fungal airway infection and proteinase-dependent atopy and asthma: an emerging paradigm
TRANSCRIPT
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Fungal airway infection and proteinase-dependent atopy
and asthma: an emerging paradigm
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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)
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Eosinophil
Corry, D.B.
What Can The Mouse Tell Us About Asthma?
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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.
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Proteinases and Asthma
Natural Sources of Proteases Linked to Asthma
Fungi Intestinal wormsPollen
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Integration of Innate and Adaptive Immune Signaling Pathways
ProteolyticProteolyticAllergenAllergen11
Th2 CellTh2 Cell(IL-13)(IL-13) 44
Pro-Allergic Pro-Allergic ChemokinesChemokinesCCL17, CCL7, CCL17, CCL7, 22
33
Kiss A, et. al.,. J Allergy Clin Immunol 2007; 120:334-342
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Can we learn more about the environmental causes of asthma by sifting through house dust?
How Do Microbial Proteinases Relate to Asthma?
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Typical Fungal Crop From a Houston House Dust Sample
P.Porter, PhDPaul Porter, PhD
Fungal Infection
Versus
Fungal Hypersensitivity?
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Dust Sample #12Dust Sample #12
Fungal Culture Fungal Culture From Sample #12From Sample #12
Dust Sample #24Dust Sample #24
Fungal Culture Fungal Culture From Sample #24From Sample #24
85kDa85kDa
200kDa200kDa
7kDa7kDa
Zymogram of House Dust Reveals Active Fungal Proteinases
P Porter, et al. Mucosal Immunol. 2009; 2:504-517
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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 80-85% of secreted protease is aspergillopepsin I (43kDa)aspergillopepsin I (43kDa)
P.Porter, PhD
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Viable Fungal Spores (A. niger) Are Required for Allergic Lung Disease
P Porter, et al. Mucosal Immunol. 2009; 2:504-517
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Universal Potential for AHR Induced by Household Fungi
P. Porter et al., submitted
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Mouse BAL Fluid Hyphae (A. niger)
Paul Porter, PhD
1. A common household fungus (A. niger) readily infects the mouse airway
2. Airway fungal infection both elicits and is required for allergic lung disease.
Is this ABPA?
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Conidia-Dependent Allergic Lung Disease Is Dose Dependent
Conidia-Dependent Allergic Lung Disease Is Dose Dependent
P Porter, et al. Mucosal Immunol. 2009; 2:504-517
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Low-Grade A. niger Infection Induces Atopy to Innocuous Antigens and Synergistic ALD
Low-Grade A. niger Infection Induces Atopy to Innocuous Antigens and Synergistic ALD
P Porter, et al. Mucosal Immunol. 2009; 2:504-517
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Ovalbumin-Specific Th2 Responses Generated in Spleen by Fungal Infection
Ovalbumin-Specific Th2 Responses Generated in Spleen by Fungal Infection
P Porter, et al. Mucosal Immunol. 2009; 2:504-517
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Summary
Paul Porter, PhD
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.
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Putative Spectrum of Fungal-Putative Spectrum of Fungal-Dependent Allergic Lung DiseaseDependent Allergic Lung Disease
Antibody positiveAntibody negative
Fungal Infectious BurdenDisease Severity
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IL-13 is Required for Fungal Clearance
P Porter, et al. Mucosal Immunol. 2009; 2:504-517
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Mouse Eosinophils Are FungicidalA. fumigatus
P Porter, et al. Mucosal Immunol. 2009; 2:504-517
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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.
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Many Thanks To:Many Thanks To:Baylor College of MedicineBaylor College of Medicine
Farrah KheradmandFarrah Kheradmand
Stuart AbramsonStuart AbramsonSumanth PolikepahadSumanth Polikepahad
Morgan KnightMorgan Knight
Paul PorterPaul Porter
Yuping QianYuping Qian
Wendy TaiWendy Tai
LaKeisha BattsLaKeisha Batts
Luz RobertsLuz Roberts
Alexander SeryshevAlexander Seryshev
Tianshu YangTianshu Yang
Wen LuWen Lu
Valentine OngeriValentine Ongeri
Manisha SinghManisha Singh
Jeong-Soo HongJeong-Soo Hong
Anna FieldsAnna Fields
U. TX. Health Sciences U. TX. Health Sciences CenterCenter
George L. DelclosGeorge L. Delclos
Joy De Los ReyesJoy De Los Reyes
Supported by:Supported by:NIH:NIH: HL075243, AI057696, HL075243, AI057696,
AI070973, AI070973, HL095382