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Microbiology and Infectious Disease

The impact of genomics on discovering drugs against infectious diseases.
 Boshoff HI & Manjunatha UH, 2006. Microbes Infect. 8(6):1654-61

Abstract

Genomics is accelerating the progress in data generation and interpretation in the global analyses of components of cells, including the spectrum of lipids, RNA, metabolites, proteins, mutational phenotypes or DNA methylation sites. Integration of the knowledge generated by these diverse strategies is predicted to have a tremendous impact on approaches to rational drug discovery against infectious diseases.

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Comment

The development of new drug targets is approached from the viewpoint of microbial adaptation. Consideration is given to genome-wide approaches to identifying targets related to different stresses encountered by microbes.

A Whole-Genome Association Study of Major Determinants for Host Control of HIV-1.

Fellay, J et al., 2007.  Science 317(5840):944-947.

Abstract

Understanding why some people establish and maintain effective control of HIV-1 and others do not is a priority in the effort to develop new treatments for HIV/AIDS. Using a whole-genome association strategy, we identified polymorphisms that explain nearly 15% of the variation among individuals in viral load during the asymptomatic set-point period of infection. One of these is found within an endogenous retroviral element and is associated with major histocompatibility allele human leukocyte antigen (HLA)B*5701, whereas a second is located near the HLA-C gene. An additional analysis of the time to HIV disease progression implicated two genes, one of which encodes an RNA polymerase I subunit. These findings emphasize the importance of studying human genetic variation as a guide to combating infectious agents.

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Molecular identification of bacteria associated with bacterial vaginosis.

Fredricks, DN et al., 2005. N. Engl. J. Med. 353(18):1899-1911.

Abstract:

Background - Bacterial vaginosis affects millions of women and is associated with several serious health conditions. The cause of bacterial vaginosis remains poorly understood despite numerous studies based on cultures. Bacteria in microbial communities can be identified without cultivation by characterizing their ribosomal DNA (rDNA) sequences. Methods - We identified bacteria in samples of vaginal fluid with a combination of broad-range polymerase-chain-reaction (PCR) amplification of 16S rDNA with clone analysis, bacterium-specific PCR assay of 16S rDNA, and fluorescence in situ hybridization (FISH) performed directly on vaginal fluid from 27 subjects with bacterial vaginosis and 46 without the condition. Twenty-one subjects were studied with the use of broad-range PCR of 16S rDNA, and 73 subjects were studied with the use of bacterium-specific PCR. Results - Women without bacterial vaginosis had 1 to 6 vaginal bacterial species (phylotypes) in each sample (mean, 3.3), as detected by broad-range PCR of 16S rDNA, and lactobacillus species were the predominant bacteria noted (83 to 100 percent of clones). Women with bacterial vaginosis had greater bacterial diversity (P<0.001), with 9 to 17 phylotypes (mean, 12.6) detected per sample and newly recognized species present in 32 to 89 percent of clones per sample library (mean, 58 percent). Thirty-five unique bacterial species were detected in the women with bacterial vaginosis, including several species with no close cultivated relatives. Bacterium-specific PCR assays showed that several bacteria that had not been previously described were highly prevalent in subjects with bacterial vaginosis but rare in healthy controls. FISH confirmed that newly recognized bacteria detected by PCR corresponded to specific bacterial morphotypes visible in vaginal fluid. Conclusions - Women with bacterial vaginosis have complex vaginal infections with many newly recognized species, including three bacteria in the Clostridiales order that were highly specific for bacterial vaginosis.

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Comments

An excellent example of the clinical application of genetic/genomics information to the identification and characterization of bacterial infections.

Polymorphisms and the Pocketbook: The cost-effectiveness of cytochrome P450 2C19 genotyping in the eradication of Helicobacter pylori infection associated with duodenal ulcer.

Lehmann, DF et al., 2003. J. Clin. Pharmacol. 43(12):1316-1323.

The clinical outcome of duodenal ulcer treated with proton pump inhibitor (PPI)-based, anti-Helicobacter pylori (H.p.) regimens varies according to cytochrome P450 2C19 (CYP2C19) genotype. CYP2C19 genotypes differ markedly in peoples of Pacific Rim descent compared with another ethnicity. The authors sought to determine the specific impact that these factors have on the cost-effectiveness of duodenal ulcer management. Their model consisted of two patient cohorts with Helicobacter pylori and duodenal ulcer, trichotomized into CYP2C19 homozygous extensive metabolizers (EMs), heterozygous EMs, and poor metabolizers (PMs), altering the anti-H.p. regimen in the genotyped cohort only. The authors took the perspective of a third-party payer, and the denominator was ulcer episode prevented. In the reference case, the use of CYP2C19 genotyping prior to initiating anti-H.p. therapy was dominant (costs were saved with each ulcer episode prevented) in all geographic regions of the United States. The subsequent break-even analysis showed a range of $89.20 to $118.96--from Hawaii to the Midwest, respectively--required to eliminate the cost-savings from each genotype test performed. Using probabilities most unfavorable to genotyping, the variation of peoples with Pacific Rim origins from 0% to 100% altered the cost-effectiveness from $495 to $2125 per ulcer event prevented, respectively. The results suggest that treatment decisions for H.p. infection that are based on a patient's CYP2C19 genotype decreases expenses for health plans implementing testing. This analysis provides an economic basis to support recent calls to expand this technology into routine clinical care to prevent toxicity of narrow therapeutic index drugs.

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Comments

Though somewhat dated, this paper illustrates the very practical economic benefit of pre-treatment genomics testing  for patients, healthcare systems and insurance companies.

Future trends and challenges in pathogenomics. A Foresight study.

Pompe S et al., 2005. EMBO Rep. 6(7):600-605.

First paragraph

The difficult thing about the future is that it is so hard to predict. After the Second World War, the availability of vaccines and antibiotics and the successes of improved hygiene and public health policies led to such a dramatic fall in mortality that in 1969 the US Surgeon General claimed that “we can close the book on infectious diseases.” In hindsight, his prediction of the future was utterly wrong—infectious diseases are back with a vengeance. Nearly 25% of the annual deaths worldwide are directly related to pathogens (Morens et al, 2004); multidrugresistant tuberculosis and HIV/AIDS are on the rise worldwide; and Staphylococcus and Enterococcus strains in Western hospitals are becoming increasingly resistant to antibiotics. In addition, the rapid spread of new pathogens, such as the SARS (severe acute respiratory syndrome) and West Nile viruses, has shown the frailty of global public health, which is further affected by tourism and trade. Experts in security and public health also worry that publicly available scientific information and advanced genetic technologies could be misused to create weapons for bioterrorism.

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Comment

This editorial is the result of analysis of 185 review articles from a literature search with keywords, pathogenomics, infectious disease, public health, bacteria, fungi, bioweapons, bioterrorism, human pathogen. The editorial defines the prospects of infectious disease in global health and how new molecular tools may play a role in identifying new therapies. Potentially useful as a quick read handout in a Micro-ID course for juxtaposition of current vs emerging therapies for infectious diseases.