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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,

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slide2

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)

caveats

Caveats

The exogenous (environmental) causes of asthma remain obscure.

These findings were derived from an experimental model using ovalbumin, an allergen with no human disease relevance.

slide5

Fungi

Pollen

Intestinal worms

Proteinases and Asthma

Natural Sources of Proteases

Linked to Asthma

integration of innate and adaptive immune signaling pathways

1

Proteolytic

Allergen

Th2 Cell

(IL-13)

4

3

Pro-Allergic

Chemokines

CCL17, CCL7,

2

Integration of Innate and Adaptive Immune Signaling Pathways

Kiss A, et. al.,. J Allergy Clin Immunol 2007; 120:334-342

slide8

Typical Fungal Crop From a Houston House Dust Sample

Fungal Infection

Versus

Fungal Hypersensitivity?

Paul Porter, PhD

P.Porter, PhD

slide9

Zymogram of House Dust Reveals Active Fungal Proteinases

85kDa

200kDa

7kDa

Fungal Culture From Sample #24

Fungal Culture From Sample #12

Dust Sample #24

Dust Sample #12

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

aspergillus niger

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
Viable Fungal Spores (A. niger) Are Required for Allergic Lung Disease

P Porter, et al. Mucosal

Immunol. 2009; 2:504-517

mouse bal fluid hyphae a niger
Mouse BAL Fluid Hyphae (A. niger)

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
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
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 fungal dependent allergic lung disease
Putative Spectrum of Fungal-Dependent Allergic Lung Disease

Antibody negative

Antibody positive

Fungal Infectious Burden

Disease Severity

il 13 is required for fungal clearance
IL-13 is Required for Fungal Clearance

P Porter, et al. Mucosal

Immunol. 2009; 2:504-517

mouse eosinophils are fungicidal
Mouse Eosinophils Are Fungicidal

A. fumigatus

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

conclusions

Conclusions

A. niger and other fungi cause allergic lung disease through airway infection and secretion of proteinases.

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.