Differential roles of MyD88 and TRIF in hematopoietic and resident cells during murine gram-negative pneumonia.
BACKGROUND
Pneumonia is frequently caused by gram-negative pathogens, among which Klebsiella pneumoniae prominently features. Recognition of pathogen-associated molecular patterns by Toll-like receptors (TLRs) is important for an appropriate immune response during infection. TLR signaling can proceed via 2 distinct routes that are dependent on the adaptor proteins Myeloid differentiation primary response gene (88) (MyD88) and TIR-domain-containing adaptor-inducing interferon-β (TRIF). The aim of the study was to determine the relative contribution of MyD88 and TRIF signaling in resident and hematopoietic cells to host defense during pneumonia.


METHODS
Bone marrow chimeras of MyD88 deficient/wild type and TRIF mutant/wild type mice were created and infected with K. pneumoniae via the airways.


RESULTS
MyD88 in both resident and hematopoietic cells contributed to survival and antibacterial defense in late-stage infection, whereas only TRIF in hematopoietic cells was protective. On the other hand, resident MyD88 and hematopoietic TRIF contributed to distant cellular injury. Resident MyD88 was pivotal for early chemokine release and neutrophil recruitment in the bronchoalveolar space.


CONCLUSIONS
MyD88- and TRIF-dependent signaling has a differential contribution to host defense in different cell types that changes from early- to late-stage gram-negative pneumonia.
Center of Infection and Immunity, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Miriam H P
MH
van Lieshout
Dana C
DC
Blok
Catharina W
CW
Wieland
Alex F
AF
de Vos
Cornelis
C
van 't Veer
Tom
T
van der Poll
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000276:immunology*; D000818:Animals; D005260:Female; D007710:Klebsiella Infections / Q000276:immunology* / Q000473:pathology; D007711:Klebsiella pneumoniae / Q000276:immunology* / Q000472:pathogenicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology*; D018410:Pneumonia, Bacterial / Q000276:immunology* / Q000473:pathology; D016019:Survival Analysis
D033942:Adaptor Proteins, Vesicular Transport; D053594:Myeloid Differentiation Factor 88; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse