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A microarray analysis of the host response to infection with Francisella tularensis
Umeå universitet, Medicinsk fakultet, Klinisk mikrobiologi.
2006 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Francisella tularensis is a gram-negative bacterium that is the cause of the serious and sometimes fatal disease, tularemia, in a wide range of animal species and in humans. The response of cells of the mouse macrophage cell line J774 to infection with Francisella tularensis LVS was analyzed by means of a DNA microarray. It was observed that the infection conferred an oxidative stress upon the target cells and many of the host defense mechanisms appeared to be intended to counteract this stress. The infection was characterized by a very modest inflammatory response.

Tularemia caused by inhalation of F. tularensis subspecies tularensis is one of the most aggressive infectious diseases known. We used the mouse model to examine in detail the host immune response in the lung. After an aerosol challenge all mice developed clinical signs of severe disease, showed weight loss by day four of infection, and died the next day. Gene transcriptional changes in the mouse lung samples were examined on day one, two, and four of infection. Genes preferentially involved in host immune responses were activated extensively on day four but on day one and two, only marginally or not at all. Several genes upregulated on day four are known to depend on IFN-gamma or TNF-alpha for their regulation. In keeping with this finding, TNF-alpha and IFN-gamma levels were found to be increased significantly in bronchoalveolar lavage on day four.

We undertook an analysis of the transcriptional response in peripheral blood during the course of ulceroglandular tularemia by use of Affymetrix microarrays. Samples were obtained from seven individuals at five occasions during two weeks after the first hospital visit and convalescent samples three months later. In total 265 genes were differentially expressed. The most prominent changes were noted in samples drawn on days 2-3 and a considerable proportion of the upregulated genes appeared to represent an IFN-gamma-induced response and also a pro-apoptotic response. Genes involved in the generation of innate and acquired immune responses were found to be downregulated, presumably a pathogen-induced event. A logistic regression analysis revealed that seven genes were good predictors of the early phase of tularemia.

Recently, a large number of methods for the analysis of microarray data have been proposed but there are few comparisons of their relative performances. We undertook a study to evaluate established and novel methods for filtration, background adjustment, scanning, and censoring. For all analyses, the sensitivities at low false positive rates were observed together with a bias measurement. In general, there was a trade off between the analyses ability to identify differentially expressed genes and their ability to obtain unbiased estimators of the desired ratios. A commonly used standard analysis using background adjustment performed poorly. Interestingly, the constrained model combining data from several scans resulted in high sensitivities. For experiments where only low false discovery rates are acceptable, the use of the constrained model or the novel partial filtration method are likely to perform better than some commonly used standard analyses.

Ort, förlag, år, upplaga, sidor
Umeå: Klinisk mikrobiologi , 2006. , s. 59
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1029
Nyckelord [en]
Francisella tularensis, tularemia, host response, gene expression, microarray
Nationell ämneskategori
Mikrobiologi inom det medicinska området
Identifikatorer
URN: urn:nbn:se:umu:diva-792ISBN: 91-7264-081-2 (tryckt)OAI: oai:DiVA.org:umu-792DiVA, id: diva2:144552
Disputation
2006-05-31, E04, 6E, Norrlands Universitetssjukhus, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2006-05-10 Skapad: 2006-05-10 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
Delarbeten
1. Evaluation of microarray data normalization procedures using spike-in experiments
Öppna denna publikation i ny flik eller fönster >>Evaluation of microarray data normalization procedures using spike-in experiments
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(Engelska)Manuskript (Övrig (populärvetenskap, debatt, mm))
Identifikatorer
urn:nbn:se:umu:diva-5147 (URN)
Tillgänglig från: 2006-05-10 Skapad: 2006-05-10 Senast uppdaterad: 2010-01-14Bibliografiskt granskad
2. A microarray analysis of the host response to intracellular infection with Francisella tularensis LVS
Öppna denna publikation i ny flik eller fönster >>A microarray analysis of the host response to intracellular infection with Francisella tularensis LVS
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(Engelska)Manuskript (Övrig (populärvetenskap, debatt, mm))
Identifikatorer
urn:nbn:se:umu:diva-5148 (URN)
Tillgänglig från: 2006-05-10 Skapad: 2006-05-10 Senast uppdaterad: 2010-01-14Bibliografiskt granskad
3. Transcriptional profiling of host responses in mouse lungs following aerosol infection with type A Francisella tularensis
Öppna denna publikation i ny flik eller fönster >>Transcriptional profiling of host responses in mouse lungs following aerosol infection with type A Francisella tularensis
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2006 (Engelska)Ingår i: Journal of Medical Microbiology, ISSN 0022-2615, E-ISSN 1473-5644, Vol. 55, nr 3, s. 263-271Artikel i tidskrift (Refereegranskat) Published
Identifikatorer
urn:nbn:se:umu:diva-5149 (URN)10.1099/jmm.0.46313-0 (DOI)16476789 (PubMedID)
Tillgänglig från: 2006-05-10 Skapad: 2006-05-10 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
4. Transcriptional profiling of the peripheral blood response during tularemia.
Öppna denna publikation i ny flik eller fönster >>Transcriptional profiling of the peripheral blood response during tularemia.
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2006 (Engelska)Ingår i: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 7, nr 6, s. 503-513Artikel i tidskrift (Refereegranskat) Published
Nationell ämneskategori
Mikrobiologi inom det medicinska området Mikrobiologi inom det medicinska området
Identifikatorer
urn:nbn:se:umu:diva-7831 (URN)10.1038/sj.gene.6364321 (DOI)16826236 (PubMedID)
Tillgänglig från: 2008-07-10 Skapad: 2008-07-10 Senast uppdaterad: 2018-06-09

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