HSP's, FUNGAL HSP's (HEAT SHOCK PROTIENS)

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Stress Protein Plays a Role in the Evolution of Drug Resistance in Fungi

Lindquist, Ph.D.

Whitehead Institute for Biomedical Research, Cambridge, Massachusetts

Pilot Project Funding from P30ES2109

Background: Heat shock proteins (HSPs), also called stress proteins, are a group

of proteins that are present in all cells in all life forms. They are induced

when a cell undergoes various types of environmental stresses like heat, cold

and oxygen deprivation. HSPs are also present in cells under perfectly normal

conditions. They act like chaperones, making sure that cellular proteins are in

the right shape and in the right place at the right time. For example, HSPs help

new or distorted proteins fold into shape, which is essential for proper

function. They also shuttle proteins from one compartment to another inside the

cell, and transport old proteins for disposal. HSPs are also believed to play a

role in the presentation of peptides on the cell surface to help the immune

system recognize diseased cells.

Recent research has suggested that a specific stress protein, known as HSP90,

could be involved in the development of antibiotic resistance in yeast. With a

small amount of funding as a pilot project from the Environmental Health

Sciences Center at the Massachusetts Institute of Technology, these researchers

performed studies to determine the capacity of HSP90 to influence the pace at

which resistance would develop and the diversity of the types of resistance that

arise.

Advance: Drug resistance was investigated in two classes of drugs; azoles, the

most broadly used antifungal compounds, and echinocandins, the first new

antifungal class in decades. HSP90 was found to enhance the evolution of drug

resistance by enabling spontaneous mutations to have immediate phenotypic

consequences. Drug resistance was attenuated by HSP inhibitors and by high

temperatures.

Implications: These results represent an entirely new function of HSP90 in

evolutionary processes. Fungal drug resistance is of great economic importance.

There are only a few clinically useful drugs and resistance has emerged in all

of them. Inhibiting HSP90 may render resistant fungal pathogens more vulnerable

to anti-fungal treatments. HSP90 inhibitors are effective in overcoming fungal

drug resistant at doses that are well tolerated.

Citation: Cowen LE, Lindquist S. Hsp90 potentiates the rapid evolution of new

traits: drug resistance in diverse fungi. Science. 2005 Sep 30;309(5744):2185-9.

http://www.niehs.nih.gov/research/supported/sep/2005/resist.cfm

Pathogenic fungi reveal new mechanism for evolution

http://www.wi.mit.edu/news/archives/2005/lc_0929.html

Thermophilic Fungi: Their Physiology and Enzymes/

FULL TEXT

http://mmbr.asm.org/cgi/content/full/64/3/461

CITED

http://mmbr.asm.org/cgi/content/abstract/64/3/461

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CANCER

Roles of Heat Shock Proteins and T Cells in Inflammation

CONCLUSIONS

Therapeutic approaches that prevent the recruitment of phagocytes to inflamed

sites may reduce host tissue damage in chronic and acute inflammation.

Treatments that hasten the clearance of inflammatory cells from inflamed tissues

may yield similar results. During infections, however, the latter approach seems

preferable, as it could be timed to encourage the resolution of inflammation

after the phagocytes have been given the opportunity to clear microbial invaders

from host tissues. The work from this and other laboratories suggests that T

cells have an important function in protecting host tissues from damage by

inflammatory cells (7, 50, 53, 54). This concept is strongly supported by

findings with mice that are deficient in T cells. These animals show abnormally

strong inflammatory responses to infectious insults, which results in extensive

tissue necrosis, delayed resolution of inflammatory infiltrates, and an

increased overall mortality (48, 49). These findings, together with our previous

work, suggest that T cells may be suitable therapeutic targets to accelerate the

clearance of phagocytes from inflamed tissues such as the lungs in attempts to

limit tissue damage (7). Future treatments that stimulate the recruitment of T

cells to the lungs or that enhance their ability to recognize and eliminate

target cells seem feasible. More work is needed to develop such treatments.

http://ajrcmb.atsjournals.org/cgi/content/full/39/5/509

CITED FROM

1999,Role of Heat Shock Proteins in Protection from and Pathogenesis of

Infectious Diseases /CITED

http://cmr.asm.org/cgi/content/abstract/12/1/19

HSPs of thermophilic and thermotolerant fungi from Taiwan.

(It is concluded that thermophilic and thermotolerant

fungi synthesized mainly high and medium-molecular

weight HSPs at 40°C and low molecular weight HSPs at

50°C.)

http://ejournal.sinica.edu.tw/bbas/content/2004/3/Bot453-09.pdf

1999,Genetic Analysis of Viable Hsp90 Alleles Reveals a Critical Role in

Drosophila Spermatogenesis/CITED

http://www.genetics.org/cgi/content/abstract/151/3/1065

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