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1567325 
Journal Article 
The NOD/RIP2 Pathway Is Essential for Host Defenses Against Chlamydophila pneumoniae Lung Infection 
Shimada, K; Chen, S; Dempsey, PW; Sorrentino, R; Alsabeh, R; Slepenkin, AV; Peterson, E; Doherty, TM; Underhill, D; Crother, TR; Arditi, M 
2009 
1 
P L o S Pathogens
ISSN: 1553-7366 
5 
4 
19360122 
WOS:000266216300023 
Here we investigated the role of the Nod/Rip2 pathway in
host responses to Chlamydophila pneumoniae-induced pneumonia in mice. Rip2(-/-) mice infected
with C. pneumoniae exhibited impaired iNOS expression and NO production, and delayed neutrophil
recruitment to the lungs. Levels of IL-6 and IFN-gamma levels as well as KC and MIP-2 levels in
bronchoalveolar lavage fluid (BALF) were significantly decreased in Rip2(-/-) mice compared to
wild-type (WT) mice at day 3. Rip2(-/-) mice showed significant delay in bacterial clearance from
the lungs and developed more severe and chronic lung inflammation that continued even on day 35
and led to increased mortality, whereas WT mice cleared the bacterial load, recovered from acute
pneumonia, and survived. Both Nod1(-/-) and Nod2(-/-) mice also showed delayed bacterial
clearance, suggesting that C. pneumoniae is recognized by both of these intracellular receptors.
Bone marrow chimera experiments demonstrated that Rip2 in BM-derived cells rather than non-
hematopoietic stromal cells played a key role in host responses in the lungs and clearance of C.
pneumoniae. Furthermore, adoptive transfer of WT macrophages intratracheally was able to rescue
the bacterial clearance defect in Rip2(-/-) mice. These results demonstrate that in addition to
the TLR/MyD88 pathway, the Nod/Rip2 signaling pathway also plays a significant role in
intracellular recognition, innate immune host responses, and ultimately has a decisive impact on
clearance of C. pneumoniae from the lungs and survival of the infectious challenge.