Neutrophil Accumulation in Bacterial Pneumonia

Summary

Principal Investigator: Samithamby Jeyaseelan
Abstract: DESCRIPTION (provided by applicant): Lung infections are a leading cause of morbidity, mortality and health care costs worldwide. Rapid clearance of pathogens from the respiratory tract is dependent on effective innate immune responses in the lung. Understanding the innate defense mechanisms in the lower respiratory tract is critical for the development of novel treatment and/or prevention strategies to reduce this burden of disease. The signaling cascades triggering innate immune responses consist of a delicate balance between pro- inflammatory responses that facilitate pathogen clearance, and counteracting anti-inflammatory responses that control excessive systemic inflammatory host responses. In general, it is poorly understood how these pathways converge to regulate host defense while minimizing inflammatory tissue injury. The long-term goal of this research is to understand how multiple innate immune events are integrated into effective antimicrobial resistance. As a model to elucidate the basic host defense mechanisms, we have focused on a primary pathogen, Klebsiella pneumoniae because this extracellular Gram-negative bacterium causes severe pneumonia;and the extensive spread of multiple drug-resistant K. pneumoniae strains worldwide. Although K. pneumoniae signals via Toll-like receptor (TLR)-4 and 9, a few studies have also indicated the involvement of NOD-like receptors (NLRs) as cytosolic immune sensors. Some NLRs termed "inflammasomes" can activate caspase-1 in order to cleave IL-1[unreadable] and IL-18. We have previously shown the NLR family CARD domain containing 4 (NLRC4;IPAF) as a new sensor to K. pneumoniae in human and mouse macrophages that regulates caspase-1 dependent maturation of the inflammatory cytokines, IL1[unreadable] and IL18. IL-1R1 knockout (KO) mice show greater susceptibility than NLRC4 KO mice to intrapulmonary K. pneumoniae infection, suggesting the involvement of other more prominent NLR proteins. Our preliminary data demonstrate that (1) human lungs with bacterial pneumonia show higher expression of NLR family pyrin domain containing 6 (NLRP6) inflammasome;(2) neutrophils show the highest expression of NLRP6 during resting stage and upon bacterial infection;(3) as compared with other NLRs (NOD1, NOD2, NLRP3 and NLRC4), NLRP6 is most prominent for bacterial clearance in the lungs during Klebsiella pneumonia;(4) neutrophils produce IL-17A and IL-17F in the lungs during bacterial pneumonia;and (5) NLRP6 knockdown human alveolar macrophages produce attenuated levels of IL-1[unreadable] and IL-18 proteins following K. pneumoniae LPS challenge. Our key findings support a critical yet unrecognized function for NLRP6 during Klebsiella infection. This renewal proposal seeks to address the central hypothesis that NLRP6 is a key mediator of host defense during gram-negative bacterial pneumonia via induction of IL-17;thus, NLRP6 is a potential therapeutic target that could augment host defenses to acute respiratory infections. The Aims are: (1) Determine the effects of NLRP6 on bacterial clearance and neutrophil function following K. pneumoniae challenge.;(2) Determine the effects of NLRP6-dependent IL-17 production on host resistance to bacterial pneumonia.;(3) Identify functional alterations in alveolar macrophages caused by NLRP6 disruption with bacterial pneumonia.;and (4) Explore if manipulation of NLRP6 signaling can augment host resistance during Klebsiella pneumonia. A unique combination of in vivo and in vitro systems, including conditional KO mice, lentiviral transduction, adoptive transfer, and cytokine restoration strategies will be employed to address these Aims. Proving that the specific inflammasome plays a critical role in lung inflammation and host defense will lead to a major paradigm shift and ultimately lead to new therapeutic and prevention strategies of the treatment of ALI and ARDS in bacterial pneumonia because prior studies of the role of NLRs and other cytosolic sensors have been exclusively confined to in vitro studies and systemic Infection models.
Funding Period: 2008-09-01 - 2018-04-30
more information: NIH RePORT

