Host response to P. carinii in neonatal mice

Summary

Principal Investigator: Beth A Garvy
Abstract: DESCRIPTION (provided by applicant): Pneumocystis pneumonia PCP) causes significant morbidity and mortality among HIV-infected individuals who are newly diagnosed, failed retroviral therapy, or do not have access to care. Infants are particularly susceptible to pulmonary infections and it has been recently appreciated that not only are individuals exposed to Pneumocystis early in life, but infants appear to carry the infection as evidenced by the high incidence found in autopsy specimens from babies that died of SIDS. HIV-infected infants tend to have a more fulminant course of PCP, likely because of the immature immune system along with depletion of CD4+ cells. In the previous funding period we found that, in contrast to our hypothesis, the delay in clearance of Pneumocystis we observed in neonatal mice was not solely due to elevated anti-inflammatory cytokines in the lungs through the first 3 weeks of life. Instead, we found that alveolar macrophages from neonatal mice are intrinsically unresponsive to Pneumocystis. The goal for this funding period is to differentiate the contribution of environmental factors and intrinsic factors to neonatal alveolar macrophage function in response to Pneumocystis. Specifically, we will test the hypothesis that: neonatal alveolar macrophages fail to respond to Pneumocystis due to a defect in signaling through pattern recognition receptors along with delayed second signals from proinflammatory cytokines or costimulatory molecules on T cells. To address this hypothesis we have proposed two aims. 1. We will determine whether alveolar macrophages from neonatal mice are intrinsically unresponsive to Pneumocystis. In vitro and in vivo experimental strategies will be used to determine whether neonatal alveolar macrophages can respond to stimuli through the dectin-1 ?-glucan receptor, mannose receptor, or TLR2. 2. We will determine whether secondary signals from T cells are required to stimulate neonatal alveolar macrophages. We will use adoptive transfer of cells and treatment with exogenous stimulatory molecules in an attempt to stimulate alveolar macrophages to respond to Pneumocystis. These studies are a logical extension of our previous funding period and will address the mechanisms responsible for neonatal unresponsiveness Pneumocystis.
Funding Period: 1998-09-30 - 2014-06-30
more information: NIH RePORT

Top Publications

  1. pmc Exogenous heat-killed Escherichia coli improves alveolar macrophage activity and reduces Pneumocystis carinii lung burden in infant mice
    Kerry M Empey
    Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky Medical Center, 800 Rose Street, Lexington, KY 40536 0298, USA
    Infect Immun 75:3382-93. 2007
  2. pmc Scavenger receptor A dampens induction of inflammation in response to the fungal pathogen Pneumocystis carinii
    Melissa Hollifield
    University of Kentucky Chandler Medical Center, 800 Rose Street, Lexington, KY 40536 0298, USA
    Infect Immun 75:3999-4005. 2007
  3. pmc Increased weight loss with reduced viral replication in interleukin-10 knock-out mice infected with murine cytomegalovirus
    O R Oakley
    Department of Clinical Sciences, University of Kentucky, Lexington, KY 40536 0084, USA
    Clin Exp Immunol 151:155-64. 2008
  4. pmc The migration of T cells in response to influenza virus is altered in neonatal mice
    J Louise Lines
    Department of Microbiology, Immunology, and Molecular Genetics, College of Medicine, University of Kentucky, Lexington, KY 40506, USA
    J Immunol 185:2980-8. 2010
  5. pmc Alveolar macrophages in neonatal mice are inherently unresponsive to Pneumocystis murina infection
    Cathryn Kurkjian
    Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, Kentucky, USA
    Infect Immun 80:2835-46. 2012

Research Grants

  1. Non-CD4 Host defense against P. carinii Pneumonia
    Jay K Kolls; Fiscal Year: 2013
  2. Oxidation in Inflammation and Cardiovascular Disease
    Stanley L Hazen; Fiscal Year: 2013
  3. Endothelial Injury and Repair: CardioPulmonary Vascular Biology COBRE
    SHARON IRENE SMITH ROUNDS; Fiscal Year: 2013
  4. New Approaches To Cardiothoracic Tolerance Induction
    Joren C Madsen; Fiscal Year: 2013
  5. Vascular Subphenotypes of Lung Disease
    Mark T Gladwin; Fiscal Year: 2013
  6. Gene Networks controlling macrophage-adipocyte interactions in insulin
    Christopher K Glass; Fiscal Year: 2013
  7. Flavivirus Infections: Pathogenesis and Prevention
    Alan L Rothman; Fiscal Year: 2013
  8. B cell immunity in HIV exposed uninfected infants in Kenya
    Arlene Dent; Fiscal Year: 2013
  9. PATHOPHYSIOLOGY OF THE ENDOTHELIUM
    Francis W Luscinskas; Fiscal Year: 2013
  10. ADAPTATIONS TO HYPOXIA
    Kurt R Stenmark; Fiscal Year: 2013

