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Inflammatory Organ Injury after Pneumonia-Derived Sepsis

Award Number: R01AI180123
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2024
PERIOD OF PERFORMANCE END DATE: 05/31/2029

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Inflammatory Organ Injury after Pneumonia-Derived Sepsis - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $715,216 )
2025	2025	LOUISIANA STATE UNIVERSITY	202 HIMES HALL	BATON ROUGE	LA	70803	EAST BATON ROUGE	USA	Allergy and Infectious Diseases Research	000	2	5/20/2025	NON-COMPETING CONTINUATION	$715,216
														Subtotal = $715,216

Issue Date FY: 2024 ( Subtotal = $715,216 )
2024	2024	LOUISIANA STATE UNIVERSITY	202 HIMES HALL	BATON ROUGE	LA	70803	EAST BATON ROUGE	USA	Allergy and Infectious Diseases Research	000	1	6/26/2024	NEW	$715,216
														Subtotal = $715,216

Grand Total All Awards = $1,430,432

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Inflammatory Organ Injury after Pneumonia-Derived Sepsis

Award Number: R01AI180123

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2024

PERIOD OF PERFORMANCE END DATE: 05/31/2029

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