Top Publications

  1. pmc Myeloid differentiation protein-2-dependent and -independent neutrophil accumulation during Escherichia coli pneumonia
    Shanshan Cai
    Laboratory of Lung Biology, Department of Pathobiological Sciences and Center for Experimental Infectious Disease Research, Louisiana State University LSU, Baton Rouge, Louisiana 70803, USA
    Am J Respir Cell Mol Biol 40:701-9. 2009
  2. pmc NLRC4 inflammasome-mediated production of IL-1β modulates mucosal immunity in the lung against gram-negative bacterial infection
    Shanshan Cai
    Laboratory of Lung Biology, Department of Pathobiological Sciences, Center for Experimental Infectious Disease Research, Louisiana State University, Baton Rouge, LA 70803, USA
    J Immunol 188:5623-35. 2012
  3. pmc NOD2 signaling contributes to host defense in the lungs against Escherichia coli infection
    Balamayooran Theivanthiran
    Laboratory of Lung Biology, Department of Pathobiological Sciences and Center for Experimental Infectious Disease Research, Harvard Medical School, Boston, Massachusetts, USA
    Infect Immun 80:2558-69. 2012
  4. pmc Intrapulmonary administration of leukotriene B(4) augments neutrophil accumulation and responses in the lung to Klebsiella infection in CXCL1 knockout mice
    Sanjay Batra
    Laboratory of Lung Biology, Department of Pathobiological Sciences, Center for Experimental Infectious Disease Research, Louisiana State University, Baton Rouge, LA 70803, USA
    J Immunol 188:3458-68. 2012
  5. pmc Role of CXCL5 in leukocyte recruitment to the lungs during secondhand smoke exposure
    Gayathriy Balamayooran
    Laboratory of Lung Biology, Department of Pathobiological Sciences, Louisiana State University, Baton Rouge, 70803, USA
    Am J Respir Cell Mol Biol 47:104-11. 2012
  6. pmc Role of chemokines in the pathogenesis of acute lung injury
    Madhav Bhatia
    Department of Pathology, University of Otago, 2 Riccarton Avenue, Christchurch, New Zealand
    Am J Respir Cell Mol Biol 46:566-72. 2012
  7. pmc Receptor-interacting protein 2 controls pulmonary host defense to Escherichia coli infection via the regulation of interleukin-17A
    Theivanthiran Balamayooran
    Laboratory of Lung Biology, Department of Pathobiological Sciences and Center for Experimental Infectious Disease Research, Louisiana State University LSU, Baton Rouge, Louisiana 708031, USA
    Infect Immun 79:4588-99. 2011
  8. pmc Monocyte chemoattractant protein 1 regulates pulmonary host defense via neutrophil recruitment during Escherichia coli infection
    Gayathriy Balamayooran
    Laboratory of Lung Biology, Department of Pathobiological Sciences, and Center for Experimental Infectious Disease Research, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA
    Infect Immun 79:2567-77. 2011
  9. pmc CXCL1 regulates pulmonary host defense to Klebsiella Infection via CXCL2, CXCL5, NF-kappaB, and MAPKs
    Shanshan Cai
    Department of Pathobiological Sciences, Louisiana State University, Baton Rouge, LA 70803, USA
    J Immunol 185:6214-25. 2010
  10. pmc CXCL5 regulates chemokine scavenging and pulmonary host defense to bacterial infection
    Junjie Mei
    Division of Neonatology, Children s Hospital of Philadelphia, Philadelphia, PA 19104, USA
    Immunity 33:106-17. 2010

Research Grants

  1. Mental Stress Ischemia: Prognosis and Genetic Influences
    Arshed A Quyyumi; Fiscal Year: 2013
  2. Pulmonary Defenses Against Intracellular Infection
    Shawn J Skerrett; Fiscal Year: 2013
  3. A TOLERANCE APPROACH TO XENOTRANSPLANTATION
    David H Sachs; Fiscal Year: 2013
  4. Host-pathogen competition in IFN mediated antiviral defense
    Jae U Jung; Fiscal Year: 2013
  5. THE OUTER MEMBRANE AS A VIRULENCE PLATFORM
    DAVID ALAN HUNSTAD; Fiscal Year: 2013
  6. Molecular mechanisms of hypoxia tolerance and susceptibility
    Gabriel G Haddad; Fiscal Year: 2013
  7. INNATE IMMUNE RESPONSE TO MICROBIAL INFECTION
    William M Nauseef; Fiscal Year: 2013
  8. CHEMISTRY AND BIOLOGY OF HEPARAN SULFATE
    UMESH RAMANLAL DESAI; Fiscal Year: 2013
  9. Transplant Tolerance in Non-Human Primates
    STUART JOHNSTON KNECHTLE; Fiscal Year: 2013
  10. Primary Immune Deficiency Treatment Consortium
    Morton Cowan; Fiscal Year: 2013

