Nod1 signaling overcomes resistance of S. pneumoniae to opsonophagocytic killing.
Airway infection by the Gram-positive pathogen Streptococcus pneumoniae (Sp) leads to recruitment of neutrophils but limited bacterial killing by these cells. Co-colonization by Sp and a Gram-negative species, Haemophilus influenzae (Hi), provides sufficient stimulus to induce neutrophil and complement-mediated clearance of Sp from the mucosal surface in a murine model. Products from Hi, but not Sp, also promote killing of Sp by ex vivo neutrophil-enriched peritoneal exudate cells. Here we identify the stimulus from Hi as its peptidoglycan. Enhancement of opsonophagocytic killing was facilitated by signaling through nucleotide-binding oligomerization domain-1 (Nod1), which is involved in recognition of gamma-D-glutamyl-meso-diaminopimelic acid (meso-DAP) contained in cell walls of Hi but not Sp. Neutrophils from mice treated with Hi or compounds containing meso-DAP, including synthetic peptidoglycan fragments, showed increased Sp killing in a Nod1-dependent manner. Moreover, Nod1(-/-) mice showed reduced Hi-induced clearance of Sp during co-colonization. These observations offer insight into mechanisms of microbial competition and demonstrate the importance of Nod1 in neutrophil-mediated clearance of bacteria in vivo.
Lysenko
Elena S
ES
Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America.
Clarke
Thomas B
TB
Shchepetov
Mikhail
M
Ratner
Adam J
AJ
Roper
David I
DI
Dowson
Christopher G
CG
Weiser
Jeffrey N
JN
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D020868:Gene Silencing; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D053474:Nod1 Signaling Adaptor Protein / Q000502:physiology*; D009895:Opsonin Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010457:Peptidoglycan / Q000276:immunology / Q000378:metabolism; D010587:Phagocytosis; D011018:Pneumonia, Pneumococcal / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D015398:Signal Transduction; D013296:Streptococcus pneumoniae / Q000276:immunology / Q000472:pathogenicity*
D048868:Adaptor Proteins, Signal Transducing; D053474:Nod1 Signaling Adaptor Protein; C507873:Nod1 protein, mouse; D009895:Opsonin Proteins; D010457:Peptidoglycan