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The dynamics of T cells during persistent Staphylococcus aureus infection: from antigen-reactivity to in vivo anergy.

Ziegler C, Goldmann O, Hobeika E, Geffers R, Peters G, Medina E - EMBO Mol Med (2011)

Bottom Line: The mechanisms by which persistent infections are maintained involve both bacterial escape strategies and modulation of the host immune response.So far, the investigations in this area have focused on strategies used by S. aureus to persist within the host.The T cell hyporesponsiveness was reverted by co-stimulation with the phorbol ester PMA, an activator of protein kinase C, suggesting that a failure in the T cell receptor (TCR)-proximal signalling events underlie the hyporesponsive phenotype.

View Article: PubMed Central - PubMed

Affiliation: Infection Immunology Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.

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Adaptive immune response is required for restraining S. aureus proliferation during persistent infectionCourse of S. aureus infection in the kidneys of RAG2−/− mice after intravenous inoculation with S. aureus (black symbols). The course of S. aureus infection in the kidneys of immunocompetent C57BL/6 mice (white symbols) is included for comparison. Data points represent the mean ± SD from cohorts of five animals from three independent analyses. *p < 0.05 and ***p < 0.001.Histopathological appearance of H&E-stained kidney tissue of S. aureus-infected RAG2−/− mice at day 30 (ii) and 56 (iii and iv) of infection. Note the intense inflammatory infiltrate indicated by arrows (ii), the extended areas of tissue destruction (iii) and the presence of high numbers of staphylococci in (iv). Original magnifications, ×40 (i), (ii) and (iii) and ×100 (iv).Adoptive transfer of spleen cells from C57BL/6 donors improves the ability of RAG2−/− to control persistent S. aureus infection. RAG2−/− mice were reconstituted with splenocytes (app. 5 × 107 cells) from C57BL/6 mice and infected with S. aureus 48 h thereafter. Bacterial loads were determined in the kidneys of infected immunocompetent C57BL/6 (white bars), reconstituted mice RAG2−/− (black bars) and RAG2−/− recipient (hatched bars) at days 7 and 56 of infection. Bars represent the mean ± SD of 4–7 mice per group. One representative experiment of three independent experiments is presented. *p < 0.05.
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fig05: Adaptive immune response is required for restraining S. aureus proliferation during persistent infectionCourse of S. aureus infection in the kidneys of RAG2−/− mice after intravenous inoculation with S. aureus (black symbols). The course of S. aureus infection in the kidneys of immunocompetent C57BL/6 mice (white symbols) is included for comparison. Data points represent the mean ± SD from cohorts of five animals from three independent analyses. *p < 0.05 and ***p < 0.001.Histopathological appearance of H&E-stained kidney tissue of S. aureus-infected RAG2−/− mice at day 30 (ii) and 56 (iii and iv) of infection. Note the intense inflammatory infiltrate indicated by arrows (ii), the extended areas of tissue destruction (iii) and the presence of high numbers of staphylococci in (iv). Original magnifications, ×40 (i), (ii) and (iii) and ×100 (iv).Adoptive transfer of spleen cells from C57BL/6 donors improves the ability of RAG2−/− to control persistent S. aureus infection. RAG2−/− mice were reconstituted with splenocytes (app. 5 × 107 cells) from C57BL/6 mice and infected with S. aureus 48 h thereafter. Bacterial loads were determined in the kidneys of infected immunocompetent C57BL/6 (white bars), reconstituted mice RAG2−/− (black bars) and RAG2−/− recipient (hatched bars) at days 7 and 56 of infection. Bars represent the mean ± SD of 4–7 mice per group. One representative experiment of three independent experiments is presented. *p < 0.05.

Mentions: We next investigated the relevance of the adaptive immune response for controlling S. aureus during the persistent phase of the infection using B and T cells-deficient RAG2−/− mice. The results in Fig 5A show that RAG2−/− mice exhibited a higher, more sustained bacterial burden in the kidneys during the persistent phase than immunocompentent C57BL/6 animals. Similarly, RAG2/IL-2Rγ−/− mice, which are devoid of B, T and natural killer (NK) cells, were significantly less capable of containing S. aureus during the persistent phase of infection than C57BL/6 mice (Fig S4 of Supporting information). These observations demonstrate that B and/or T cells are responsible for the superior restriction of S. aureus proliferation observed in C57BL/6 mice. Nevertheless, RAG2−/− and RAG2/IL-2Rγ−/− mice were also able to exert certain levels of control over S. aureus proliferation in the kidneys during the persistent phase that was mediated by innate immune mechanisms since depletion of neutrophils or macrophages resulted in enhanced bacterial multiplication in this organ (Fig S5 of Supporting information).