Detail Information

Publications17

  1. pmc Myeloid differentiation protein-2-dependent and -independent neutrophil accumulation during Escherichia coli pneumonia
    Shanshan Cai
    Laboratory of Lung Biology, Department of Pathobiological Sciences and Center for Experimental Infectious Disease Research, Louisiana State University LSU, Baton Rouge, Louisiana 70803, USA
    Am J Respir Cell Mol Biol 40:701-9. 2009
    ..coli-induced neutrophil accumulation and pulmonary host defense...
  2. pmc NLRC4 inflammasome-mediated production of IL-1β modulates mucosal immunity in the lung against gram-negative bacterial infection
    Shanshan Cai
    Laboratory of Lung Biology, Department of Pathobiological Sciences, Center for Experimental Infectious Disease Research, Louisiana State University, Baton Rouge, LA 70803, USA
    J Immunol 188:5623-35. 2012
    ..Furthermore, IL-1R1(-/-) mice displayed a decrease in neutrophilic inflammation in the lungs postinfection. Taken together, these findings provide novel insights into the role of NLRC4 in host defense against K. pneumoniae infection...
  3. pmc NOD2 signaling contributes to host defense in the lungs against Escherichia coli infection
    Balamayooran Theivanthiran
    Laboratory of Lung Biology, Department of Pathobiological Sciences and Center for Experimental Infectious Disease Research, Harvard Medical School, Boston, Massachusetts, USA
    Infect Immun 80:2558-69. 2012
    ..coli. These findings unveil a previously unrecognized role of the NOD2-RIP2 axis for host defense against extracellular Gram-negative bacteria. This pathway may represent a novel target for the treatment of lung infection/inflammation...
  4. pmc Intrapulmonary administration of leukotriene B(4) augments neutrophil accumulation and responses in the lung to Klebsiella infection in CXCL1 knockout mice
    Sanjay Batra
    Laboratory of Lung Biology, Department of Pathobiological Sciences, Center for Experimental Infectious Disease Research, Louisiana State University, Baton Rouge, LA 70803, USA
    J Immunol 188:3458-68. 2012
    ..pneumoniae infection. Our findings suggest that LTB(4) could be used to correct defects in neutrophil recruitment and function in individuals lacking or expressing malfunctional CXCL1...
  5. pmc Role of CXCL5 in leukocyte recruitment to the lungs during secondhand smoke exposure
    Gayathriy Balamayooran
    Laboratory of Lung Biology, Department of Pathobiological Sciences, Louisiana State University, Baton Rouge, 70803, USA
    Am J Respir Cell Mol Biol 47:104-11. 2012
    ..Our findings suggest an important role for CXCL5 in augmenting leukocyte recruitment in SHS-induced lung inflammation, and provide novel insights into CXCL5-driven pathogenesis...
  6. pmc Role of chemokines in the pathogenesis of acute lung injury
    Madhav Bhatia
    Department of Pathology, University of Otago, 2 Riccarton Avenue, Christchurch, New Zealand
    Am J Respir Cell Mol Biol 46:566-72. 2012
    ..Understanding the mechanisms that contribute to leukocyte recruitment in ALI may ultimately lead to the development of effective therapeutic strategies...
  7. pmc Receptor-interacting protein 2 controls pulmonary host defense to Escherichia coli infection via the regulation of interleukin-17A
    Theivanthiran Balamayooran
    Laboratory of Lung Biology, Department of Pathobiological Sciences and Center for Experimental Infectious Disease Research, Louisiana State University LSU, Baton Rouge, Louisiana 708031, USA
    Infect Immun 79:4588-99. 2011
    ..Thus, RIP2 contributes to neutrophil-dependent host defense against an extracellular Gram-negative pathogen via (i) IL-17A regulation and (ii) neutrophil mobilization to the blood...
