Saturday, September 7, 2024
9/7/2024
SUMMARY Pneumonia-derived sepsis remains a persistent and pervasive public health problem. Pneumonia and sepsis are the major causes of Acute Respiratory Distress Syndrome (ARDS). No clinical studies other than the ARDSnet ventilator trial provided better outcomes for ALI/ARDS. Therefore, an improved understanding of the pathogenesis of pneumonia-derived sepsis is warranted. Despite the use of newer- generation antibiotics to control pneumonia, the mortality rate of bacterial pneumonia has increased due to multidrug-resistant and hypervirulent bacterial strains. Infections due to Enterobacteriaceae present a public health threat due to the emergence of multidrug-resistant strains and limited available therapeutic options. The acquisition of carbapenemeses by K. pneumoniae makes the bacteria resistant to all - lactams. Moreover, there are no effective vaccines available to control carbapenem-resistant K. pneumoniae (CRKP). Therefore, harnessing the host’s immune system may be a more effective strategy for combating CRKP and developing novel treatment against this pathogen-induced devastating diseases. The long-term goal is to understand the mechanism by which Nrf2 activation in the lung is integrated into successful antibacterial resistance and if it is possible to reduce pulmonary and extrapulmonary organ injury during CRKP infection through host-targeted therapies. My lab has made substantial contributions toward understanding protective antibacterial defense against pulmonary infection and pneumonia-induced sepsis. Bacterial pneumonia induces extensive oxidative stress in pulmonary tissues. The transcription factor Nrf2 (nuclear factor-erythroid 2 p45-related factor 2, Nfe2l2) is a critical regulator of the expression of oxidative stress genes. The central hypothesis that Nrf2 is a master regulator of host defense during CRKP-induced infection. Four aims have been proposed: Aim 1 will investigate the effects of Nrf2 on survival, bacterial clearance and neutrophil accumulation and function, Aim 2 will explore the role of Nrf2 in emergency granulopoiesis, Aim 3 will characterize if Nrf2 ablation can alter the function of alveolar macrophages, and Aim 4 will determine if enhancing Nrf2 signaling in the lungs improve host defense. We will use both in vivo (mouse model) and in vitro (human cells) strategies. We anticipate gaining a better understanding of the signaling cascades involved in the innate responses to CRKP infection to design improved therapies to augment host defense and mitigate collateral tissue damage.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
