MECHANISM OF IL-12 INHIBITION BY CANDIDA ALBICANS

Summary

Principal Investigator: M A Ghannoum
Abstract: DESCRIPTION (provided by applicant): Host response to Candida infection is a complex interplay between innate and adaptive immunity. The first line of defense against candidiasis is the innate immune response, which involves stimulation of proinflammatory cytokines like interleukin-12 (IL-12) and/or inhibition of anti-inflammatory cytokines (e.g., IL-10) by the host monocytes (MNs)/macrophages (MOs). Many pathogenic microbes overcome host immune response by suppressing IL-12 production. The overall hypothesis of the current proposal is that CA secretes a soluble glycoprotein, which inhibits production of IL-12 by host MNs/MOs, thereby helping the pathogen invade host tissues. In support of this hypothesis, we demonstrated that (i) CA cells inhibit IL-12 production by MNs (Publication 8,9, Appendix 2), (ii) inhibition of IL-12 production by CA culture supernatant is mediated by Secretory IL-12 Inhibitory Factor (CA-SIIF, Publication 10, Appendix 2), (iii) CA-SIIF is not the candidal phospholipase B (Plb1p) enzyme/protein, (iv) CA-SIIF is a heat-resistant, non-enzymatic glycoprotein of size >30 kDa, (v) CA-SIIF is Candida-specific, (vi) CA-SIIF inhibits IL-12 production by both murine and human MNs, (vii) intravenous (I.V.) injection of CA-SIIF in mice induces a reduction in the murine serum levels of IL-12, and (viii) the mechanism of CA-SIIF-mediated IL-12 inhibition involves the ERK MAPK signaling pathway (see Publication 10, Appendix 2). In the current proposal, we will purify and characterize CA-SIIF, and determine its mechanism/s of action under in vitro and in vivo conditions. Specific aims of the current proposal are: Aim I: (A) Purification and identification of CA-SIIF protein/s. (B) Characterization of the IL-12 inhibitory activity of purified CA-SIIF;Aim Il: (A) Construct a C. albicans delta casiif null mutant strain disrupted for CA-SIIF gene/s, and the corresponding revertant strain (SlIFr) with the CA-SIIF gene reintroduced. (B) Construct a C. albicans strain that produces recombinant CA-SIIF protein (FLAG-CASIIF) tagged to FLAG epitope;Aim IIl: Determine the mechanism by which CA-SIIF inhibits IL-12 production by MNs/MOs and dendritic cells;and Aim IV: (A) Determine whether a biologically relevant CA infection in vivo results in decreased IL-12 production. (B) Determine whether CA-SIIF inhibition of IL-12 is niche-specific. Data obtained from these studies will lead to a better understanding of the complex immune response to CA infection and may identify novel prevention/treatment strategies for candidiasis.
Funding Period: 1995-09-30 - 2010-01-31
more information: NIH RePORT

Top Publications

  1. pmc Metabolomics reveals differential levels of oral metabolites in HIV-infected patients: toward novel diagnostic targets
    Mahmoud A Ghannoum
    Center for Medical Mycology, Case Western Reserve University, Ohio 44106 5028, USA
    OMICS 17:5-15. 2013
  2. pmc Characterization of bacterial communities in venous insufficiency wounds by use of conventional culture and molecular diagnostic methods
    Marie S Tuttle
    Case Western Reserve University, University Hospitals Case Medical Center, Department of Dermatology, Cleveland, OH 44106, USA
    J Clin Microbiol 49:3812-9. 2011
  3. pmc Lipidomics of Candida albicans biofilms reveals phase-dependent production of phospholipid molecular classes and role for lipid rafts in biofilm formation
    Ali Abdul Lattif
    Center for Medical Mycology, University Hospitals Case Medical Center, and Department of Dermatology, Case Western Reserve University, 11100 Euclid Ave, Cleveland, OH 44106 502, USA
    Microbiology 157:3232-42. 2011
  4. pmc Interaction of Candida albicans with adherent human peripheral blood mononuclear cells increases C. albicans biofilm formation and results in differential expression of pro- and anti-inflammatory cytokines
    Jyotsna Chandra
    Center for Medical Mycology, University Hospitals Case Medical Center, Cleveland, OH, USA
    Infect Immun 75:2612-20. 2007
  5. pmc MyD88 regulation of Fusarium keratitis is dependent on TLR4 and IL-1R1 but not TLR2
    Ahmad B Tarabishy
    Department of Ophthalmology and Visual Sciences, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, OH 44106, USA
    J Immunol 181:593-600. 2008
  6. ncbi In vitro growth and analysis of Candida biofilms
    Jyotsna Chandra
    Center for Medical Mycology and Department of Dermatology, University Hospitals Case Medical Center, Case Western Reserve University, 11100 Euclid Avenue, Cleveland, Ohio 44106, USA
    Nat Protoc 3:1909-24. 2008