  8. pmc Monocyte chemoattractant protein 1 regulates pulmonary host defense via neutrophil recruitment during Escherichia coli infection
    Gayathriy Balamayooran
    Laboratory of Lung Biology, Department of Pathobiological Sciences, and Center for Experimental Infectious Disease Research, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA
    Infect Immun 79:2567-77. 2011
    ..coli-induced MCP-1 causes neutrophil recruitment directly via chemotaxis as well as indirectly via modulation of keratinocyte cell-derived chemokine, macrophage inflammatory protein 2, and LTB(4)...
  9. pmc CXCL1 regulates pulmonary host defense to Klebsiella Infection via CXCL2, CXCL5, NF-kappaB, and MAPKs
    Shanshan Cai
    Department of Pathobiological Sciences, Louisiana State University, Baton Rouge, LA 70803, USA
    J Immunol 185:6214-25. 2010
    ....
  10. pmc CXCL5 regulates chemokine scavenging and pulmonary host defense to bacterial infection
    Junjie Mei
    Division of Neonatology, Children s Hospital of Philadelphia, Philadelphia, PA 19104, USA
    Immunity 33:106-17. 2010
    ..This study presents a paradigm whereby platelets and red cells alter chemokine scavenging and neutrophil-chemokine interaction during inflammation...
  11. pmc Review: Toll-like receptors and NOD-like receptors in pulmonary antibacterial immunity
    Theivanthiran Balamayooran
    Department of Pathobiological Sciences, Center for Experimental Infectious Disease Research, Louisiana State University, Baton Rouge, USA
    Innate Immun 16:201-10. 2010
    ....
  12. pmc Both TRIF- and MyD88-dependent signaling contribute to host defense against pulmonary Klebsiella infection
    Shanshan Cai
    Department of Pathobiological Sciences, Louisiana State University, Baton Rouge, LA 70803, USA
    J Immunol 183:6629-38. 2009
    ..pneumoniae infection in the lungs and demonstrate the therapeutic potential of MyD88 in reducing excessive neutrophil influx in human disease during Gram-negative bacterial pneumonia...
  13. pmc Mechanisms of neutrophil accumulation in the lungs against bacteria
    Gayathriy Balamayooran
    D V M, Pathobiolgical Sciences and Center for Experimental Infectious Disease Research, LSU, Baton Rouge, LA 70803, USA
    Am J Respir Cell Mol Biol 43:5-16. 2010
    ....
  14. pmc Age-associated parallel increase of Foxp3(+)CD4(+) regulatory and CD44(+)CD4(+) memory T cells in SJL/J mice
    Guang Ming Han
    Department of Comparative Biomedical Sciences, Louisiana State University, Baton Rouge, 70803, USA
    Cell Immunol 258:188-96. 2009
    ..Our results suggest that an age-associated imbalance of T cell repertoire is a mechanism that contributes to spontaneous occurrence of Hodgkin's-like lymphoma in aged SJL/J mice...
  15. pmc Ethanol exposure impairs LPS-induced pulmonary LIX expression: alveolar epithelial cell dysfunction as a consequence of acute intoxication
    James E Walker
    Section of Pulmonary and Critical Care Medicine, Department of Medicine, Louisiana State University Health Sciences Center, 1901 Perdido Street, New Orleans, LA 70112, USA
    Alcohol Clin Exp Res 33:357-65. 2009
    ..The effect of acute alcohol intoxication on AE2 cell expression of LIX is unknown...
  16. pmc Intrapulmonary G-CSF rescues neutrophil recruitment to the lung and neutrophil release to blood in Gram-negative bacterial infection in MCP-1-/- mice
    Gayathriy Balamayooran
    Laboratory of Lung Biology, Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA
    J Immunol 189:5849-59. 2012
    ..pneumoniae pneumonia and illustrate that G-CSF could be used to rescue impairment in host immunity in individuals with absent or malfunctional MCP-1...

