Innate Immune System Targets Asthma-linked Fungus For Destruction

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ScienceDaily (Sep. 5, 2008) — A new study shows that the innate immune system of

humans is capable of killing a fungus linked to airway inflammation, chronic

rhinosinusitis and bronchial asthma.

 

 

Researchers at Mayo Clinic and the Virginia Bioinformatics Institute (VBI) have

revealed that eosinophils, a particular type of white blood cell, exert a strong

immune response against the environmental fungus Alternaria alternata. The

groundbreaking findings shed light on some of the early events involved in the

recognition of A. alternata by the human immune system.

 

Eosinophils typically combat parasitic invaders of the human body larger than

bacteria or viruses, such as flukes or parasitic worms (collectively known as

helminths). Evidence from different experimental approaches suggests that asthma

and chronic sinusitis can arise when the body perceives that it has encountered

a disease-causing organism. Environmental fungi such as Alternaria do not

typically cause invasive infections like parasites but for some reason, in

certain people, the body responds as if it is being attacked and chronic

inflammation can result from the ensuing cascade of immune-related events.

 

Principal Investigator Hirohito Kita, M.D., from Mayo Clinic, remarked: " Our

results strongly demonstrate that eosinophils have the capacity to recognize and

exert immunological responses to certain fungi such as Alternaria. We have shown

that CD11b receptors on the surface of eosinophils recognize and adhere to

beta-glucan, a major cell wall component of the fungus. This in turn sets in

motion the release of toxic granule proteins by the white blood cells, leading

to extensive damage and ultimate destruction of the fungus. To the best of our

knowledge, this is the first time that live eosinophils and not just the

intracellular components have been shown to target and destroy a fungus. "

 

The researchers used fluorescence microscopy to determine the outcome of the

interaction between eosinophils and A. alternata. The contact of fungus with

eosinophils resulted in bright red fluorescence due to the damaged fungal cell

wall and subsequent death of Alternaria. Immunohistochemistry confirmed the

release of toxic granular proteins by eosinophils due to contact with the

fungus.

 

Dr. Lawrence, Associate Professor at VBI and the Department of Biological

Sciences at Virginia Tech, remarked: " T helper 2 (Th2) cells in the immune

system typically produce cytokine signaling molecules or interleukins that lead

to the recruitment of eosinophils for the dysregulated immune response commonly

associated with airway inflammatory disorders.

 

Continual exposure of sensitized individuals to common environmental fungi like

Alternaria may result in Th2 cells being constantly activated to recruit

eosinophils and this sustained defense mechanism results in chronic

inflammation. It has been shown previously that degranulation of eosinophils

causes damage of airway mucosa and enhances inflammation. The next step in our

transdisciplinary research collaboration will be to use recombinant fungal

proteins and fungal knockout mutants for specific genes to dissect the different

molecular steps involved in the development and progression of this acute immune

response. "

 

Hirohito Kita added: " We have taken an important step in showing that the innate

immune system of eosinophils is capable of targeting an asthma-associated fungus

for destruction. The biological significance of these results will need to be

verified further in animal models and in humans and our collaborative efforts

with Dr. Lawrence's research group for proteomics and functional genomics will

be invaluable in this respect. We suspect that the dysregulated immune responses

to Alternaria, other filamentous fungi, and perhaps chitin-encased insects, such

as mites and cockroaches, may play a pivotal role in chronic inflammation and

the subsequent development of bronchial airway disease. "