Molekulare Charakterisierung eines neuen phagolysosomalen Rezeptors für RNA von Streptokokken
Zusammenfassung der Projektergebnisse
The central aim of our grant proposal was the identification of a phagolysosomal GBS-ssRNA-Receptor. This aim has been achieved in mouse cells by the identification of TLR13 as the cognate receptor for GBS ssRNA. A respective manuscript has been submitted to the Journal of Immunology (currently in revision). We furthermore contributed to the identification of TLR8 as a relatively promiscuous receptor for bacterial ssRNA in human monocytes. Furthermore, we were substantially involved in the identification of NLRP3 as part of a cytosolic receptor complex for GBS ssRNA. A second aim was the resolution of the dynamic composition of the phagosomal GBS receptor complex. With respect to dissection of the MyD88 dependent adapter, we have found that spatial association of TLR13 with MyD88 is critical for activation of the kinase IRAK1 and cytokine activation by GBS, and that these effects depend on the integrity of the death domain of MyD88. Moreover, we have identified TRIF is a novel and unique adapter with respect to its compensatory properties for loss of MyD88 in mediating GBS-induced reactive oxygen species (ROS). Finally, we aimed at better defining the role of iNOS / nitric oxide (NO) in TLR induced macrophage (Mφ) activation. We found NO to occur as early as 30 minutes after the first contact between GBS and Mφs, thereby altering the activation program. Moreover we found that NO is critically involved in TLR2-induced programming of Mφs.
Projektbezogene Publikationen (Auswahl)
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2012. Activation of the NLRP3 inflammasome by group B streptococci. J Immunol. 188:1953-60
Costa, A., Gupta, R., Signorino, G., Malara, A., Cardile, F., Biondo, C., Midiri, A., Galbo, R., Trieu-Cuot, P., Papasergi, S., Teti, G., Henneke, P., Mancuso, G., Golenbock, D., and C. Beninati
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2012. NO is a macrophage autonomous modifier of the cytokine response to streptococcal single-stranded RNA. J Immunol.188:774-80
Deshmukh, S.D., Müller, S., Hese, K., Rauc,h K.S., Wennekamp, J., Takeuchi, O., Akira, S., Golenbock, D.T., and P. Henneke
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2014. Interaction of Streptococcus agalactiae and Cellular Innate Immunity in Colonization and Disease. Front Immunol. 5:519
Landwehr-Kenzel, S. and P. Henneke
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2014. RNA and β-hemolysin of group B Streptococcus induce interleukin-1β (IL-1β) by activating NLRP3 inflammasomes in mouse macrophages. J Biol Chem. 289:13701-5
Gupta, R., Ghosh, S., Monks, B., DeOliveira, R.B., Tzeng, T.C., Kalantari, P., Nandy, A., Bhattacharjee, B., Chan, J., Ferreira, F., Rathinam, V., Sharma, S., Lien, E., Silverman, N., Fitzgerald, K., Firon, A., Trieu-Cuot, P., Henneke, P. and D.T. Golenbock DT
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2014. Synchronous recurrence of group B streptococcal late-onset sepsis in twins. Pediatrics. 133:e1388-91
Elling, R., Hufnagel, M., de Zoysa, A., Lander, F., Zumstein, K., Krueger, M. and P. Henneke
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2015. Human TLR8 senses UR/URR motifs in bacterial and mitochondrial RNA. EMBO Rep 16, 1656-1663
Krüger, A., Oldenburg, M., Chebrolu, C., Beißer, D., Kolter, J., Sigmund, A., Steinmann, J., Schäfer, S., Hochrein, H., Rahmann, S., Wagner, H., Henneke, P., Hornung, V., Buer, J., and C. Kirschning
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Preserved effector functions of human ORAI1- and STIM1-deficient neutrophils. J Allergy Clin Immunol May 2016, Volume 137, Issue 5, Pages 1587–1591.e7
Elling, R., Keller, B.,Weidinger, C., Haeffner , M., Deshmukh, S.D., Zee, I., Speckmann, C., Ehl, S., Schwarz, K., Feske, S., and P. Henneke
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Streptococci engage TLR13 on myeloid cells in a site-specific fashion. J Immunol February 12, 2016, 1501014
Kolter, J., Feuerstein, R., Spoeri, E., Gharun.,K., Elling, R., Trieu-Cuot, P., Goldmann, Waskow. C., Chen, J. , Kirschning, C.J., Deshmukh, S.D., and P. Henneke