Research Grants30

  1. Mental Stress Ischemia: Prognosis and Genetic Influences
    Arshed A Quyyumi; Fiscal Year: 2013
    ....
  2. Pulmonary Defenses Against Intracellular Infection
    Shawn J Skerrett; Fiscal Year: 2013
    ....
  3. A TOLERANCE APPROACH TO XENOTRANSPLANTATION
    David H Sachs; Fiscal Year: 2013
    ..abstract_text> ..
  4. Host-pathogen competition in IFN mediated antiviral defense
    Jae U Jung; Fiscal Year: 2013
    ....
  5. THE OUTER MEMBRANE AS A VIRULENCE PLATFORM
    DAVID ALAN HUNSTAD; Fiscal Year: 2013
    ..Understanding the functions of OmpA will lead to new strategies for preventing and treating bacterial infections. ..
  6. Molecular mechanisms of hypoxia tolerance and susceptibility
    Gabriel G Haddad; Fiscal Year: 2013
    ..abstract_text> ..
  7. INNATE IMMUNE RESPONSE TO MICROBIAL INFECTION
    William M Nauseef; Fiscal Year: 2013
    ....
  8. CHEMISTRY AND BIOLOGY OF HEPARAN SULFATE
    UMESH RAMANLAL DESAI; Fiscal Year: 2013
    ..End of Abstract) ..
  9. Transplant Tolerance in Non-Human Primates
    STUART JOHNSTON KNECHTLE; Fiscal Year: 2013
    ..This goal will be accomplished via four interrelated projects and two supporting cores. ..
  10. Primary Immune Deficiency Treatment Consortium
    Morton Cowan; Fiscal Year: 2013
    ..These studies will resolve critical questions concerning HCT for these disorders and form the basis for future prospective clinical trials. ..
  11. B Cells in Health and Disease
    IGNACIO E SANZ; Fiscal Year: 2013
    ..Finally, and central to this PPG, our results will greatly enhance our ability to design better and safer BCDT therapies and to develop biomarkers of B cell targeted treatments efficacy and safety. ..
  12. NOD-Like Receptor Signaling is Critical to Secondhand Smoke-Induced Immunity and
    Sanjay Batra; Fiscal Year: 2013
    ..Unique resources include NALP12 knockout mice and human alveolar macrophages. The R15 mechanism will help to train undergraduates including minority students in the field of emerging and devastating lung diseases such as COPD/Emphysema. ..
  13. Cell Adhesion Mechanisms in Vascular Disease &Thrombosis
    MARK HOWARD GINSBERG; Fiscal Year: 2013
    ..abstract_text> ..
  14. Pulmonary Pathogen-Recognition Pathways in Melioidosis
    TIMOTHY EOIN WEST; Fiscal Year: 2013
    ..The findings may also be applicable to other respiratory infections - leading causes of death and disability worldwide that disproportionately impact the poor. ..
  15. Immune-Based Interventions Against Infectious Diseases
    Alan L Rothman; Fiscal Year: 2013
    ..3. Recruit promising junior investigators and provide mentoring by established NIH-funded researchers. 4. Support a multidisciplinary research program led by junior investigators in translational infectious diseases immunology. ..
  16. Oklahoma Center for Respiratory and Infectious Diseases
    Lin Liu; Fiscal Year: 2013
    ..The completion of the goals of the present COBRE will have a major impact on research programs on respiratory infectious diseases in the State of Oklahoma. ..
  17. Endothelial Injury and Repair: CardioPulmonary Vascular Biology COBRE
    SHARON IRENE SMITH ROUNDS; Fiscal Year: 2013
    ..abstract_text> ..
  18. Pacific NorthWest Regional Center of Excellence (PNWRCE)
    Jay A Nelson; Fiscal Year: 2013
    ..pseudomallei host pathogen response during both the septicemic as well as the intracellular phases of the disease. ..
  19. Northeast Biodefense Center
    W Ian Lipkin; Fiscal Year: 2013
    ..As a Center based in a School of Public Health and a State Department of Health, the NBC has a firm commitment to and practical understanding of Emergency Preparedness. ..
  20. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
    ..The insights gained from the data generated from these studies will provide novel molecular targets for the development of new therapeutic strategies to treat patients with lung injury. ..
  21. Molecular Analyses and Interventions for Biodefense and Emerging Pathogens
    Olaf Schneewind; Fiscal Year: 2013
    ..Research and training at the GLRCE is governed by a mechanism involving ongoing review of scientific excellence and translational goals, inter-institutional advisory boards and external scientific advisory bodies. ..
  22. Linking the physical and chemical characteristics of Qdots to their toxicity
    TERRANCE JAMES KAVANAGH; Fiscal Year: 2013
    ..These advances can then be used in safe design and manufacturing of nanomaterials so as to maximize their utility for many applications. ..
  23. Integrating Structive Activity, Biokinetics and Response for ENP Risk Assessment
    Brian D Thrall; Fiscal Year: 2013
    ....
  24. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  25. Improving Cardiac Function After Myocardial Infarction
    Steven R Houser; Fiscal Year: 2013
    ..A gene vector core will generate AAV6 vectors with novel therapeutics for testing in the pig Ml model. An administrative core will ensure data sharing and effective use of all resources. ..
  26. Immune Regulation of Virus Clearance and Tissue Injury at Sites of Infection
    Thomas J Braciale; Fiscal Year: 2013
    ..To determine the impact of viral infection on the production of Te-derived IL- 10. The proposed studies are designed to complement ongoing related studies in Projects 2, 3 and 4. ..