Scientific Experts

  • Marie S Tuttle
  • Mahmoud A Ghannoum
  • Pranab K Mukherjee
  • Jyotsna Chandra
  • Ali Abdul Lattif
  • Ahmad B Tarabishy
  • Yoshifumi Imamura
  • Robert E Brown
  • Jennifer Webster-Cyriaque
  • Masoumeh Sikaroodi
  • Patrick M Gillevet
  • Mauricio Retuerto
  • Richard J Jurevic
  • Mahmoud Rouabhia
  • Ruth Welti
  • Mary R Roth
  • Jonathan H Lass
  • Eric Pearlman
  • Yan Sun
  • Bishr Aldabagh
  • Thomas S McCormick

Detail Information

Publications6

  1. pmc Metabolomics reveals differential levels of oral metabolites in HIV-infected patients: toward novel diagnostic targets
    Mahmoud A Ghannoum
    Center for Medical Mycology, Case Western Reserve University, Ohio 44106 5028, USA
    OMICS 17:5-15. 2013
    ....
  2. pmc Characterization of bacterial communities in venous insufficiency wounds by use of conventional culture and molecular diagnostic methods
    Marie S Tuttle
    Case Western Reserve University, University Hospitals Case Medical Center, Department of Dermatology, Cleveland, OH 44106, USA
    J Clin Microbiol 49:3812-9. 2011
    ..Thus, pyrosequencing identified distinctive baseline characteristics of wounds that did not heal by the 6-month follow-up, furthering our understanding of potentially unique microbiome characteristics of chronic wounds...
  3. pmc Lipidomics of Candida albicans biofilms reveals phase-dependent production of phospholipid molecular classes and role for lipid rafts in biofilm formation
    Ali Abdul Lattif
    Center for Medical Mycology, University Hospitals Case Medical Center, and Department of Dermatology, Case Western Reserve University, 11100 Euclid Ave, Cleveland, OH 44106 502, USA
    Microbiology 157:3232-42. 2011
    ..albicans to form biofilms. The differences in lipid profiles between biofilms and planktonic Candida cells may have important implications for the biology and antifungal resistance of biofilms...
  4. pmc Interaction of Candida albicans with adherent human peripheral blood mononuclear cells increases C. albicans biofilm formation and results in differential expression of pro- and anti-inflammatory cytokines
    Jyotsna Chandra
    Center for Medical Mycology, University Hospitals Case Medical Center, Cleveland, OH, USA
    Infect Immun 75:2612-20. 2007
    ..Our studies provide new insight into the interaction between Candida biofilm and host immune cells and demonstrate that immunocytes may influence the ability of C. albicans to form biofilms...
  5. pmc MyD88 regulation of Fusarium keratitis is dependent on TLR4 and IL-1R1 but not TLR2
    Ahmad B Tarabishy
    Department of Ophthalmology and Visual Sciences, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, OH 44106, USA
    J Immunol 181:593-600. 2008
    ..Together, these findings indicate that IL-1R1 and MyD88 regulate CXC chemokine production and neutrophil recruitment to the cornea, and that TLR4 has an important role in controlling growth and replication of these pathogenic fungi...
  6. ncbi In vitro growth and analysis of Candida biofilms
    Jyotsna Chandra
    Center for Medical Mycology and Department of Dermatology, University Hospitals Case Medical Center, Case Western Reserve University, 11100 Euclid Avenue, Cleveland, Ohio 44106, USA
    Nat Protoc 3:1909-24. 2008
    ..The methods described here can be completed in a typical laboratory with minimum involvement of software. Evaluation of the growth of fungal biofilms and their analyses can be completed using the described methods in approximately 15 d...