Dark side of fungal membrane protein revealed

November 20, 2009

I was exposed from 1987 until 1998 to extremely high levels of A. fumigatis (as

well as stachybotrys atra) at a university. It is my understanding that A.

fumigatis can infect immunocompromised patients and that it can be fatal in some

cases. A recent cause of death identified as a brain hemmorhage was later

correctly identified as an A. fumigatis infection of the brain. The following

article indicates that a specific fungal protein may lead to more effective

treatment for patients with A. fumigatis infections.

Joanne

ARTICLE

Pathogen protection and virulence: Blacksburg, Va. -- Researchers at the

Virginia Bioinformatics Institute (VBI) at Virginia Tech and Montana State

University have discovered a fungal protein that plays a key role in causing

disease in plants and animals and which also shields the pathogen from oxidative

stress. The researchers have found that the fungal protein TmpL is critical for

the infection of host tissue and helps these pathogens regulate oxidative stress

responses that are caused by the presence of destructive reactive oxygen

species, a natural feature of the adaptive response to infection.

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

Sciences at Virginia Tech and leader of the project, remarked: " The critical

roles of reactive oxygen species in fungal development and virulence have been

well established over the past half century. However little is known about how

these molecules are produced or how the balance is achieved between their cell

signaling roles on the one hand and their potentially destructive properties on

the other. I believe we now have a unique opportunity to study a common fungal

disease-associated mechanism in plants and animals that appears to be

inextricably linked to the oxidative stress of the host-pathogen environment. "

The scientists looked at two different fungal pathogens: Alternaria

brassicicola, which causes widespread damage in crops like canola, cabbage and

broccoli, and Aspergillus fumigatus, a human pathogen that often leads to fatal

disease in immunocompromised patients. Infection with A. fumigatus can lead to

invasive pulmonary aspergillosis, the leading cause of death due to invasive

fungal infections in humans.

Said Lawrence: " This transdisciplinary project has involved bioinformatics,

functional genomics, molecular biology, biochemistry, plant pathology,

immunology, and medical mycology. We first discovered the gene encoding TmpL by

computational screening and analysis of the A. brassicicola genome at VBI.

Further investigation of the tmpL sequence and functional genomics analysis has

allowed us to build up a picture of what the protein may look like in many

filamentous fungi. "

Dr. Biswarup Mukhopadhyay, an expert in microbial enzyme biochemistry at VBI,

remarked: " The scientific evidence suggests that TmpL is a flavin-containing

enzyme that possesses six membrane-spanning domains. Flavins are molecules that

are involved in biological oxidation and reduction reactions. It seems likely

that TmpL deploys electrons from NADPH, a key energy currency in the cell, via a

flavin molecule to somehow modify subsequent signaling events that are linked to

the overall oxidative state of the cell. "

Dr. Cramer, director of the Aspergillus-associated aspects of the

research and Assistant Professor of Fungal Pathogenesis in the Department of

Veterinary Molecular Biology at Montana State University, said: " We suspect that

TmpL may act as a detoxifier of intracellular reactive oxygen species. These

toxic molecules are highly elevated in the fungus at the initial stages of

infection and during various developmental stages. While these molecules are

toxic at inappropriate levels, they are also likely key signaling molecules

involved in directing fungal development. " He added: " TmpL-deficient mutants

were also more sensitive to external oxidative stress which suggests that TmpL

may aid the onset of disease by protecting the pathogen from the host's defense

mechanism. Experiments with oxidative-burst-deficient mice suggest that the

intracellular regulation of reactive oxygen species in the fungus is most likely

more important for pathogenesis than resistance to host-derived oxidative

stress. However, more work is needed to confirm this hypothesis and to dissect

the precise molecular mechanism that is involved. "

The current study shows that TmpL is essential for both types of fungi to cause

disease in their host cells. Dr. Kwang-Hyung Kim at VBI, the lead author on the

paper and a scientist working on the project, remarked, " TmpL appears to be

located in the membrane of the Woronin body, a specialized peroxisomal organelle

found specifically in the cells of hyphae in filamentous fungi. When the

function of TmpL is impaired or its gene inactivated, both A. brassicicola and

A. fumigatus show drastic decreases in their ability to cause disease in our

experimental host systems of cabbage, Arabidopsis, and mouse. Deletion of the

tmpL gene also makes the fungi extremely sensitive to oxidative stress in the

laboratory. Whether or not TmpL aids in protection against host-derived

oxidative stress remains to be elucidated and will be one of our primary

research areas in the future. "

Lawrence said: " In this study, we provide the first evidence that a certain type

of disease-related protein from both a plant and animal fungal pathogen is

critical for protecting the pathogen and for causing infection of healthy host

tissue. As such, this protein represents a good starting point as a potential

target for the development of efficient and novel therapeutics for both plant

and animal fungal diseases. "

###

The results will be published in PLoS Pathogens: Kim K-H, Willger SD, Park S-W,

Puttikamonkul S, Grahl N, Cho Y, Mukhopadhyay B, Cramer RA, Lawrence CB (2009)

TmpL, a transmembrane protein required for intracellular redox homeostasis and

virulence in a plant and an animal fungal pathogen. PLoS Pathogens doi:

10.1371/journal.ppat.1000653.

