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Fungal airway infection and proteinase-dependent atopy and asthma: an emerging paradigm Asthma is an Inflammatory Disease of the Airways (Adapted from Greenlee, Werb, Kheradmand; Physiol Review 2007 Jan;87(1):69-98, nhlbi.nih.gov/health/dci/images/asthma.gif and apps.uwhealth.org/images/en/19321.jpg) What Can The Mouse Tell Us About Asthma? Eosinophil Corry, D.B. Caveats 1. The exogenous (environmental) causes of asthma remain obscure. 2. These findings were derived from an experimental model using ovalbumin, an allergen with no human disease relevance. Proteinases and Asthma Natural Sources of Proteases Linked to Asthma Fungi Pollen Intestinal worms Integration of Innate and Adaptive Immune Signaling Pathways 1 Proteolytic Allergen Th2 Cell (IL-13) 4 3 2 Pro-Allergic Chemokines CCL17, CCL7, Kiss A, et. al.,. J Allergy Clin Immunol 2007; 120:334-342 How Do Microbial Proteinases Relate to Asthma? Can we learn more about the environmental causes of asthma by sifting through house dust? Typical Fungal Crop From a Houston House Dust Sample Fungal Infection Versus Fungal Hypersensitivity? Paul Porter, PhD P.Porter, PhD Zymogram of House Dust Reveals Active Fungal Proteinases 200kDa 85kDa Fungal Culture From Sample #12 Dust Sample #12 Fungal Culture From Sample #24 Dust Sample #24 P Porter, et al. Mucosal Immunol. 2009; 2:504-517 7kDa Aspergillus niger • Reservoirs: found ubiquitously in soil world wild and common in homes. • Human infections (rare): Invasive sinobronchial aspergillosis, otomycosis • Many industrial uses: food industry • 80-85% of secreted protease is aspergillopepsin I (43kDa) P.Porter, PhD Viable Fungal Spores (A. niger) Are Required for Allergic Lung Disease P Porter, et al. Mucosal Immunol. 2009; 2:504-517 Universal Potential for AHR Induced by Household Fungi P. Porter et al., submitted Mouse BAL Fluid Hyphae (A. niger) 1. 2. A common household fungus (A. niger) readily infects the mouse airway Airway fungal infection both elicits and is required for allergic lung disease. Is this ABPA? Paul Porter, PhD Conidia-Dependent Allergic Lung Disease Is Dose Dependent P Porter, et al. Mucosal Immunol. 2009; 2:504-517 Low-Grade A. niger Infection Induces Atopy to Innocuous Antigens and Synergistic ALD P Porter, et al. Mucosal Immunol. 2009; 2:504-517 Ovalbumin-Specific Th2 Responses Generated in Spleen by Fungal Infection P Porter, et al. Mucosal Immunol. 2009; 2:504-517 Summary 1. A ubiquitous household fungus (A. niger) accounts for much of the detectable household proteinase activity in Houston. 2. A. niger infection induces allergic lung disease in mice through active infection. 3. A. niger induces atopy to bystander antigens, but not itself. Paul Porter, PhD Putative Spectrum of FungalDependent Allergic Lung Disease Antibody negative Antibody positive Fungal Infectious Burden Disease Severity IL-13 is Required for Fungal Clearance P Porter, et al. Mucosal Immunol. 2009; 2:504-517 Mouse Eosinophils Are Fungicidal A. fumigatus P Porter, et al. Mucosal Immunol. 2009; 2:504-517 Conclusions 1. A. niger and other fungi cause allergic lung disease through airway infection and secretion of proteinases. 2. Common household fungi are candidate infectious causes of human respiratory tract allergic diseases and atopy. Future Studies Apply advanced methods of detection and immunodiagnosis to determine the etiological role of fungi in all forms of asthma. Many Thanks To: Baylor College of Medicine Farrah Kheradmand Stuart Abramson Sumanth Polikepahad Morgan Knight Paul Porter Yuping Qian Wendy Tai LaKeisha Batts Luz Roberts Alexander Seryshev Tianshu Yang Wen Lu Valentine Ongeri Manisha Singh Jeong-Soo Hong Anna Fields U. TX. Health Sciences Center George L. Delclos Joy De Los Reyes Supported by: NIH: HL075243, AI057696, AI070973, HL095382