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Both TRIF- and MyD88-dependent signaling contribute to host defense against pulmonary Klebsiella infection.
J Immunol 2009; 183(10):6629-38JI

Abstract

Klebsiella pneumoniae causes extensive lung damage. TLR signaling involves adaptors TRIF and MyD88. However, the relative contribution of TRIF and MyD88 signaling in host defense against pulmonary K. pneumoniae infection has not been elucidated. Therefore, we investigated the role of TRIF and MyD88 in K. pneumoniae pneumonia. TRIF(-/-) mice infected with K. pneumoniae showed impaired survival and reduced bacterial clearance, neutrophil influx, histopathologic evidence of inflammation, and TNF-alpha, IL-6, KC, MIP-2, but not LIX, expression in the lungs. In addition, K. pneumoniae-induced late NF-kappaB activation and phosphorylation of MAPKs was attenuated in the lungs of TRIF(-/-) mice. However, MyD88(-/-) mice infected with K. pneumoniae showed a much more remarkable phenotype, including impaired survival and reduced bacterial clearance, histopathology, and TNF-alpha, IL-6, KC, MIP-2, and LIX expression with almost no neutrophil influx in the lungs. In MyD88(-/-) mice, K. pneumoniae-induced early NF-kappaB and MAPK activation in the lungs was also reduced. Furthermore, the role of MyD88 is dominant over TRIF because TRIF/MyD88 double knockout mice displayed a more pronounced phenotype than TRIF(-/-) mice. Moreover, human alveolar macrophages pretreated with MyD88 blocking peptide showed attenuated TNF-alpha, IL-6, and IL-8 expression. Also, C57BL/6 mice pretreated with MyD88 blocking peptide exhibited attenuation in K. pneumoniae-induced neutrophil influx and enhanced bacterial burden in the lungs and dissemination. Overall, this investigation provides new insights into the TRIF and MyD88 signaling triggered by pulmonary K. pneumoniae infection in the lungs and demonstrate the therapeutic potential of MyD88 in reducing excessive neutrophil influx in human disease during Gram-negative bacterial pneumonia.

Authors+Show Affiliations

Department of Pathobiological Sciences, Louisiana State University, Baton Rouge, LA 70803, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19846873

Citation

Cai, Shanshan, et al. "Both TRIF- and MyD88-dependent Signaling Contribute to Host Defense Against Pulmonary Klebsiella Infection." Journal of Immunology (Baltimore, Md. : 1950), vol. 183, no. 10, 2009, pp. 6629-38.
Cai S, Batra S, Shen L, et al. Both TRIF- and MyD88-dependent signaling contribute to host defense against pulmonary Klebsiella infection. J Immunol. 2009;183(10):6629-38.
Cai, S., Batra, S., Shen, L., Wakamatsu, N., & Jeyaseelan, S. (2009). Both TRIF- and MyD88-dependent signaling contribute to host defense against pulmonary Klebsiella infection. Journal of Immunology (Baltimore, Md. : 1950), 183(10), pp. 6629-38. doi:10.4049/jimmunol.0901033.
Cai S, et al. Both TRIF- and MyD88-dependent Signaling Contribute to Host Defense Against Pulmonary Klebsiella Infection. J Immunol. 2009 Nov 15;183(10):6629-38. PubMed PMID: 19846873.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Both TRIF- and MyD88-dependent signaling contribute to host defense against pulmonary Klebsiella infection. AU - Cai,Shanshan, AU - Batra,Sanjay, AU - Shen,Li, AU - Wakamatsu,Nobuko, AU - Jeyaseelan,Samithamby, Y1 - 2009/10/21/ PY - 2009/10/23/entrez PY - 2009/10/23/pubmed PY - 2009/12/16/medline SP - 6629 EP - 38 JF - Journal of immunology (Baltimore, Md. : 1950) JO - J. Immunol. VL - 183 IS - 10 N2 - Klebsiella pneumoniae causes extensive lung damage. TLR signaling involves adaptors TRIF and MyD88. However, the relative contribution of TRIF and MyD88 signaling in host defense against pulmonary K. pneumoniae infection has not been elucidated. Therefore, we investigated the role of TRIF and MyD88 in K. pneumoniae pneumonia. TRIF(-/-) mice infected with K. pneumoniae showed impaired survival and reduced bacterial clearance, neutrophil influx, histopathologic evidence of inflammation, and TNF-alpha, IL-6, KC, MIP-2, but not LIX, expression in the lungs. In addition, K. pneumoniae-induced late NF-kappaB activation and phosphorylation of MAPKs was attenuated in the lungs of TRIF(-/-) mice. However, MyD88(-/-) mice infected with K. pneumoniae showed a much more remarkable phenotype, including impaired survival and reduced bacterial clearance, histopathology, and TNF-alpha, IL-6, KC, MIP-2, and LIX expression with almost no neutrophil influx in the lungs. In MyD88(-/-) mice, K. pneumoniae-induced early NF-kappaB and MAPK activation in the lungs was also reduced. Furthermore, the role of MyD88 is dominant over TRIF because TRIF/MyD88 double knockout mice displayed a more pronounced phenotype than TRIF(-/-) mice. Moreover, human alveolar macrophages pretreated with MyD88 blocking peptide showed attenuated TNF-alpha, IL-6, and IL-8 expression. Also, C57BL/6 mice pretreated with MyD88 blocking peptide exhibited attenuation in K. pneumoniae-induced neutrophil influx and enhanced bacterial burden in the lungs and dissemination. Overall, this investigation provides new insights into the TRIF and MyD88 signaling triggered by pulmonary K. pneumoniae infection in the lungs and demonstrate the therapeutic potential of MyD88 in reducing excessive neutrophil influx in human disease during Gram-negative bacterial pneumonia. SN - 1550-6606 UR - https://www.unboundmedicine.com/medline/citation/19846873/Both_TRIF__and_MyD88_dependent_signaling_contribute_to_host_defense_against_pulmonary_Klebsiella_infection_ L2 - http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=19846873 DB - PRIME DP - Unbound Medicine ER -