Role of CD38 in Pulmonary Host Defense against Gram-negative Pneumonia

Abstract

The Gram-negative bacterium, Klebsiella pneumoniae, is a major cause of hospital-acquired pneumonia in the U.S. In particular, the dramatic increase in carbapenem-resistant K. pneumoniae infections poses a serious threat to the public health both in the United States and worldwide. Clearance of bacteria in the lungs depends on effective pulmonary immune response. It may be possible to design improved therapies that augment host immune responses while attenuating excessive pulmonary inflammation through modulation of key innate immunity molecules during pneumonic infections. Cluster differentiation CD38 (CD38) has been detected on the surface of many immune cells or intracellular compartments, acting as an enzyme or a receptor. Although deficiency of CD38 has been shown to attenuate neutrophil recruitment and bacterial clearance in mice with Gram-positive pathogens, its role in Gram-negative bacterial pneumonia is largely unknown. In the present study, we determined the role of CD38 in pulmonary host defense against the Gram-negative bacterium Carbapenem-resistant K. pneumoniae (CRKP) in a model of bacteria-induced pneumonia. Both wild-type (WT) and CD38-deficient mice (CD38-/-) mice were infected with CRKP (1×108 CFU/mouse) by oropharyngeal aspiration. We monitored survival and determined the phenotype of the bronchoalveolar lavage fluid (BALF) cells and bacterial burden in the pulmonary and extrapulmonary organs following infection. We quantified the level of cytokines in the BALF, as well as the level of myeloperoxidase (MPO) in the lung homogenates following CRKP infection. We also examined the intracellular bacterial killing of CRKP by WT and CD38-deficient bone marrow-derived neutrophils (BMDN). In addition, we conducted bone marrow transplantation studies to determine the contribution of CD38 from hematopoietic cells versus non-hematopoietic tissue to host defense following CRKP infection.