The medical community has long recognized fungi as important allergens for patients with asthma. Interestingly, fungal sensitization is more common in children and has been linked to severe asthma resulting in death. The accepted paradigm is that fungal sensitization occurs as a result of recurrent, transient environmental exposures. Yet, increasing evidence suggests that fungi may interact with people in unrecognized ways to promote asthma. My lab is interested in understanding the role of subclinical fungal infections in asthma and their potential contribution to the high prevalence of asthma in urban areas.
Cryptococcus neoformans is an encapsulated fungus that is well suited to serve as co-factor in urban asthma. C. neoformans colonizes pigeon droppings and is endemic to urban areas. Once inhaled, this fungus causes persistent, subclinical infections. We have demonstrated that the majority of Bronx children older than 2 years have serologic evidence of cryptococcal infection. Cryptococcal infection induces TH2 inflammation in animal models. In a rat model, we have shown that cryptococcal pulmonary infection acts a co-factor to enhance allergic inflammation to allergen challenge and promotes airway hyper-responsiveness, both hallmark features of asthma. Pulmonary cryptococcosis also induces chitinase expression, which has recently been implicated as an essential mediator of allergic inflammation.
To study this phenomenon, we have established collaborations with Pulmonary Medicine, Critical Care and Emergency Medicine at the ChildrenÃ¢â‚¬â„¢s Hospital of Montefiore. These collaborations provide access to the large number of children with asthma in the Bronx. Current studies underway include a characterization of chitinase expression among asthmatics and a comparison of cryptococcal infection prevalence among asthmatics and non-asthmatics. Animal experimentation directed at understanding the mechanisms and variables related to fungal induced asthma are also underway.
In addition to fungal studies, my lab is interested in anthrax pathogenesis. Bacillus anthracis is widely recognized as a potential agent of bioterrorism as evidenced by the 2001 anthrax attack. The toxins of B. anthracis are essential to virulence. In collaborations with Drs. Arturo Casadevall and Jurgen Brojatsch, we have studied the mechanisms by which Bacillus anthracis toxins contribute to host death. We have identified a previously unrecognized protease in human serum that inactivates the protective antigen component of lethal toxin in vitro. The precise protease and its role in the host response and susceptibility to anthrax remain to be determined. We have also identified a potential role for platelet activating factor (PAF) in mediating the lethal effects of toxin, including the alterations in vascular permeability which is characteristic of anthrax. Together, these observations may have important implications in developing new approaches to the treatment of anthrax.
1. Fungal sensitization in childhood persistent asthma is associated with disease severity. Vicencio AG, Santiago MT, Tsirilakis K, Stone A, Worgall S, Foley EA, Bush D, Goldman DL. Pediatr Pulmonol. 2013 Feb 8. doi: 10.1002/ppul.22779. [Epub ahead of print]
2. Increased chitinase expression and fungal-specific antibodies in the bronchoalveolar lavage fluid of asthmatic children. Goldman DL, Li X, Tsirilakis K, Andrade C, Casadevall A, Vicencio AG. Clin Exp Allergy. 2012 Apr;42(4):523-30. doi: 10.1111/j.1365-2222.2011.03886.x. Epub 2011 Oct 10.
3. CHIT1 mutations: genetic risk factor for severe asthma with fungal sensitization? Vicencio AG, Chupp GL, Tsirilakis K, He X, Kessel A, Nandalike K, Veler H, Kipperman S, Young MC, Goldman DL.
Pediatrics. 2010 Oct;126(4):e982-5. doi: 10.1542/peds.2010-0321. Epub 2010 Sep 6.
4. Proteasome inhibitors prevent caspase-1-mediated disease in rodents challenged with anthrax lethal toxin.Muehlbauer SM, Lima H Jr, Goldman DL, Jacobson LS, Rivera J, Goldberg MF, Palladino MA, Casadevall A, Brojatsch J. Am J Pathol. 2010 Aug;177(2):735-43. doi: 10.2353/ajpath.2010.090828. Epub 2010 Jul 1. Erratum in: Am J Pathol. 2010 Oct;177(4):2145.
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Montefiore Medical Center
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Bronx, NY 10467