Role of Fungal Microflora in Mucosal Tolerance/Immunity

Summary

Principal Investigator: GARY HUFFNAGLE
Affiliation: University of Michigan
Country: USA
Abstract: In the past 40 years, the rates of asthma and allergies have increased dramatically in westernized countries (>30% of school age children in the US, Great Britain, New Zealand and Australia currently have asthma). The mechanism(s) underlying this increase is unknown. However, this staggering increase in the incidence of asthma in this time frame indicates that factors beyond genetics play a major role in the development of the disease. Numerous epidemiologic studies in humans have shown a correlation between antibiotic use or altered fecal microflora and the development of allergies. The hypothesis of this proposal is that the microflora plays a central role in maintaining mucosal tolerance to inhaled/swallowed antigens, which prevents the development of over-exuberant inflammatory responses to these antigens (i. e. allergies). Thus, changes in microflora populations, including increased growth of fungal microflora (Candida), decrease mucosal tolerance resulting in the development of allergic responses to inhaled allergens. Antibiotics and diet have a major impact on the composition of the microflora. We have generated an animal model to test this hypothesis and our preliminary studies with this model support the concept that altered microflora can be a potential mechanism underlying the development of allergic airway disease. The specific aims of this proposal are the following: 1. To analyze the dynamics of microbiota reconstitution that occurs following the cessation of antibiotics in the presence and absence of Candida in the gastrointestinal tract. 2. To determine the effect of different Candida species and isolates on disrupting mucosal tolerance and to determine the duration of defective mucosal tolerance. 3. To analyze the contribution of Candida "virulence" factors in disrupting mucosal tolerance in mice during Candida persistence in the Gl tract. 4. To determine whether antibiotic-induced microbiota disruption alters the development of antigen-specific regulatory T cell responses for the lungs. These studies will provide the basic science foundation for future studies in humans for understanding how and why manipulation of the microflora (by diet or probiotics) can alter or prevent allergies.
Funding Period: 2005-04-01 - 2010-03-31
more information: NIH RePORT

Top Publications

  1. pmc The emerging world of the fungal microbiome
    Gary B Huffnagle
    Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
    Trends Microbiol 21:334-41. 2013
  2. pmc Significance of the microbiome in obstructive lung disease
    MeiLan K Han
    Division of Pulmonary and Critical Care Medicine, University of Michigan Health System, 3916 Taubman Center, Box 5360, 1500 E Medical Center Drive, Ann Arbor, MI 48109 5360, USA
    Thorax 67:456-63. 2012
  3. pmc Ecological succession of bacterial communities during conventionalization of germ-free mice
    Merritt G Gillilland
    Division of Pulmonary and Critical Care Medicine, The University of Michigan Medical School, Ann Arbor, Michigan, USA
    Appl Environ Microbiol 78:2359-66. 2012
  4. pmc Interleukin-17 drives pulmonary eosinophilia following repeated exposure to Aspergillus fumigatus conidia
    Benjamin J Murdock
    Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
    Infect Immun 80:1424-36. 2012
  5. pmc Repeated exposure to Aspergillus fumigatus conidia results in CD4+ T cell-dependent and -independent pulmonary arterial remodeling in a mixed Th1/Th2/Th17 microenvironment that requires interleukin-4 (IL-4) and IL-10
    Andrew B Shreiner
    Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
    Infect Immun 80:388-97. 2012
  6. pmc Interplay between the gastric bacterial microbiota and Candida albicans during postantibiotic recolonization and gastritis
    Katie L Mason
    Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
    Infect Immun 80:150-8. 2012
  7. pmc Coevolution of TH1, TH2, and TH17 responses during repeated pulmonary exposure to Aspergillus fumigatus conidia
    Benjamin J Murdock
    Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109 5642, USA
    Infect Immun 79:125-35. 2011
  8. ncbi Control of mucosal polymicrobial populations by innate immunity
    Katie L Mason
    Pulmonary Division, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
    Cell Microbiol 11:1297-305. 2009
  9. doi The "Microflora Hypothesis" of allergic disease
    Andrew Shreiner
    Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
    Adv Exp Med Biol 635:113-34. 2008
  10. pmc Role of neutrophils in preventing and resolving acute fungal sinusitis
    Tobias E Rodriguez
    Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109 0642, USA
    Infect Immun 75:5663-8. 2007

