RGD Reference Report - Both TRIF- and MyD88-dependent signaling contribute to host defense against pulmonary Klebsiella infection. - Rat Genome Database

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Both TRIF- and MyD88-dependent signaling contribute to host defense against pulmonary Klebsiella infection.

Authors: Cai, S  Batra, S  Shen, L  Wakamatsu, N  Jeyaseelan, S 
Citation: Cai S, etal., J Immunol. 2009 Nov 15;183(10):6629-38. Epub 2009 Oct 21.
RGD ID: 4145490
Pubmed: PMID:19846873   (View Abstract at PubMed)
PMCID: PMC2777750   (View Article at PubMed Central)
DOI: DOI:10.4049/jimmunol.0901033   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
CXCL5Humanbacterial pneumonia  ISOCxcl5 (Mus musculus) RGD 
Cxcl5Mousebacterial pneumonia  IEP  RGD 
Cxcl6Ratbacterial pneumonia  ISOCxcl5 (Mus musculus) RGD 
ICAM1Humanbacterial pneumonia  ISOIcam1 (Mus musculus)protein:increased expression:lung (mouse)RGD 
Icam1Ratbacterial pneumonia  ISOIcam1 (Mus musculus)protein:increased expression:lung (mouse)RGD 
Icam1Mousebacterial pneumonia  IEP protein:increased expression:lung (mouse)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Cxcl6  (C-X-C motif chemokine ligand 6)
Icam1  (intercellular adhesion molecule 1)

Genes (Mus musculus)
Cxcl5  (C-X-C motif chemokine ligand 5)
Icam1  (intercellular adhesion molecule 1)

Genes (Homo sapiens)
CXCL5  (C-X-C motif chemokine ligand 5)
ICAM1  (intercellular adhesion molecule 1)


Additional Information