ASM News Vol 63, Num 4, April, 1997

Journal Highlights

Long Homonucleotide Runs Raise Risk of Mutations, Cancer

A number of cancers are known to involve defects in mismatch repair. Homonucleotide runs in coding sequences are hot spots for frameshift mutations and potential sources of genetic changes leading to cancer in humans with mismatch repair defects.

Working with S. cerevisiae, Dmitry Gordenin of St. Petersburg State University, Russia, and colleagues at the National Institute of Environmental Health Sciences found that DNA polymerase E proofreading and mismatch repair are efficient for short runs, but that only the mismatch repair system could prevent frameshifts in runs longer than 8 nucleotides. Risk of mutational inactivation is 100-fold higher in genes with long homonucleotide runs than in genes without long runs.

In the future, "We want to identify novel genes controlling stability of homonucleotide runs," say Gordenin. "We want to identify other at-risk DNA motifs that are poor substrates for specific enzymatic processes that normally protect against mutations."

(H.T. Tran, J.D. Keen, M. Kricker, M.A. Resnick, and D.A. Gordenin. 1997. Hypermutability of homonucleotide runs in mismatch repair and DNA polymerase proofreading yeast mutants. Mol. Cell Biol. 17:2859-2865.)

Ginseng Protects Animals from Bacterial Infection

Within the ancient Chinese herbal pharmacopoeia, genseng is the most valued agent. Modern researchers have found it to have a wide range of pharmacological and therapeutic effects on the central nervous, cardiovascular, endocrine, and immune systems. Now, for the first time, researchers have found that it stimulates antimicrobial activity in the immune system.

In a rat model of chronic P. aeruginosa pneumonia mimicking cystic fibrosis (CF), ginseng improved the ability to clear infection by P. aeruginosa and to reduce lung damage. It does so by inducing a TH1-like immune response in lieu of the highly inflammatory TH2 response. Chronic P. aeruginosa is a leading contributor to mortality in patients with CF, says Song. Antibiotics are unable to eradicate it because the bacteria produce a protective biofilm. Song plans to investigate the mechanisms of ginseng's actions on chronic P. aeruginosa lung infection and to identify, isolate, and, if possible, synthesize the active ingredients.

(Z. Song, H.K. Johansen, V. Faber, C. Moser, A. Kharazmi, J. Rygaard, and N. Holby. 1997. Ginseng Treatment reduces bacterial load and lung pathology in chronic Pseudomonas aeruginosa pneumonia in rats. Antimicrob. Agents Chemother. 41:961-964.)

Variation in Helicobacter pylori Genome Suggests Promiscuou Past, Reasons for Unpredictable Medical Outcomes

Helicobacter pylori causes chronic superficial gastritis in humans and contributes to development of peptic ulcer disease and gastric cancer. Timothy L. Cover and Ping Cao of Vanderbilt University School of Medicine found that one gene, vapD, closely related to the virulence-associated protein D (vapD) of Dichelobacter nodosus, is present in about 60% of H. pylori strains but is absent from others. Its presence is not associated with any specific family of the variable vacA alleles, just 3.5 kilobases distant, which suggests that recombination has occurred among H. pylori strains.

"That suggests that this organism shares properties with other organisms such as Neisseria species and S. pneumonia, which are also mucosal pathogens that are naturally transformable and have a recombinatorial population structure," says Cover. Cover is seeking to identify genetic markers that are uniquely present in strains that cause ulcer disease and gastric cancer.

(P. Cao and T.L. Cover. 1997. High-level genetic diversity inf the vapD chromosomal region of Helicobacter pylori. J. Bacteriol. 179:2852-2856.)

Syphilis May Use Chemotaxis Protein to Home in on Organs

Unlike other sexually transmitted diseases, syphilis is always a systemic infection. Inability to culture Treponema pallidum has hampered efforts to resolve the mechanism that governs dissemination during pathogenesis.

One myster concerns the question of how T. pallidum finds its way from skin to blood and to organ systems. Michael V. Norgard and his colleagues at University of jTexas southwestern Medical Center had earlier discovered in T. pallidum a homolog of an E. coli gene which can interact with the sensory transducer Trg, a methyl-accepting chemotaxis protein (MCP) involved in bacterial chemotaxis. The researchers found that T. pallidum contains at least one analog of MCPs, a 64-kilodalton methylated protein, suggesting that "chemotactic responses are in some way involved in the host dissemination process," says Norgard. This discovery involved exceptionally difficult experiments, including a 10-month X-ray film exposure time. Norgard hopes to develop a chemotaxis assay for T. pallidum to obtain important correlative evidence for glucose and other nutrients as chemoattractants.

(K.E. Hagman, S.F. Porcella, T.G. Popova, and M.V. Norgard. 1997. Evidence for a methyl-accepting chemotaxis protein gene (MCP1) that encodes a putative sensory transfducer in virulent Treponema pallidum. Infect. Immun. 65:1701-1709.)

Convergent Evolution of Fatty Acid Synthesis in Barophiles

Wings and the streamlining associated with fast swimming are major traits which have evolved independently among different groups of vertebrates. Similar convergent evolution appears to take place among microbes.

Edward F. DeLong of the University of California, Santa Barbara, and colleagues have found that the ability to synthesize long-chain polyunsaturated fatty acids (PUFAs) appears to have evolved independently among barophiles, microorganisms that grow at bressures greater than 1 atmosphere. "These lipids are apparently important for these marine microbes," says DeLong.

"Cultivated barophilic bacteria seem often to be associated with animals, like deep-sea fish and crustacea, that also contain high quantities of PUFAs," says DeLong. "An interesting question is whether barophiles associated with deep-sea animals are providing their hosts with essential dietary PUFAs in a nutritional symbiosis. Since PUFAs are essential to human diets, understanding such relationships has practical importance as well as ecological significance."

(E.F. DeLong, D.G. Franks, and A.A. Yayanos. 1997. Evolutionary relationships of cultivated psychrophilic and barophilic deep-sea bacteria. Appl. Environ. Microbiol. 63:2105-2108.)

Female Reproductive Tract Susceptible to HIV at All Sites

In the United States, 40,000 to 80,000 new cases of human immunodeficiency virus (HIV) infection occur each year, and estimated 70% of which occur through heterosexual transmission. Using normal hysterectomy tissues, Alexandra L. Howell and colleagues at the VA and Dartmouth Medical School demonstratred for the first time that HIV can infect cells at all sites within the female reproductive tract, including the fallopian tubes and epithelial cells and stromal cells. "HIV-1 can infect any site within the female reproductive tract, not only at the vagina and cervix as previously believed," says Howell. "This suggests that efforts to control heterosexual transmission should include induction of immune protection at all sites, not just the lower reproductive tract."

"We are studying whether menstrual variations of hormone levels alter susceptibility of female reproductive tract cells," says Howell. "This is important because we have demonstrated that killer T cell activity in the uterus is suppressed during the latter half of the menstrual cycle, when progesterone levels are highest." In other words, susceptbility to HIV may vary with time of menstrual cycle.

(A.L. Howell, R.D. Edkins, S.E. Rier, G.R. Yeaman, J.E. Stern, M.W. Fanger, and C.R. Wira. 1997. Human immunodeficiency virus type 1 infection of cells and tissues from the upper and lower human female reproductive tract. J. Virol. 71:3498-3506.)

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