Lung infections are a leading cause of sepsis that poses global mortality and morbidity. Effective clearance of pathogens from the lung is dependent on successful innate immunity. Understanding the innate defense mechanisms in the lung is crucial for improved immunotherapeutics or vaccines to reduce this burden of disease. The signaling cascades triggering innate immunity consist of a delicate balance between pro-inflammatory responses, and counteracting anti-inflammatory responses. It is however poorly understood how these innate immune signaling cascades converge to provide efficient host defense while attenuating inflammatory tissue damage. To delineate the host defense mechanisms in the lungs and extrapulmonary organs, we have focused on a primary gram-negative extracellular pathogen, Klebsiella pneumoniae since this bacterium induces severe pneumonia followed by sepsis; and multiple drug-resistant and hypervirulent variants have recently emerged to cause devastating pulmonary and systemic infections. Recognition of pathogens is the first critical step leading to neutrophil influx in the lung. Regarding bacterial recognition, nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) were implicated. However, the role of NLRs, such as NOD1 and NOD2 s in host defense against K. pneumoniae remains unexplored. NOD1/2 signaling cascades involve the adaptor protein RIP2. We now provide preliminary evidence that NOD2 is involved in host defense during K. pneumoniae infection, which include: 1) Mice deficient in RIP2 demonstrate reduced survival, higher bacterial burden and decreased neutrophil recruitment to the lungs and extrapulmonary organs; 2) NOD2-deficient mice show attenuated neutrophil recruitment to the lungs; 3) NOD2-deficient mice demonstrate decreased caspase- 1 activation and interleukin (IL)-1? production in the lung; 4) Both IL-1? and IL-18 are important for host resistance against K. pneumoniae and 5) RIP2 regulates IL-23 and IL-17 production in the lungs. These findings collectively support the hypothesis that the initial interaction of K. pneumoniae with the lung cells leads to NOD2 activation followed by IL-1? and IL-18 production which then induces IL-17A- mediated neutrophil-dependent immunity in the host.
The Aims are: (1) Investigate the in vivo mechanisms by which NOD2 modulates neutrophil-mediated host defense during pneumonic sepsis; (2) Explore the in vivo mechanisms by which NOD2 enhances IL-17A production during pneumonic sepsis; and (3) Determine if modulation of NOD2 alters host defense during pneumonic sepsis. A unique combination of in vivo and in vitro systems, including KO mice, overexpression and adoptive transfer strategies will be employed to address these aims. We believe that this conceptually, technically and translationally innovative proposal will reveal NOD2 as a master regulator for pneumonic sepsis and advance our understanding of how NOD2 promotes a beneficial response for pneumonic sepsis.

Public Health Relevance

Pneumonic sepsis, a clinical condition caused by an underlying infection, remains a major cause of mortality and morbidity worldwide. Although there have been efforts to improve the treatment and prevention strategies, death rates are still high. The goal of our proposed work is to understand how immune mechanisms are integrated into successful host resistance in the lungs and extrapulmonary organs. We have focused on the bacterium Klebsiella pneumoniae, because 1) this bacterium causes extensive lung damage followed by severe sepsis; and 2) neutrophils are crucial to control K. pneumoniae infections; 3) the emergence of carbapenemase-resistant K. pneumoniae (CRKP) spreads rapidly, causes substantial mortality and has reduced antibiotic treatment options; and 4) no effective vaccine is available. The ultimate goal of the translational investigation is to discover ways in which these lung cells augment host resistance to eradicate the infection while attenuating exaggerated organ damage during pneumonic sepsis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
High Priority, Short Term Project Award (R56)
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Special Emphasis Panel (ZRG1-SBIB-V (02)M)
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Caler, Elisabet V
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Louisiana State University A&M Col Baton Rouge
Schools of Veterinary Medicine
Baton Rouge
United States
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