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 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
  2. 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
  3. 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
  4. 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
  5. doi 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

Scientific Experts

  • John R Erb-Downward
  • Gary B Huffnagle
  • Katie L Mason
  • Andrew Shreiner
  • Tobias E Rodriguez
  • Jami E Milam
  • Mairi C Noverr
  • Raj Pandrangi
  • Nicole R Falkowski
  • Roderick A McDonald
  • Jack R Harkema
  • Galen B Toews
  • Amy C Herring-Palmer

Detail Information

Publications5

  1. 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
    ....
  2. 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
    ....
  3. 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...
  4. 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...
  5. doi 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
    ....