VBI, Mayo Clinic investigate link between fungal proteins, innate immunity and a

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VBI, Mayo Clinic investigate link between fungal proteins, innate

immunity and asthma

Public release date: 27-Feb-2008

EurekAlert (press release) - Washington,DC*

Contact: Barry Whyte

whyte@...

540-231-1767

Virginia Tech

http://www.eurekalert.org/pub_releases/2008-02/vt-vmc022708.php

Blacksburg, Va. – Researchers at Mayo Clinic and the Virginia

Bioinformatics Institute (VBI) have received a second grant from the

National Institute of Allergy and Infectious Diseases (NIAID) to

advance understanding of the role of environmental fungi in chronic

airway disorders. Recently NIAID awarded the researchers a further

$1.8 million for these studies over a five-year period to

investigate how the environmental fungus Alternaria triggers airway

inflammation and bronchial asthma. Exposure to the fungus Alternaria

has long been implicated in the development and exacerbation of

asthma, especially life-threatening asthma, although little is known

about the molecular events in the immune system that underlie the

etiology and progress of this chronic disease. By understanding how

the innate immune system responds to environmental stimuli and helps

shape the adaptive immune system, scientists hope in the long term

to develop more specific therapies as well as prevention strategies

for bronchial diseases.

Principal Investigator Hirohito Kita, M.D., from Mayo Clinic,

remarked: " In this investigation, we will be looking closely at how

fungal enzymes from Alternaria cause innate immune responses in a

variety of cells and how they influence naïve T cells in the immune

system to differentiate into T helper 2 cells or Th2 cells, a

process which takes place in partnership with antigen-presenting

cells called dendritic cells. Th2 cells are part of the adaptive

immune system and are linked to the events that lead to inflammation

of the airway. " He added: " Th2 cells typically produce cytokine

signaling molecules or interleukins and the production of these

interleukins leads to the recruitment of a specific class of white

blood cells (eosinophils) that usually destroy parasitic organisms

larger than bacteria or viruses. Mounting evidence suggests that

allergic airway disorders such as asthma and chronic sinusitis are

actually the result of our bodies believing we are being attacked by

parasites. Environmental fungi such as Alternaria do not typically

cause invasive infections like parasites but for some reason, in

certain people, the body thinks it is being attacked. This results

in Th2 cells constantly recruiting eosinophils and chronic

inflammation occurs because humans are continually exposed to common

environmental fungi like Alternaria. "

The hypothesis that will be tested is that certain immunoactive

enzymes from Alternaria activate dendritic cells through yet

unidentified receptors that allow for tailoring of the adaptive

immune response and the formation of Th2 cells. This in turn leads

to the strong immune responses in the airways. The research team

will use different approaches to determine the potential role of

these receptors in the cascade of immune interactions that comprise

inflammation of the airways. This should allow them to better

understand how certain environmental stimuli are linked via the

innate immune system to the adaptive immune system and development

of inflammation and disease.

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

Biological Sciences at Virginia Tech, one of the leading experts in

Alternaria biology and principal investigator of the Alternaria

genome sequencing project funded by the National Science Foundation-

United States Department of Agriculture (NSF-USDA) Microbial Genome

Sequencing Program, stated: " Our part of the collaboration is

critical and will involve the use of proteomics and functional

genomics approaches to identify the novel enzymes produced by

Alternaria that are triggers of innate immune responses that shape

the adaptive immune system. Recombinant fungal proteins will be used

to dissect the different molecular steps involved in the development

and progression of inflammation and asthma. " He added: " We will

create a series of fungal knockout mutants for specific genes that

will be used to examine the specific role of fungal proteins in the

activation of the innate immune system response. It is our belief

that understanding how and why asthma patients develop Th2 immune

responses to environmental proteins is one of the prerequisites for

the future development of treatments, diagnostic tools and

preventative measures for patients suffering from the disease. We

are truly excited about being able to participate in this

transdisciplinary, team-based scientific effort. "

Asthma is a chronic disease characterized by recurrent attacks of

breathlessness and wheezing. The most common chronic disease among

children, it currently affects 300 million people worldwide.* In

2000, the Asthma and Allergy Foundation of America estimated that

direct health care costs for asthma in the United States total more

than $10 billion annually; indirect costs (lost productivity) add

another $8 billion for a total of $18 billion. In 2005 alone, 255

000 people died of asthma worldwide.*

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* World Health Organization, May 2007:

www.who.int/features/factfiles/asthma/en/index.html

About VBI

The Virginia Bioinformatics Institute (VBI) at Virginia Tech

(www.vbi.vt.edu) has a research platform centered on understanding

the " disease triangle " of host-pathogen-environment interactions in

plants, humans and other animals. By successfully channeling

innovation into transdisciplinary approaches that combine

information technology and biology, researchers at VBI are

addressing some of today's key challenges in the biomedical,

environmental and plant sciences.

About Mayo Clinic

Mayo Clinic is the first and largest integrated, not-for-profit

group practice in the world. Doctors from every medical specialty

work together to care for patients, joined by common systems and a

philosophy of " the needs of the patient come first. " More than 3,300

physicians, scientists and researchers and 46,000 allied health

staff work at Mayo Clinic, which has sites in Rochester, Minn.,

ville, Fla., and sdale/Phoenix, Ariz. Collectively, the

three locations treat more than half a million people each year.