November 20, 2009

this fugal protein helps the fungi cause infection, not help the patient get rid

of infection. sorry

they are basicly saying that this is one medthod that fungi uses to cause

infection in the host by hindering the hosts reaction

to rid the body of the mold and/or because the immune system doesn't even

reconize the invasion.

also it's been reconized that you dont have to be immunocompromized to

get fungal infections. a fungal infection to a immunocompromized patient may

mean a quick death, while immuncompitant people may deal with fungal

re-infections off and on for many years. weather they are colonized or the main

exposure leaves them unable to fight off further fungal exposures, ? maybe both.

antifugals may be needed to rid the body and brain of fungal infections if the

immune system doesn't.

>

> I was exposed from 1987 until 1998 to extremely high levels of A. fumigatis

(as well as stachybotrys atra) at a university. It is my understanding that A.

fumigatis can infect immunocompromised patients and that it can be fatal in some

cases. A recent cause of death identified as a brain hemmorhage was later

correctly identified as an A. fumigatis infection of the brain. The following

article indicates that a specific fungal protein may lead to more effective

treatment for patients with A. fumigatis infections.

>

> Joanne

>

> ARTICLE

> Pathoge

November 21, 2009

Thank you for this article...

>

> I was exposed from 1987 until 1998 to extremely high levels of A. fumigatis

(as well as stachybotrys atra) at a university. It is my understanding that A.

fumigatis can infect immunocompromised patients and that it can be fatal in some

cases. A recent cause of death identified as a brain hemmorhage was later

correctly identified as an A. fumigatis infection of the brain. The following

article indicates that a specific fungal protein may lead to more effective

treatment for patients with A. fumigatis infections.

>

> Joanne

>

> ARTICLE

> Pathogen protection and virulence: Blacksburg, Va. -- Researchers at the

Virginia Bioinformatics Institute (VBI) at Virginia Tech and Montana State

University have discovered a fungal protein that plays a key role in causing

disease in plants and animals and which also shields the pathogen from oxidative

stress. The researchers have found that the fungal protein TmpL is critical for

the infection of host tissue and helps these pathogens regulate oxidative stress

responses that are caused by the presence of destructive reactive oxygen

species, a natural feature of the adaptive response to infection.

>

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

Biological Sciences at Virginia Tech and leader of the project, remarked: " The

critical roles of reactive oxygen species in fungal development and virulence

have been well established over the past half century. However little is known

about how these molecules are produced or how the balance is achieved between

their cell signaling roles on the one hand and their potentially destructive

properties on the other. I believe we now have a unique opportunity to study a

common fungal disease-associated mechanism in plants and animals that appears to

be inextricably linked to the oxidative stress of the host-pathogen

environment. "

>

> The scientists looked at two different fungal pathogens: Alternaria

brassicicola, which causes widespread damage in crops like canola, cabbage and

broccoli, and Aspergillus fumigatus, a human pathogen that often leads to fatal

disease in immunocompromised patients. Infection with A. fumigatus can lead to

invasive pulmonary aspergillosis, the leading cause of death due to invasive

fungal infections in humans.

>

> Said Lawrence: " This transdisciplinary project has involved bioinformatics,

functional genomics, molecular biology, biochemistry, plant pathology,

immunology, and medical mycology. We first discovered the gene encoding TmpL by

computational screening and analysis of the A. brassicicola genome at VBI.

Further investigation of the tmpL sequence and functional genomics analysis has

allowed us to build up a picture of what the protein may look like in many

filamentous fungi. "

>

> Dr. Biswarup Mukhopadhyay, an expert in microbial enzyme biochemistry at VBI,

remarked: " The scientific evidence suggests that TmpL is a flavin-containing

enzyme that possesses six membrane-spanning domains. Flavins are molecules that

are involved in biological oxidation and reduction reactions. It seems likely

that TmpL deploys electrons from NADPH, a key energy currency in the cell, via a

flavin molecule to somehow modify subsequent signaling events that are linked to

the overall oxidative state of the cell. "

>

> Dr. Cramer, director of the Aspergillus-associated aspects of the