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Transcript
Differential Immune Modulatory Activity of P. Aeruginosa Quorumsensing Signal Molecules Presented by Inderdeep S. Atwal Background Information • Pseudomonas aeruginosa is a gram- negative bacteria • Capable of causing disease in plants, animals and immunocompromised humans • Has the ability to colonize a wide variety of tissues in the body and is capable of causing extensive tissue damage • This ability to cause damage is a direct result of its quorum sensing P. Aeruginosa Quorum-sensing signal molecules QSSM and immune response • Early immunological experiments showed that 3-oxo-C12-HSL were shown to suppress interleukin-12(IL-12) and tumor necrosis factor alpha(TNF-ά) secretion by LPS stimulated macrophages and suppresses T-cell proliferation. • In contrast T-helper 2 (Th2)-dependent antibody secretion was enhanced by 3oxo-C12-HSL at low micromolar concentrations. Subverting the Immune System • The observations led to a hypothesis that the QSSM is a subversive system • The QSSM could steer T-cell responses away from a host-protective T-helper 1(TH1) phenotype, to possibly promote pathogen survival Experimental Basis • The goal of this study was to study PQS, a chemically distinct QSSM from 3-oxo-C12HSL • They were especially looking to see if this QSSM was capable of modulating immune responses in a similar manner Results-PBMC proliferation and IL-2 secretion following stimulation with ConA • Intially screened PQS, 3-oxo-C12-HSL, and 3-oxo• • • C6-HSL in a mitogen-driven T-cell proliferation. C4-HSL and C6-HSL were shown to have no activity in a previous study They found that PQS and 3-oxo-C12-HSL inhibited cell proliferation in a dose dependent manner when peripheral blood cells isolated and stimulated with ConA PQS was shown to be the more potent antiproliferative molecule in the assay Continued • Concurrent MTS assay showed that the immune-suppressive window for 3-oxoC12-HSL and PQS was evident in the absence of cytotoxicity Effect of P. Aeruginosa QSSM on hPBMC proliferation viability and IL-2 secretion Effect of P. Aeruginosa QSSM on hPBMC proliferation viability-stimulated by ConA The levels of IL-2 released from ConA-stimulated hPBMC in the prescence of QSSM revealed similar patterns to those for cellular proliferation. PBMC proliferation and IL-2 secretion following stimulation with anti-CD3/anti-CD28 antibodies • Specific stimulation of T cells by the engagement of the T cell receptor CD3 complex with specific antibodies requires a further antibody coligation of CD28, a coreceptor of T cell activation • The CD28 pathway provides intracellular coactivation signals which are required for the production of cytokines, such as IL-2 and gamma interferon to drive Tcell proliferation. • Using this fact, the group further studyed 3-oxo-C12-HSL and PQS • Both QSSMs consistently inhibited T-cell proliferation when the cells were cross-linked with anti-CD3 and antiCD28 antibodies Effect of P. Aeruginosa QSSM on hPBMC proliferation and IL-2 secretion following stimulation by anti-CD3/anti-CD28 antibodies PQS and 3oxo-C12HSL inhibited cell proliferation induced by antiCD3/antiCD28 antibodies. Effect of P. Aeruginosa QSSM on hPBMC proliferation and IL-2 secretion following stimulation by anti-CD3/anti-CD28 antibodies Only 3oxo-C12HSL inhibited IL-2 release. PQS actually showed a slight induction of IL-2 release. LPS-stimulated TNF-ά secretion from hPBMC • LPS driven TNF-ά secretion assay, 3-oxoC12-HSL at 50 µM and above suppressed secretion • PQS significantly promoted secretion above 25 µM Effect of P. Aeruginosa QSSM on hPBMC TNF-ά , stimulated by E. Coli LPS of hPBMC. Conclusions • The experiment showed that QSSM, 3-oxo-C12- • • HSL and PQS are able to regulate several cascades on mammalian immune response in vitro. PQS and 3-oxo-C12-HSL significantly reduced the ability of lymphocytes to respond to ConA. The antiproliferative activity of PQS occurred without any effect on cell viability, while 3-oxoC12-HSL suppressed proliferation before cell viability.—this effect is what they term as immune-suppressive window Conclusion Continued • Attempting to study specifically the two compounds • • • • affects on T-cell stimulation, a more specific T cell assay was used with anti-CD3 antibody and anti-CD28 antibody to drive T-cell proliferation PQS was more potent than 3-oxo-C12-HSL in suppressing T-cell proliferation With respect to IL-2 production in response to T cell activation, 3-oxo-C12-HSL inhibited the release of this cytokine when T cells were stimulated Suggesting that 3-oxo-C12-HSL is acting upstream of IL2 secretion while PQS is preventing proliferation by acting downstream of IL-2 TNF-ά secretion was assessed in assays where LPS was used to drive TNF-ά secretion from hPBMC— showing that 3-oxo.. Plays a suppresive role and PQS playing a stimulatory What comes of this research? • The production of a dual wave of immune modulants in compromised patients, in combination with other immunologically confounding virulence factors, may confer an advantage for the bacteria • Further studies need to be made to elaborate the actual mechanisms behind the subversion system.