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Mucosal Immunity in Mycobacterial infections
Stockholm University, Faculty of Science, The Wenner-Gren Institute .
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

More than a century after the identification of the tubercle bacillus and the first attempts at vaccination, tuberculosis (TB) still remains one of the world’s most serious infectious diseases. TB, caused by the bacterium Mycobacterium tuberculosis, is typically a disease of the lung, which serves both as port of entry and as the major site of disease manifestation. The currently used vaccine, BCG, is administered parenterally and induces a systemic immune response. However, it fails to protect against pulmonary TB, thereby raising the question whether vaccination targeting the mucosal immunity in the lungs could be favourable.

The respiratory mucosal surfaces represent the first line of defence against a multitude of pathogens. Secretory IgA, in mucosal secretions has an important function by blocking entrance of pathogenic organisms and preventing infections. Additionally, a role for IgA in modulation of immune responses is currently being revealed. In this work, we investigated the relevance of mucosal IgA in protection against mycobacterial infections using mice deficient for IgA and the polymeric Ig receptor, the receptor responsible for mucosal secretions of IgA. Gene-targeted mice were more susceptible to mycobacterial infections in the respiratory tract and displayed reduced production of proinflammatory, and protective, factors such as IFN-γ and TNF-α in the lungs. The mechanisms explaining the defective proinflammatory responses in the lungs of deficient mice might involve impaired signalling through Fcα receptors, or homologous receptors, which could lead to inadequate activation of pulmonary macrophages. This could subsequently result in suboptimal induction and production of cytokines and chemokines important for attraction and migration of immune cells to the site of infection.

Induction of optimal adaptive immune responses to combat mycobacterial infections requires prompt innate immune activation. Toll-like receptors (TLRs) are vital components of the innate branch of the immune system, ensuring early recognition of invading pathogens. Using TLR-deficient mice we demonstrated an important role for TLR2, and partly TLR4, in protection against mycobacterial infection in the respiratory tract. TLR2-deficient mice failed to induce proper proinflammatory responses at the site of infection, and macrophages derived from the knockout mice displayed impaired anti-mycobacterial activity.

Experimental evidence has concluded that the immune response upon an infection can influence the outcome of succeeding infections with other pathogens. Concurrent infections might additionally interfere with responses to vaccinations and have deleterious effects. We developed an in vitro model to study the effect of a malaria infection on a successive M. tuberculosis infection. Our results demonstrate that a malaria blood-stage infection enhances the innate immune response to a subsequent M. tuberculosis infection with a Th1 prone profile. Reduced infectivity of malaria-exposed dendritic cells implies that a malaria infection could impose relative resistance to ensuing M. tuberculosis infection. However, a prolonged Th1 response may interfere with malaria parasite control.

The outcome of this work emphasizes the importance of generating effective immune responses in the local mucosal environment upon respiratory mycobacterial infections. It furthermore puts new light on the immunological interaction between parasites and mycobacteria, which could have implications for future vaccine research.

Place, publisher, year, edition, pages
Stockholm: Wenner-Grens institut för experimentell biologi , 2007. , 80 p.
National Category
Immunology
Research subject
Immunology
Identifiers
URN: urn:nbn:se:su:diva-6782ISBN: 91-7155-388-6 (print)OAI: oai:DiVA.org:su-6782DiVA: diva2:197035
Public defence
2007-06-01, Nordenskiöldsalen, Geovetenskapens hus, Svante Arrhenius väg 8 C, Stockholm, 10:00
Opponent
Supervisors
Available from: 2007-05-11 Created: 2007-05-09 Last updated: 2011-05-30Bibliographically approved
List of papers
1. Role of IgA in the defense against respiratory infections: IgA deficient mice exhibited increased susceptibility to intranasal infection with Mycobacterium bovis BCG
Open this publication in new window or tab >>Role of IgA in the defense against respiratory infections: IgA deficient mice exhibited increased susceptibility to intranasal infection with Mycobacterium bovis BCG
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2005 (English)In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 23, no 20, 2565-2572 p.Article in journal (Refereed) Published
Abstract [en]

IgA is the predominant Ig isotype in mucosal tissue and is believed to be involved in defense against viral and bacterial infections at these sites. Here, we examined the role of IgA in the protection against intranasal (i.n.) infection with Mycobacterium bovis Bacillus Calmette-Guérin (BCG). IgA deficient (IgA−/−) mice and wild type non-targeted littermate (IgA+/+) mice were immunized by i.n. route with the mycobacterium surface antigen PstS-1 formulated with cholera toxin (CT). Our data showed that IgA−/− mice were more susceptible to BCG infection compared to IgA+/+ mice, as revealed by the higher bacterial loads in the lungs and bronchoalveolar lavage (BAL). Analysis of the Ig levels and the antibody responses to PstS-1 showed that IgA−/− mice had no detectable IgA either in the saliva or in the BAL. However, these mice displayed higher levels of total and specific IgM than IgA+/+ mice in both mucosal fluids. More importantly, analysis of the cytokine responses revealed a reduction in the IFN-γ and TNF-α production in the lungs of IgA−/− compared to IgA+/+ mice. Altogether, our results suggest that IgA may play a role in protection against mycobacterial infections in the respiratory tract by blocking the pathogen entrance and/or by modulating the pro-inflammatory responses.

Keyword
Mucosal immunity, IgA, BCG
National Category
Natural Sciences
Identifiers
urn:nbn:se:su:diva-23925 (URN)10.1016/j.vaccine.2004.11.032 (DOI)
Available from: 2005-06-23 Created: 2005-06-23 Last updated: 2011-05-30Bibliographically approved
2. Polymeric IgR knockout mice are more susceptible to mycobacterial infections in the respiratory tract than wild-type mice
Open this publication in new window or tab >>Polymeric IgR knockout mice are more susceptible to mycobacterial infections in the respiratory tract than wild-type mice
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2006 In: International Immunology, ISSN 0953-8178, Vol. 18, no 5, 807-816 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-24214 (URN)
Note
Part of urn:nbn:se:su:diva-6782Available from: 2007-05-11 Created: 2007-05-09Bibliographically approved
3. Determinant role for Toll-like receptor signalling in acute mycobacterial infection in the respiratory tract
Open this publication in new window or tab >>Determinant role for Toll-like receptor signalling in acute mycobacterial infection in the respiratory tract
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2006 In: Microbes and Infection, ISSN 1286-4579, Vol. 8, no 7, 1790-1800 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-24215 (URN)
Note
Part of urn:nbn:se:su:diva-6782Available from: 2007-05-11 Created: 2007-05-09Bibliographically approved
4. The effect of malaria parasite-derived materials on dendritic cell susceptibility and response to subsequent Mycobacterium tuberculosis infection
Open this publication in new window or tab >>The effect of malaria parasite-derived materials on dendritic cell susceptibility and response to subsequent Mycobacterium tuberculosis infection
Manuscript (Other academic)
Identifiers
urn:nbn:se:su:diva-24216 (URN)
Note
Part of urn:nbn:se:su:diva-6782Available from: 2007-05-11 Created: 2007-05-09 Last updated: 2010-01-13Bibliographically approved

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