Enzyme revealed that is key to fungus's ability to breach immune system

[Guest guest]

I have never seen this study before. I was looking up information on fungal

nitric oxide when I came upon this. Nitric oxide appears to play a key role

in MCS. So does that mean fungal nitric oxide could be a key to explaining

MCS in mold victims?

Sharon

November 2003

From _Duke University Medical Center_ (http://www.dukemednews.org/)

Enzyme revealed that is key to fungus's ability to breach immune system

DURHAM, N.C. – A newly discovered mechanism by which an infectious fungus

evades the immune system could lead to novel methods to fight the fungus and

other disease-causing microbes, according to Medical Institute

investigators at Duke University Medical Center.

Disruption of a key enzyme in the fungus Cryptococcus neoformans – a common

cause of infection of the central nervous system in patients such as organ

transplant recipients who lack a functioning immune system -- led to a

significant loss of fungal virulence in mice, the team found. That loss of

virulence

stemmed from the fungus's inability to launch a counterattack against

components of the innate immune system, the body's first line of defense against

infection, the study showed.

The Duke-based team -- led by HHMI geneticist ph Heitman, M.D., director

of Duke's Center for Microbial Pathogenesis, and HHMI biochemist

Stamler, M.D. -- reported their findings in the Nov. 11, 2003, issue of Current

Biology. The work was funded by the National Institutes of Allergy and

Infectious Diseases and the Burroughs Wellcome Fund.

The " fungal defense " enzyme, called flavohemoglobin, is prevalent among many

bacterial and fungal pathogens, Heitman said, which suggests that the

findings in Cryptococcus are likely relevant to other infectious microbes. New

drugs

that target these enzymes might therefore represent effective treatments for

a wide range of infectious diseases, he said.

The human immune system uses a two-pronged mechanism to fight infection: a

rapid innate response and a slower adaptive response that depends on the

production of antibodies. Key components of the innate immune system are

" search-and-destroy " cells called macrophages that engulf and kill invading

pathogens.

Macrophages kill infectious microbes using a combination of oxidants,

including hydrogen peroxide, nitric oxide and related molecules.

" The body must rely on macrophages of the innate immune system to protect

itself before the adaptive immune system can respond to invasion, " Heitman said.

" While much is known about how pathogens defend themselves against hydrogen

peroxide produced by the macrophages, this study is the first biologically

relevant test of what microbes do to counteract nitric oxide and promote

infection. "

The researchers found that a mutant C. neoformans strain lacking the

flavohemoglobin enzyme failed to break down nitric oxide in laboratory cultures.

Fungus with the enzyme deficiency also ceased to grow when in the presence of

nitric oxide, whereas ordinary fungus survived normally.

Mice infected with the flavohemoglobin-deficient C. neoformans survived for

five days longer than those infected with the normally virulent strain. In

contrast, the normal and mutant fungal strains were equally virulent in mice

whose immune cells could not produce nitric oxide, the team reported.

The mutant fungus also failed to grow normally in laboratory dishes

containing macrophage cells, further implicating the innate immune system in the

loss

of virulence exhibited by fungi lacking flavohemoglobin.

The team discovered a second enzyme, known as GSNO reductase, which also

plays a role in defending the fungus against nitric oxide-related molecules

produced by macrophages. Mutant fungal strains deficient in both enzymes were

more severely impaired than those lacking flavohemoglobin only.

" By disabling either the fungal nitric oxide defense system or the immune

system's ability to produce nitric oxide, we were able to tip the balance one

way or the other – in favor of the fungal infection or the host, " Heitman

said.

" That raises the possibility that we could treat infectious disease with

drugs that either inhibit fungal defense enzymes or increase the innate immune

system's ability to mount a nitrosative attack. "

Collaborators on the study include Marisol de Jesus-Berrios, Ph.D., ,

M.D., Limin Liu, Ph.D., and Nussbaum, all of Duke.