Interferons in immunity to chlamydia pneumoniae
Author: Rothfuchs, Antonio Carlos Gigliotti (Tony)
Date: 2004-03-04
Location: Hörsalen, Theorells väg 1, Mikrobiologiskt och Tumörbiologiskt Centrum (MTC), Karolinska Institutet
Time: 9.00
Department: Mikrobiologiskt och Tumörbiologiskt Centrum (MTC) / Microbiology and Tumor Biology Center (MTC)
Abstract
The cytokine IFN-gamma is the architect behind an amazing immunological
program of host resistance to intracellular bacterial and protozoan
infections. IFN-gamma activates macrophages, making them into
inhospitable habitats for parasites attempting to grow inside them. The
family of obligate intracellular Gram-negative bacteria Chlamydia is an
example of such pathogens. The overall aim of this thesis was to unravel
resistance to infection with the human respiratory pathogen C. pneumoniae.
Specific focus was placed on innate immune responses to C. pneumoniae and
the regulation and role of IFN-gamma in the outcome of infection. An
experimental mouse model of lung infection and a macrophage model of in
vitro infection were used for this purpose.
A protective role for infection-induced IFN-gamma in restricting C. pneumoniae growth in vivo was observed, though IFN-gamma was not required for resolution of infection. IL-12 and/or IL-23 was a necessary but not an absolute requirement for expression of IFN-gamma. IFN-gamma-dependent protection was in part mediated by iNOS expression. TNF-alpha, known to be synergistic with IFN-gamma, was not required for restricting Chlamydial growth. Innate immune cells in the lung constituted an important source of IFN-gamma and were essential for restricting C. pneumoniae growth and for containment of bacteria in the lungs. However, NK cells were not implicated in such protective IFN-gamma release. On the other hand, lung macrophages isolated from C.pneumoniae-infected mice expressed IFN-gamma. Moreover, bone marrow-derived macrophages (BMMphi) conferred upon transfer to RAG-1-/-/IFN-gamma-/-mice, enhanced resistance to C. pneumoniae infection via their ability to release IFN-gamma. Innate IFN-gamma was however not required for protection conferred by CD4+ or CD8+ T cells. Innate and T cell-derived IFN-gamma are also non-redundant (complementary) in protesting mice against C. pneumoniae.
C. pneumoniae-infected BMMphi also expressed IFN-gamma in vitro. Such IFN-gamma release was IL-12independent but required instead IFN-alpha/beta and restricted Chlamydial growth. IFN-alpha/beta, and not IFNgamma, was required for iNOS-mediated protection in BMMphi. The molecular details of BMMphi-derived IFNgamma expression revealed a TLR4-MyD88-dependent pathway of IFN-alpha and IFN-gamma induction. Also surprising was the presente of a TLR4- and MyD88-independent, infection-induced NF-kappaB activation and proinflammatory cytokine expression. Phosphorylation of STAT1 during infection was IFN-alpha/beta-dependent, and necessary for increased IFN-gamma expression and for restricting Chlamydial growth. Expression of IFN-gamma and restriction of C. pneumoniae growth also required NF-kappaB activation, but such activation was independent of IFN-alpha/beta, revealing a dual pathway of C.pneumoniae-induced IFN-gamma expression in BMMphi: a TLR4-MyD88-IFNalpha/beta-STAT1 -dependent pathway, and a TLR4-independent pathway leading to NF-kappaB activation.
IFN-alpha/beta was also protective in vivo by cooperating with IFN-gamma for activation of STAT1, which was required for restricting Chlamydial growth. Different from the in vitro situation, IFN-gamma was sufficient on its own for this effect and did not require IFN-alpha/beta for its expression.
In summary, IFN-gamma is important for restricting C. pneumoniae growth. Innate IFN-gamma is protective both in lungs and in BMMphi. IFN-alpha/beta are pivotal in regulating protective responses in BMMphi, including IFNgamma release, but are dispensable for IFN-gamma expression and protection in vivo. This discrepancy may be a qualitative feature in C. pneumoniae pattern recognition by different cell types; lung cells convey the generation of protective, IL-12-driven responses, while IFN-alpha/beta-driven protection in BMMphi is essential.
A protective role for infection-induced IFN-gamma in restricting C. pneumoniae growth in vivo was observed, though IFN-gamma was not required for resolution of infection. IL-12 and/or IL-23 was a necessary but not an absolute requirement for expression of IFN-gamma. IFN-gamma-dependent protection was in part mediated by iNOS expression. TNF-alpha, known to be synergistic with IFN-gamma, was not required for restricting Chlamydial growth. Innate immune cells in the lung constituted an important source of IFN-gamma and were essential for restricting C. pneumoniae growth and for containment of bacteria in the lungs. However, NK cells were not implicated in such protective IFN-gamma release. On the other hand, lung macrophages isolated from C.pneumoniae-infected mice expressed IFN-gamma. Moreover, bone marrow-derived macrophages (BMMphi) conferred upon transfer to RAG-1-/-/IFN-gamma-/-mice, enhanced resistance to C. pneumoniae infection via their ability to release IFN-gamma. Innate IFN-gamma was however not required for protection conferred by CD4+ or CD8+ T cells. Innate and T cell-derived IFN-gamma are also non-redundant (complementary) in protesting mice against C. pneumoniae.
