Semester of Graduation
Fall of 2022
Master of Science (MS)
Department of Pathobiological Sciences
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.
Our results indicated that CD38-/- mice showed enhanced survival and increased bacterial clearance in lungs and extrapulmonary organs as compared with WT counterparts during CRKP-induced pneumonia. Augmented host protection in CD38-/- mice was associated with the increased neutrophil influx and increased level of cytokines in BALF, as well as accumulated neutrophil (MPO) in the lung parenchyma following CRKP infection. Furthermore, CD38-deficient neutrophils demonstrated enhanced intracellular bacterial killing ability against CRKP. Interestingly, CD38 deficiency in non-hematopoietic tissue contributes to host protection against CRKP infection. Collectively, our study clearly demonstrates the detrimental role of CD38 in pulmonary host protection against CRKP-induced pneumonia. These findings suggest that neutralization of CD38 could be a potential target for therapeutic intervention of Gram-negative bacterial pneumonia.
Shan, Xiaoqian, "Role of CD38 in Pulmonary Host Defense against Gram-negative Pneumonia" (2022). LSU Master's Theses. 5684.
Available for download on Friday, November 03, 2023