantavirus in a highly endemic area of Sweden. In: : . Paper presented at 6th European Meeting on viral Zoonoses (EVZ). St Raphael, France, October 1-4, 2011.
Open this publication in new window or tab >>Seroepidemiology, comorbidity and riskfactors for Puumula hantavirus in a highly endemic area of Sweden
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2011 (English)Conference paper, Poster (with or without abstract) (Other academic)
National Category
Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-79859 (URN)
Conference
6th European Meeting on viral Zoonoses (EVZ). St Raphael, France, October 1-4, 2011
Available from: 2013-09-03 Created: 2013-09-03 Last updated: 2018-09-17
Baudin, M., Hossain, D. & Evander, M.Importance of charge interactions in Rift Valley fever virus attachment to host cells.
Open this publication in new window or tab >>Importance of charge interactions in Rift Valley fever virus attachment to host cells
(English)Manuscript (preprint) (Other academic)
Abstract [en]

The mosquito-borne Rift Valley fever virus (RVFV) cause disease in both humans and animals and can infect a large range of animals as well as humans. Many different cell types are infected both in vivo and in vitro. To enter a cell the virus needs to attach and enter, and this initial binding to the host cell surface could depend on both general mechanisms, and different specific receptors. Our aim was to characterize determinants for RVFV entry into its host cells.To examine RVFV attachment to host cells we based our experimental assay on RVF virus-like particles containing a reporter gene. The enveloped RVFV uses protruding glycoproteins (Gn and Gc) for attachment and entry and to investigate potential virus-cell surface interactions, the net surface charge of the glycoproteins was first calculated. The RVFV glycoprotein Gn had a predicted isoelectric point (pI) of 7.6 and a net positive charge of +6.9 at pH 7.0, suggesting a charge interaction between the Gn ectodomain and the negatively charged cell surface. RVFV Gc on the other hand, was highly negatively charged, -12.8 at neutral pH, most probably reflecting that Gc is not exposed until after receptor binding. To characterize the general conditions needed for RVFV attachment, cells or virus were treated with various compounds. Both sodium chloride and the negatively charged heparin inhibited RVF virus-like particle infection, strongly indicating that viral binding was charge-dependent. Treatment with sodium periodate pointed to a carbohydrate structure as a cellular interaction partner. Removal of sialic acid or heparan sulfate receptors on the cell surface by enzymatic treatment and blocking of the heparan sulfate receptor did not inhibit virus attachment.In conclusion, RVFV binding to host cells was charge dependent and the results point to a carbohydrate structure with negative charge as a potential attachment factor.

Keywords
Rift Valley fever, receptor, entry, charge, carbohydrates
National Category
Cell and Molecular Biology Microbiology in the medical area
Research subject
Molecular Medicine; Infectious Diseases
Identifiers
urn:nbn:se:umu:diva-126473 (URN)
Available from: 2016-10-07 Created: 2016-10-07 Last updated: 2018-06-09
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