Detail Information

Publications5

  1. pmc Exogenous heat-killed Escherichia coli improves alveolar macrophage activity and reduces Pneumocystis carinii lung burden in infant mice
    Kerry M Empey
    Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky Medical Center, 800 Rose Street, Lexington, KY 40536 0298, USA
    Infect Immun 75:3382-93. 2007
    ..The lack of response of pup mice to P. carinii f. sp. muris may reflect protective mechanisms specific to the developing pup lung, but ultimately it results in insufficient clearance of Pneumocystis organisms...
  2. pmc Scavenger receptor A dampens induction of inflammation in response to the fungal pathogen Pneumocystis carinii
    Melissa Hollifield
    University of Kentucky Chandler Medical Center, 800 Rose Street, Lexington, KY 40536 0298, USA
    Infect Immun 75:3999-4005. 2007
    ..carinii infection than did wild-type mice. Together, these data indicate that SRA controls inflammatory cytokines produced by alveolar macrophages in the context of P. carinii infection...
  3. pmc Increased weight loss with reduced viral replication in interleukin-10 knock-out mice infected with murine cytomegalovirus
    O R Oakley
    Department of Clinical Sciences, University of Kentucky, Lexington, KY 40536 0084, USA
    Clin Exp Immunol 151:155-64. 2008
    ..These data suggest that increased weight loss observed in IL-10 knock-out mice may be attributed to the uncontrolled production of proinflammatory cytokines, including IL-6...
  4. pmc The migration of T cells in response to influenza virus is altered in neonatal mice
    J Louise Lines
    Department of Microbiology, Immunology, and Molecular Genetics, College of Medicine, University of Kentucky, Lexington, KY 40506, USA
    J Immunol 185:2980-8. 2010
    ..Together, these data suggest that the T cell response to influenza virus is qualitatively different in neonatal mice and may contribute to an increased morbidity...
  5. pmc Alveolar macrophages in neonatal mice are inherently unresponsive to Pneumocystis murina infection
    Cathryn Kurkjian
    Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, Kentucky, USA
    Infect Immun 80:2835-46. 2012
    ..These data indicate that there is an early unresponsiveness of neonatal alveolar macrophages to Pneumocystis infection that is both intrinsic and related to the immunosuppressive environment found in neonatal lungs...

Research Grants30

  1. Non-CD4 Host defense against P. carinii Pneumonia
    Jay K Kolls; Fiscal Year: 2013
    ..3. Test the hypothesis that the combination of anti-Kex1 and anti-carbohydrate antibodies can mediate primary prophylaxis or treatment of PCP in T-cell deficient mice. ..
  2. Oxidation in Inflammation and Cardiovascular Disease
    Stanley L Hazen; Fiscal Year: 2013
    ..It may also lead to important insights for atherosclerosis risk assessment, diagnosis and therapy. ..
  3. Endothelial Injury and Repair: CardioPulmonary Vascular Biology COBRE
    SHARON IRENE SMITH ROUNDS; Fiscal Year: 2013
    ..abstract_text> ..
  4. New Approaches To Cardiothoracic Tolerance Induction
    Joren C Madsen; Fiscal Year: 2013
    ..We anticipate ongoing progress will continue to contribute to a reduction in the morbidity and mortality associated with solid organ transplantation. ..
  5. Vascular Subphenotypes of Lung Disease
    Mark T Gladwin; Fiscal Year: 2013
    ..vascular disease Project 3: Pulmonary vascular-targeted NO therapeutic strategies Core A: Administrative core Core B: Pre-Clinical Models of PAH Core C: Translational Vascular Phenomics, Genomics and Epidemiology Core ..
  6. Gene Networks controlling macrophage-adipocyte interactions in insulin
    Christopher K Glass; Fiscal Year: 2013
    ..abstract_text> ..
  7. Flavivirus Infections: Pathogenesis and Prevention
    Alan L Rothman; Fiscal Year: 2013
    ..The findings from these proposed research studies should have broad basic science as well as clinical and public health implications. ..
  8. B cell immunity in HIV exposed uninfected infants in Kenya
    Arlene Dent; Fiscal Year: 2013
    ..The long term results will advance fundamental knowledge of how in utero exposure to HIV affects fetal/infant B cell ontogeny and responses to vaccines of public health importance in resource-limited countries. ..
  9. PATHOPHYSIOLOGY OF THE ENDOTHELIUM
    Francis W Luscinskas; Fiscal Year: 2013
    ..g., heart attacks and strokes), as well as other organs and tissues of the body. These mechanistic insights may help identify novel therapeutic targets for the treatment of a broad spectrum of inflammatory diseases. ..
  10. ADAPTATIONS TO HYPOXIA
    Kurt R Stenmark; Fiscal Year: 2013
    ..abstract_text> ..
  11. A role of osteopontin in innate immunity against fungal infection
    Mari L Shinohara; Fiscal Year: 2013
    ..Relevance of this study to public health, upon successful completion, is to apply findings from this study to develop new approaches in prophylaxis and treatment of fungal infection in immunocompromised patients. ..