Rationale: The Gram-negative bacterium, Klebsiella pneumoniae, is a leading cause of community-acquired pneumonia globally. In particular, the dramatic increase in carbapenem-resistant K. pneumoniae infections poses a therapeutic challenge both in the United States and worldwide. Clearance of bacteria in the lungs depends on effective pulmonary innate immunity. It may be possible to design improved therapies that attenuate excessive pulmonary inflammation through modulation of key innate immunity molecules during bacterial pneumonia. Cluster differentiation CD38 (CD38) has been detected on the surface of many immune cells or intracellular compartments, acting as an enzyme or a receptor. Nevertheless, the role of CD38 in pulmonary host defense against CRKP-induced pneumonia remains elusive.

Methods:  Both wild-type (WT) and CD38-deficient mice (CD38^-/-) mice were infected with CRKP (1 x 10⁸ CFU/mouse) by oropharyngeal aspiration. We monitored survival and determined the phenotype of the bronchoalveolar lavage fluid (BALF) cells and the bacterial burden in the pulmonary and extrapulmonary organs following infection. We also quantified the level of cytokines and protein in the BALF, as well as the level of myeloperoxidase (MPO) in the lung homogenates following infection. In addition, we examined the intracellular bacterial killing of CRKP by WT and CD38-deficient bone marrow-derived neutrophils (BMDN).

Results:  Compared to WT mice, CD38^-/- mice showed increased survival and enhanced bacterial clearance in lungs and extrapulmonary organs during CRKP-induced pneumonia. Augmented host protection in CD38^-/- mice was associated with increased neutrophil influx and increased level of cytokines in BALF, as well as accumulated neutrophil (MPO) in the lung parenchyma following infection. Furthermore, CD38^-/- neutrophils demonstrated enhanced intracellular bacterial killing ability against CRKP. 

Conclusions: Our study clearly demonstrates the detrimental role of CD38 during Gram-negative bacterial pneumoniae. Therefore, inhibition of CD38 could be a potential therapeutic strategy to augment pulmonary host defense against CRKP-induced pneumonia. We are currently conducting bone marrow transplantation studies to determine the contribution of myeloid cells versus stromal cells following CRKP infection.