Inflammatory Organ Injury after Pneumonia-Derived Sepsis

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: Samithamby  Jeyaseelan
Organization: LOUISIANA STATE UNIV A&M COL BATON ROUGE
Fiscal Year: 2024
Award: $715,216
Funding agency: National Institute of Allergy and Infectious Diseases

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.

Terms: <ARDS><Ablation><Acute Lung Injury><Acute Pulmonary Injury><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Adoptive Transfer><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Airway failure><Allergic asthma><Alveolar><Alveolar Macrophages><Anti-Bacterial Agents><Antibiotic Agents><Antibiotic Drugs><Antibiotic Resistance><Antibiotics><Antioxidants><Bacteria resistance><Bacteria resistant><Bacterial Drug Resistance><Bacterial Pneumonia><Bacterial resistant><Basal Transcription Factor><Basal transcription factor genes><Binding><Blood><Blood Neutrophil><Blood Poisoning><Blood Polymorphonuclear Neutrophil><Blood Reticuloendothelial System><Blood leukocyte><Body Tissues><Bone Marrow><Bone Marrow Examination><Bone Marrow Reticuloendothelial System><Cause of Death><Cell Body><Cell Communication and Signaling><Cell Nucleus><Cell Signaling><Cells><Clinical Research><Clinical Study><Coliform Bacilli><Cytosol><Da Nang Lung><Data Display><Death Rate><Disease><Disorder><Dropsy><Dysfunction><Edema><Emergencies><Emergency Situation><Emphysema><Enteric Bacteria><Enterobacteria><Enterobacteriaceae><Extrinsic asthma><Functional disorder><Gene Expression><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Generations><Genes><Genetic Transcription><Goals><Granulopoiesis><Hematopoietic><Host Defense><Human><Hydrops><Hypoxia><Hypoxic><Immune system><Impairment><In Vitro><Infection><Inflammatory><Innate Immunity><Intracellular Communication and Signaling><K pneumoniae><K. pneumoniae><KO mice><Klebsiella pneumoniae><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Lactams><Leukocytes><Leukocytes Reticuloendothelial System><Life><Lung><Lung Respiratory System><Lung infections><Macrophage><Marrow><Marrow Neutrophil><Marrow leukocyte><Methods><Mice><Mice Mammals><Miscellaneous Antibiotic><Modeling><Modern Man><Molecular Interaction><Multi-Drug Resistance><Multidrug Resistance><Multiple Drug Resistance><Multiple Drug Resistant><Murine><Mus><Myeloid Cells><Mφ><NF-E2 protein><NF-E2 transcription factor><NFE2 protein><Native Immunity><Natural Immunity><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Non-Specific Immunity><Nonspecific Immunity><Nucleus><Null Mouse><Organ><Organ failure><Outcome><Oxidative Stress><Oxygen Deficiency><P aeruginosa><P. aeruginosa><Pathogenesis><Patients><Phagocytes><Phagocytic Cell><Physiopathology><Pneumonia><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Predisposition><Progenitor Cells><Pseudomonas aeruginosa><Pseudomonas pyocyanea><Public Health><Pulmonary Emphysema><Pulmonary Macrophages><RNA Expression><Resistance to Multi-drug><Resistance to Multidrug><Resistance to Multiple Drug><Resistance to antibiotics><Resistant to Multiple Drug><Resistant to antibiotics><Resistant to multi-drug><Resistant to multidrug><Resolution><Respiratory Failure><Response Elements><Role><S aureus><S. aureus><Sepsis><Septic Shock><Septicemia><Shock Lung><Short interfering RNA><Signal Transduction><Signal Transduction Systems><Signaling><Small Interfering RNA><Staph aureus><Staphylococcus aureus><Stiff lung><Stress><Susceptibility><Testing><Therapeutic><Tissues><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Ventilator><White Blood Cells><White Cell><access to vaccination><access to vaccines><amebocyte><anti-bacterial><anti-bacterial drug resistance><anti-bacterial drug resistant><anti-bacterial resistance><anti-bacterial resistant><antibiotic drug resistance><antibiotic resistant><atopic asthma><bacteria pneumonia><bacterial resistance><biological signal transduction><blood infection><bloodstream infection><bone marrow exam><carbapenem resistance><carbapenem resistant><cigarette smoke-induced><design><designing><emphysematous><extrinsic allergic asthma><hemopoietic><improved><in vivo><injury to organs><innate immune function><insight><knock-down><knockdown><migration><mortality rate><mortality ratio><mouse model><multi-drug resistant><multidrug resistant><murine model><neutrophil><novel><nuclear factor-erythroid 2><organ injury><overexpress><overexpression><pathogen><pathophysiology><peripheral blood><pulmonary><pulmonary infections><recruit><resistance in K pneumoniae><resistance in K. pneumoniae><resistance in Klebsiella pneumoniae><resistance strain><resistance to Bacteria><resistance to Bacterial><resistance to anti-bacterial><resistance to carbapenem><resistant K pneumoniae><resistant K. pneumoniae><resistant Klebsiella pneumoniae><resistant strain><resistant to Bacteria><resistant to Bacterial><resistant to anti-bacterial><resistant to carbapenem><resolutions><response><septicaemia><septicemic><siRNA><social role><stem cells><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><transcription factor><vaccination access><vaccination availability><vaccine access><vaccine availability><wet lung><white blood cell><white blood corpuscle>