<i>Plac8</i>-Dependent and Inducible NO Synthase-Dependent Mechanisms Clear<i>Chlamydia muridarum</i>Infections from the Genital Tract

Johnson, Raymond M.; Kerr, Micah S.; Slaven, James E.

doi:10.4049/jimmunol.1102764

Cited by 65 publications

(63 citation statements)

References 41 publications

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“…A comprehensive analysis of TCR Tg cell production of cytokines, chemokines, and cytotoxic effectors, as well as their helper function for antibody production by B cells is needed to fully delineate their protective, or pathological, mechanisms. Alternative effectors (83) and antibody (84, 85) have been shown to play a significant role in mediating chlamydial clearance. Additional analysis of the recall response is needed to determine the mechanisms whereby equivalent protection from reinfection occurred in Tcra −/− mice that had received 10 3 polyclonal T cells or 10 3 monoclonal TCR Tg T cells.…”

Section: Discussionmentioning

confidence: 99%

A Chlamydia-Specific TCR-Transgenic Mouse Demonstrates Th1 Polyfunctionality with Enhanced Effector Function

Poston

Girardi

et al. 2017

The Journal of Immunology

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Chlamydia is responsible for millions of new infections annually, and current efforts focus on understanding cellular immunity for targeted vaccine development. The Chlamydia-specific CD4 T cell response is characterized by the production of IFNγ, and polyfunctional Th1 responses are associated with enhanced protection. A major limitation in studying these responses is the paucity of tools available for detection, quantification, and characterization of polyfunctional, antigen-specific T cells. We addressed this problem by developing a TCR transgenic mouse with CD4 T cells that respond to a common antigen in Chlamydia muridarum and Chlamydia trachomatis. Using an adoptive transfer approach, we show that naïve transgenic CD4 T cells become activated, proliferate, migrate to the infected tissue, and acquire a polyfunctional Th1 phenotype in infected mice. Polyfunctional Tg Th1 effectors demonstrated enhanced IFNγ production compared to polyclonal cells, protected immune deficient mice against lethality, mediated bacterial clearance, and orchestrated an anamnestic response. Adoptive transfer of Chlamydia-specific CD4 TCR Tg T cells with polyfunctional capacity offers a powerful approach for analysis of protective effector and memory responses against chlamydial infection, and demonstrates that an effective monoclonal CD4 T cell response may successfully guide subunit vaccination strategies.

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Section: Discussionmentioning

confidence: 99%

A Chlamydia-Specific TCR-Transgenic Mouse Demonstrates Th1 Polyfunctionality with Enhanced Effector Function

Poston

Girardi

et al. 2017

The Journal of Immunology

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“…In other experiments, mice lacking iNOS were found to restrict chlamydial growth as efficiently as wild type mice (23,24). There is evidence that clearance of Chlamydia from the genital tract depends on IFN-g-induced iNOS and NO production and on iNOS-independent mechanisms (25). The variety of strategies used by Chlamydia to ensure its survival inside the host cell suggest that it also has evolved strategies to evade the host NO response.…”

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confidence: 99%

Chlamydia trachomatisInhibits Inducible NO Synthase in Human Mesenchymal Stem Cells by Stimulating Polyamine Synthesis

Abu-Lubad

Meyer

Al‐Zeer

2014

The Journal of Immunology

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Chlamydia trachomatis is considered the most common agent of sexually transmitted disease worldwide. As an obligate intracellular bacterium, it relies on the host for survival. Production of NO is an effective antimicrobial defense mechanism of the innate immune system. However, whether NO is able to arrest chlamydial growth remains unclear. Similarly, little is known about the mechanisms underlying subversion of cellular innate immunity by C. trachomatis. By analyzing protein and mRNA expression in infected human mesenchymal stem cells, combined with RNA interference and biochemical assays, we observed that infection with C. trachomatis led to downregulated expression of inducible NO synthase (iNOS) in human mesenchymal stem cells in vitro. Furthermore, infection upregulated the expression of the rate-limiting enzyme in the polyamine biosynthetic pathway, ornithine decarboxylase, diverting the iNOS substrate l-arginine toward the synthesis of polyamines. Inhibition of ornithine decarboxylase activity using small interfering RNA or the competitive inhibitor difluoromethylornithine restored iNOS protein expression and activity in infected cells and inhibited chlamydial growth. This inhibition was mediated through tyrosine nitration of chlamydial protein by peroxynitrite, an NO metabolite. Thus, Chlamydia evades innate immunity by inhibiting NO production through induction of the alternative polyamine pathway.

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“…No upregulated genes were shared among these phagocytes, and only two genes were down-modulated by all three subsets (39): Plac8 implicated in clearance of certain microorganisms (93), and Itgb7 encoding integrin-β7 that mediates homing to gut-associated lymphoid tissue. Integrin-β7 is notably the target for a current IBD therapy with humanized monoclonal antibodies Vedolizumab and Etrolizumab (94).…”

Section: Suppression Of Inflammation and Immune Response By Apoptoticmentioning

confidence: 99%

The many ways tissue phagocytes respond to dying cells

Blander

2017

Immunological Reviews

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Summary Apoptosis is an important component of normal tissue physiology, and the prompt removal of apoptotic cells is equally essential to avoid the undesirable consequences of their accumulation and disintegration. Professional phagocytes are highly specialized for engulfing apoptotic cells. The recent ability to track cells that have undergone apoptosis in situ has revealed a division of labor among the tissue resident phagocytes that sample them. Macrophages are uniquely programmed to process internalized apoptotic cell-derived fatty acids, cholesterol and nucleotides, as a reflection of their dominant role in clearing the bulk of apoptotic cells. Dendritic cells carry apoptotic cells to lymph nodes where they signal the emergence and expansion of highly suppressive regulatory CD4 T cells. A broad suppression of inflammation is executed through distinct phagocyte-specific mechanisms. A clever induction of negative regulatory nodes is notable in dendritic cells serving to simultaneously shut down multiple pathways of inflammation. Several of the genes and pathways modulated in phagocytes in response to apoptotic cells have been linked to chronic inflammatory and autoimmune diseases such as atherosclerosis, inflammatory bowel disease and systemic lupus erythematosus. Our collective understanding of old and new phagocyte functions after apoptotic cell phagocytosis demonstrates the enormity of ways to mediate immune suppression and enforce tissue homeostasis.

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Plac8-Dependent and Inducible NO Synthase-Dependent Mechanisms ClearChlamydia muridarumInfections from the Genital Tract

Cited by 65 publications

References 41 publications

A Chlamydia-Specific TCR-Transgenic Mouse Demonstrates Th1 Polyfunctionality with Enhanced Effector Function

A Chlamydia-Specific TCR-Transgenic Mouse Demonstrates Th1 Polyfunctionality with Enhanced Effector Function

Chlamydia trachomatisInhibits Inducible NO Synthase in Human Mesenchymal Stem Cells by Stimulating Polyamine Synthesis

The many ways tissue phagocytes respond to dying cells

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