Scientific Experts

  • MeiLan K Han
  • John R Erb-Downward
  • Gary B Huffnagle
  • Benjamin J Murdock
  • Andrew B Shreiner
  • Nicole R Falkowski
  • Katie L Mason
  • Galen B Toews
  • Eric S White
  • Roderick A McDonald
  • Merritt G Gillilland
  • Amir A Sadighi Akha
  • Vincent B Young
  • Mairi C Noverr
  • Andrew Shreiner
  • Tobias E Rodriguez
  • Jami E Milam
  • Cory M Hogaboam
  • Michael C Shen
  • Christine M Bassis
  • John Y Kao
  • John R Erb Downward
  • Paul J Christensen
  • John J Osterholzer
  • Jack R Harkema
  • Amy C Herring-Palmer
  • Raj Pandrangi

Detail Information

Publications12

  1. pmc The emerging world of the fungal microbiome
    Gary B Huffnagle
    Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
    Trends Microbiol 21:334-41. 2013
    ..However, the impact of the mycobiome on human health is significant, especially as a reservoir for blooms of pathogenic microbes when the host is compromised and as a potential cofactor in inflammatory diseases and metabolic disorders. ..
  2. pmc Significance of the microbiome in obstructive lung disease
    MeiLan K Han
    Division of Pulmonary and Critical Care Medicine, University of Michigan Health System, 3916 Taubman Center, Box 5360, 1500 E Medical Center Drive, Ann Arbor, MI 48109 5360, USA
    Thorax 67:456-63. 2012
    ..Whether we can manipulate bacterial communities to improve clinical outcomes remains to be seen...
  3. pmc Ecological succession of bacterial communities during conventionalization of germ-free mice
    Merritt G Gillilland
    Division of Pulmonary and Critical Care Medicine, The University of Michigan Medical School, Ann Arbor, Michigan, USA
    Appl Environ Microbiol 78:2359-66. 2012
    ....
  4. pmc Interleukin-17 drives pulmonary eosinophilia following repeated exposure to Aspergillus fumigatus conidia
    Benjamin J Murdock
    Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
    Infect Immun 80:1424-36. 2012
    ..These observations point to an expanded role for IL-17 in driving T(H)2-type inflammation to repeated inhalation of fungal conidia...
  5. pmc Repeated exposure to Aspergillus fumigatus conidia results in CD4+ T cell-dependent and -independent pulmonary arterial remodeling in a mixed Th1/Th2/Th17 microenvironment that requires interleukin-4 (IL-4) and IL-10
    Andrew B Shreiner
    Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
    Infect Immun 80:388-97. 2012
    ..Remodeling was completely abrogated in IL-10-/- mice, suggesting that a second, CD4+ T cell-independent, IL-10-dependent pathway was also driving pulmonary arterial remodeling in response to repeated conidial exposure...
  6. pmc Interplay between the gastric bacterial microbiota and Candida albicans during postantibiotic recolonization and gastritis
    Katie L Mason
    Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
    Infect Immun 80:150-8. 2012
    ..albicans. Altogether, these data implicate a dichotomy between C. albicans colonization and gastric disease that is bacterial microbiome dependent...
  7. pmc Coevolution of TH1, TH2, and TH17 responses during repeated pulmonary exposure to Aspergillus fumigatus conidia
    Benjamin J Murdock
    Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109 5642, USA
    Infect Immun 79:125-35. 2011
    ..fumigatus conidia...
  8. ncbi Control of mucosal polymicrobial populations by innate immunity
    Katie L Mason
    Pulmonary Division, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
    Cell Microbiol 11:1297-305. 2009
    ....
  9. doi The "Microflora Hypothesis" of allergic disease
    Andrew Shreiner
    Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
    Adv Exp Med Biol 635:113-34. 2008
    ..In testing this hypothesis, our laboratory has recently reported that mice can develop allergic airway responses if their microbiota is altered at the time of first allergen exposure...
  10. pmc Role of neutrophils in preventing and resolving acute fungal sinusitis
    Tobias E Rodriguez
    Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109 0642, USA
    Infect Immun 75:5663-8. 2007
    ..These studies demonstrate the feasibility of using this model to study AFS and implicate neutrophils in protection of the sinuses against acute Aspergillus infection and in clearance of established hyphal masses...
  11. ncbi Role of oxylipins and other lipid mediators in fungal pathogenesis
    John R Erb-Downward
    University of Michigan Medical School, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Ann Arbor, MI 48109 0642, USA
    Future Microbiol 1:219-27. 2006
    ....
  12. pmc Modulation of the pulmonary type 2 T-cell response to Cryptococcus neoformans by intratracheal delivery of a tumor necrosis factor alpha-expressing adenoviral vector
    Jami E Milam
    Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109 0642, USA
    Infect Immun 75:4951-8. 2007
    ....