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)

Eosinophil

Corry, D.B.

What Can The Mouse Tell Us About Asthma?

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 Intestinal wormsPollen

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

Can we learn more about the environmental causes of asthma by sifting through house dust?

How Do Microbial Proteinases Relate to Asthma?

Typical Fungal Crop From a Houston House Dust Sample

P.Porter, PhDPaul Porter, PhD

Fungal Infection

Versus

Fungal Hypersensitivity?

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

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

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)

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?

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

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

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

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.

Putative Spectrum of Fungal-Putative Spectrum of Fungal-Dependent Allergic Lung DiseaseDependent Allergic Lung Disease

Antibody positiveAntibody negative

Fungal Infectious BurdenDisease Severity

IL-13 is Required for Fungal Clearance

P Porter, et al. Mucosal Immunol. 2009; 2:504-517

Mouse Eosinophils Are FungicidalA. 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: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