The dynamics of T cells during persistent Staphylococcus aureus infection: from antigen-reactivity to in vivo anergy.

Ziegler C, Goldmann O, Hobeika E, Geffers R, Peters G, Medina E - EMBO Mol Med (2011)

Adaptive immune response is required for restraining S. aureus proliferation during persistent infectionCourse of S. aureus infection in the kidneys of RAG2−/− mice after intravenous inoculation with S. aureus (black symbols). The course of S. aureus infection in the kidneys of immunocompetent C57BL/6 mice (white symbols) is included for comparison. Data points represent the mean ± SD from cohorts of five animals from three independent analyses. *p < 0.05 and ***p < 0.001.Histopathological appearance of H&E-stained kidney tissue of S. aureus-infected RAG2−/− mice at day 30 (ii) and 56 (iii and iv) of infection. Note the intense inflammatory infiltrate indicated by arrows (ii), the extended areas of tissue destruction (iii) and the presence of high numbers of staphylococci in (iv). Original magnifications, ×40 (i), (ii) and (iii) and ×100 (iv).Adoptive transfer of spleen cells from C57BL/6 donors improves the ability of RAG2−/− to control persistent S. aureus infection. RAG2−/− mice were reconstituted with splenocytes (app. 5 × 107 cells) from C57BL/6 mice and infected with S. aureus 48 h thereafter. Bacterial loads were determined in the kidneys of infected immunocompetent C57BL/6 (white bars), reconstituted mice RAG2−/− (black bars) and RAG2−/− recipient (hatched bars) at days 7 and 56 of infection. Bars represent the mean ± SD of 4–7 mice per group. One representative experiment of three independent experiments is presented. *p < 0.05.
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fig05: Adaptive immune response is required for restraining S. aureus proliferation during persistent infectionCourse of S. aureus infection in the kidneys of RAG2−/− mice after intravenous inoculation with S. aureus (black symbols). The course of S. aureus infection in the kidneys of immunocompetent C57BL/6 mice (white symbols) is included for comparison. Data points represent the mean ± SD from cohorts of five animals from three independent analyses. *p < 0.05 and ***p < 0.001.Histopathological appearance of H&E-stained kidney tissue of S. aureus-infected RAG2−/− mice at day 30 (ii) and 56 (iii and iv) of infection. Note the intense inflammatory infiltrate indicated by arrows (ii), the extended areas of tissue destruction (iii) and the presence of high numbers of staphylococci in (iv). Original magnifications, ×40 (i), (ii) and (iii) and ×100 (iv).Adoptive transfer of spleen cells from C57BL/6 donors improves the ability of RAG2−/− to control persistent S. aureus infection. RAG2−/− mice were reconstituted with splenocytes (app. 5 × 107 cells) from C57BL/6 mice and infected with S. aureus 48 h thereafter. Bacterial loads were determined in the kidneys of infected immunocompetent C57BL/6 (white bars), reconstituted mice RAG2−/− (black bars) and RAG2−/− recipient (hatched bars) at days 7 and 56 of infection. Bars represent the mean ± SD of 4–7 mice per group. One representative experiment of three independent experiments is presented. *p < 0.05.
Mentions: We next investigated the relevance of the adaptive immune response for controlling S. aureus during the persistent phase of the infection using B and T cells-deficient RAG2−/− mice. The results in Fig 5A show that RAG2−/− mice exhibited a higher, more sustained bacterial burden in the kidneys during the persistent phase than immunocompentent C57BL/6 animals. Similarly, RAG2/IL-2Rγ−/− mice, which are devoid of B, T and natural killer (NK) cells, were significantly less capable of containing S. aureus during the persistent phase of infection than C57BL/6 mice (Fig S4 of Supporting information). These observations demonstrate that B and/or T cells are responsible for the superior restriction of S. aureus proliferation observed in C57BL/6 mice. Nevertheless, RAG2−/− and RAG2/IL-2Rγ−/− mice were also able to exert certain levels of control over S. aureus proliferation in the kidneys during the persistent phase that was mediated by innate immune mechanisms since depletion of neutrophils or macrophages resulted in enhanced bacterial multiplication in this organ (Fig S5 of Supporting information).

Bottom Line: The mechanisms by which persistent infections are maintained involve both bacterial escape strategies and modulation of the host immune response.So far, the investigations in this area have focused on strategies used by S. aureus to persist within the host.The T cell hyporesponsiveness was reverted by co-stimulation with the phorbol ester PMA, an activator of protein kinase C, suggesting that a failure in the T cell receptor (TCR)-proximal signalling events underlie the hyporesponsive phenotype.

View Article: PubMed Central - PubMed

Affiliation: Infection Immunology Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.

Show MeSH
Related in: MedlinePlus