New England Journal of Medicine
July 28, 2011  Vol. 365 No. 4
http://content.nejm.org/current.shtml

Review Article
Genomic Medicine: Microbial Genomics and Infectious Diseases
D.A. Relman
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Extract
The pace of technical advancement in microbial genomics has been breathtaking. Since 1995, when the first complete genome sequence of a free-living organism, Haemophilus influenzae, was published,1 1554 complete bacterial genome sequences (the majority of which are from pathogens) and 112 complete archaeal genome sequences have been determined, and more than 4800 and 90, respectively, are in progress.2 A total of 41 complete eukaryotic genome sequences have been determined (19 from fungi), and more than 1100 are in progress. Complete reference genome sequences are available for 2675 viral species, and for some of these species, a large number of strains have been completely sequenced. Nearly 40,000 strains of influenza virus3 and more than 300,000 strains of human immunodeficiency virus (HIV) type 1 have been partially sequenced.4 However, the selection of microbes and viruses for genome sequencing is heavily biased toward the tiny minority that are amenable to cultivation in the laboratory, numerically dominant in particular habitats of interest (e.g., the human body), and associated with disease….

“…Vaccines
In the same way that genome sequences reveal drug-resistance profiles, vulnerabilities, and synthetic capabilities of microbes and viruses, these sequences also provide clues about antigenic repertoire. This information can be exploited for vaccine design and other immunoprophylactic interventions. Genome-based antigen discovery has also been undertaken for more complex pathogens. One approach, known as reverse vaccinology, involves cloning and expressing all proteins that are predicted (from the organism’s complete genome) to be secreted or surface-associated, starting with the complete genome sequence (Figure 3).80 After immunizing mice with each of the proteins, each of the corresponding antiserum samples is tested for its ability to neutralize or kill the original target organism. On the basis of this approach, a small group of proteins from group B meningococcus,81 a pathogen that has so far eluded vaccine development, has shown promise as a candidate multivalent subunit vaccine. A similar approach has been taken with group B streptococcus82 and extraintestinal pathogenic E. coli.83 Protective antigens that are discovered through these sorts of methods may have been previously ignored because they are not immunogenic during natural infections.

Future Directions
Without question, the techniques for microbial and viral genome sequencing are becoming increasingly rapid and less expensive. Genome sequencing of a microbe or virus will soon be easier than characterization of its growth-based behavior in the laboratory. In the next 3 to 5 years, direct shotgun sequencing of the DNA and RNA in a clinical sample may become a routine matter. What is less clear is how clinically relevant information will be most effectively extracted from the ensuing massive amounts of data. In the near term, genomic and metagenomic analyses of microbes are most likely to be useful in areas such as the cataloguing and understanding of microbial and viral diversity in the human body, the identification of molecular determinants of virulence and symbiosis, and real-time tracking of particular strains of pathogens. Such analyses will also provide a deeper understanding of how pathogens spread and cause disease and will identify new targets for therapies and antigens for vaccines. Thoughtfully designed clinical and epidemiologic studies will be required to see the full realization of these benefits.”