C. pneumoniae-infected BMMphi also expressed IFN-gamma in vitro. Such IFN-gamma release was IL-12independent but required instead IFN-alpha/beta and restricted Chlamydial growth. IFN-alpha/beta, and not IFNgamma, was required for iNOS-mediated protection in BMMphi. The molecular details of BMMphi-derived IFNgamma expression revealed a TLR4-MyD88-dependent pathway of IFN-alpha and IFN-gamma induction. Also surprising was the presente of a TLR4- and MyD88-independent, infection-induced NF-kappaB activation and proinflammatory cytokine expression. Phosphorylation of STAT1 during infection was IFN-alpha/beta-dependent, and necessary for increased IFN-gamma expression and for restricting Chlamydial growth. Expression of IFN-gamma and restriction of C. pneumoniae growth also required NF-kappaB activation, but such activation was independent of IFN-alpha/beta, revealing a dual pathway of C.pneumoniae-induced IFN-gamma expression in BMMphi: a TLR4-MyD88-IFNalpha/beta-STAT1 -dependent pathway, and a TLR4-independent pathway leading to NF-kappaB activation.
IFN-alpha/beta was also protective in vivo by cooperating with IFN-gamma for activation of STAT1, which was required for restricting Chlamydial growth. Different from the in vitro situation, IFN-gamma was sufficient on its own for this effect and did not require IFN-alpha/beta for its expression.
In summary, IFN-gamma is important for restricting C. pneumoniae growth. Innate IFN-gamma is protective both in lungs and in BMMphi. IFN-alpha/beta are pivotal in regulating protective responses in BMMphi, including IFNgamma release, but are dispensable for IFN-gamma expression and protection in vivo. This discrepancy may be a qualitative feature in C. pneumoniae pattern recognition by different cell types; lung cells convey the generation of protective, IL-12-driven responses, while IFN-alpha/beta-driven protection in BMMphi is essential.
List of papers:
I. Rottenberg ME, Gigliotti Rothfuchs AC, Gigliotti D, Svanholm C, Bandholtz L, Wigzell H (1999). "Role of innate and adaptive immunity in the outcome of primary infection with Chlamydia pneumoniae, as analyzed in genetically modified mice. " J Immunol 162(5): 2829-36
Pubmed
View record in Web of Science®
II. Rottenberg ME, Gigliotti Rothfuchs A, Gigliotti D, Ceausu M, Une C, Levitsky V, Wigzell H (2000). "Regulation and role of IFN-gamma in the innate resistance to infection with Chlamydia pneumoniae. " J Immunol 164(9): 4812-8
Pubmed
View record in Web of Science®
III. Gigliotti Rothfuchs A, Kreuger MR, Wigzell H, Rottenberg ME (2004). "Macrophages, CD4(+) or CD8(+) Cells Are Each Sufficient for Protection against Chlamydia pneumoniae Infection through their Ability to Secrete IFN-gamma. " J Immunol 172(4): 2407-15
Pubmed
View record in Web of Science®
IV. Rothfuchs AG, Gigliotti D, Palmblad K, Andersson U, Wigzell H, Rottenberg ME (1970). "IFN-alpha beta-dependent, IFN-gamma secretion by bone marrow-derived macrophages controls an intracellular bacterial infection. " J Immunol 167(11): 6453-61
Pubmed
View record in Web of Science®
V. Gigliotti Rothfuchs A, Trumstedt C, Wigzell H, Rottenberg ME (2004). "Intracellular bacterial infection-induced IFN-gamma is critically but not solely dependent on TLR-MyD88-IFN-alpha/beta-STAT1 signaling." (Submitted)
VI. Gigliotti Rothfuchs A, Trumstedt C, Wigzell H, Rottenberg ME (2004). "Protective role of IFN-alpha/beta against murine infection with Chlamydia pneumoniae." (Manuscript)
I. Rottenberg ME, Gigliotti Rothfuchs AC, Gigliotti D, Svanholm C, Bandholtz L, Wigzell H (1999). "Role of innate and adaptive immunity in the outcome of primary infection with Chlamydia pneumoniae, as analyzed in genetically modified mice. " J Immunol 162(5): 2829-36
Pubmed
View record in Web of Science®
II. Rottenberg ME, Gigliotti Rothfuchs A, Gigliotti D, Ceausu M, Une C, Levitsky V, Wigzell H (2000). "Regulation and role of IFN-gamma in the innate resistance to infection with Chlamydia pneumoniae. " J Immunol 164(9): 4812-8
Pubmed
View record in Web of Science®
III. Gigliotti Rothfuchs A, Kreuger MR, Wigzell H, Rottenberg ME (2004). "Macrophages, CD4(+) or CD8(+) Cells Are Each Sufficient for Protection against Chlamydia pneumoniae Infection through their Ability to Secrete IFN-gamma. " J Immunol 172(4): 2407-15
Pubmed
View record in Web of Science®
IV. Rothfuchs AG, Gigliotti D, Palmblad K, Andersson U, Wigzell H, Rottenberg ME (1970). "IFN-alpha beta-dependent, IFN-gamma secretion by bone marrow-derived macrophages controls an intracellular bacterial infection. " J Immunol 167(11): 6453-61
Pubmed
View record in Web of Science®
V. Gigliotti Rothfuchs A, Trumstedt C, Wigzell H, Rottenberg ME (2004). "Intracellular bacterial infection-induced IFN-gamma is critically but not solely dependent on TLR-MyD88-IFN-alpha/beta-STAT1 signaling." (Submitted)
VI. Gigliotti Rothfuchs A, Trumstedt C, Wigzell H, Rottenberg ME (2004). "Protective role of IFN-alpha/beta against murine infection with Chlamydia pneumoniae." (Manuscript)
Issue date: 2004-02-12
Rights:
Publication year: 2004
ISBN: 91-7349-830-0
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