The Continuing Evolution of a Bacterial Pathogen
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COMMENTARY The continuing evolution of a bacterial pathogen James B. Kaper*† and Mohamed A. Karmali‡ *Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201; and ‡Laboratory for Foodborne Zoonoses, Public Health Agency of Canada, Guelph, ON, Canada N1G 3W4 lthough Escherichia coli is a verted the somatic O antigen from O55 96 loci of Ͼ500 strains dating back to prototypic commensal bacterial to O157, and additional chromosomal the first human outbreak in 1982. They species of the mammalian in- mutations. Comparative genomic studies identified 39 SNP genotypes that differ testine and a laboratory work- of several E. coli O157:H7 strains have at 20% of SNP loci and separated them Ahorse for molecular biology, certain into nine clades. The spinach outbreak revealed extensive genomic diversity re- strains of this species are capable of lated to the structure, position, and ge- strain corresponded to clade 8 as did causing significant human disease. The netic content of bacteriophages and another 2006 isolate from a lettuce- spectrum of disease caused by E. coli variability in the content of putative vir- borne outbreak involving 71 cases. Man- includes enteric/diarrheal disease, uri- ulence genes, including those encoding ning et al. observed differences between nary tract infections, renal failure, and adhesins, Shiga toxins, and non-LEE clades in the frequency and distribution sepsis/meningitis (1). The different effector proteins. These developments of Shiga toxin genes and in the type of pathotypes of E. coli possess genes en- have led Wick et al. (3) to conclude that clinical disease reported. In particular, coding a wide variety of virulence fac- ‘‘O157:H7 genomes are rapidly diverging they found that patients with HUS were tors that are frequently encoded on and radiating into new niches as the significantly more likely to be infected mobile genetic elements such as bacte- pathogen disseminates.’’ with clade 8 strains. The 2006 spinach riophages, plasmids, and pathogenicity and lettuce outbreaks caused by clade 8 islands. E. coli strains can be serotyped Widespread Outbreak Associated strains were notable for an average as one of Ͼ10,000 possible combinations with Spinach HUS rate of 13%, which is three times of O (LPS) and H (flagellar) antigens, Although the first outbreaks of E. coli greater than the average HUS rate for but one serotype, O157:H7, has O157:H7 disease were associated with 350 U.S. outbreaks between 1982 and achieved particular notoriety as a cause insufficiently cooked hamburgers, many 2002. Characterization of isolates from of deadly outbreaks of food-borne ill- subsequent outbreaks have been associ- all 444 patients infected with E. coli ness throughout the world. The work of ated with the consumption of raw vege- O157 in Michigan since 2001 shows that et al. the frequency of clade 8 strains has in- Manning (2) in this issue of PNAS tables, including the large 1996 outbreak reveals significant new information on creased from 10% in 2002 to 46% in the evolution and genetic composition 2006 despite the steady decrease in total of E. coli strains belonging to the O157 cases identified via surveillance in O157:H7 serotype and reports the emer- No specific therapeutic this time period. Although the number gence of a new variant that appears to of HUS cases in this collection was cause more severe disease. regimens have been small (n ϭ 11), HUS patients were First recognized a quarter of a cen- developed for E. coli seven times more likely to be infected tury ago, E. coli O157:H7 causes bloody with clade 8 strains than patients with and nonbloody diarrhea, hemorrhagic O157:H7. strains from all other clades combined. colitis, and hemolytic uremic syndrome Manning et al. conclude that ‘‘an emer- (HUS), which is the leading cause of gent subpopulation of the clade 8 lin- acute renal failure in children. One of eage has acquired critical factors that in Japan in which contaminated radish the most potent toxins ever described, contribute to more severe disease.’’ sprouts infected Ϸ8,000 persons. In Shiga toxin, is a critical virulence factor They further assert that genomic con- in HUS, and different variants of this 2006, a widespread outbreak affecting tent variability among the different bacteriophage-encoded toxin, e.g., Stx1, 204 persons in 26 states was linked to clades likely explains differences in clini- Stx2, Stx2c, are found in this pathogen. contaminated spinach. In this outbreak, cal and epidemiological characteristics. The mechanism of Shiga toxin is similar 52% of cases were hospitalized, 16% to that of ricin and involves inhibition of had HUS, and one person died. The Recent Emergence of a Clade protein synthesis in renal endothelial higher-than-typical rates of hospitaliza- Their study provides new insights into and other cells. Toxin produced in the tion and HUS fueled speculation that the evolution of a bacterial pathogen intestine enters the circulation, resulting the implicated strain of E. coli O157:H7 that was rarely isolated before 1982. The in direct and indirect effects on the kid- had greater virulence potential than strains characterized by Manning et al. ney. Other important virulence factors ‘‘typical’’ strains of the serotype. This (2) span the entire outbreak history of include the type III secretion system outbreak forms the basis of the hypothe- E. coli O157:H7, and the results of the encoded on the locus of enterocyte ef- sis of the present study by Manning et analysis provide a roadmap for charac- facement (LEE) pathogenicity island al. (2) who investigated genomic diver- terizing future isolates. The data show- and a variety of secreted effector pro- sity of E. coli O157:H7 strains by SNP ing the recent emergence of a clade that teins encoded in the LEE and elsewhere analysis in an effort to better appreciate is associated with more severe disease is in the genome. Previous work from the the evolutionary dynamics of E. coli Whittam laboratory (3) indicates that O157:H7 at a population level and to E. coli O157:H7 evolved from entero- place the spinach outbreak strain within Author contributions: J.B.K. and M.A.K. wrote the paper. pathogenic E. coli serotype O55:H7, a an evolutionary framework. The authors declare no conflict of interest. cause of nonbloody diarrhea, in a step- Using comparative genomic sequenc- See companion article on page 4868. wise manner through the sequential ac- ing microarrays previously developed by †To whom correspondence should be addressed. E-mail: quisition of phage-encoded Stx2, a large Zhang et al. (4) for E. coli O157:H7, [email protected]. virulence plasmid, an rfb locus that con- Manning et al. (2) investigated SNPs in © 2008 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0801435105 PNAS ͉ March 25, 2008 ͉ vol. 105 ͉ no. 12 ͉ 4535–4536 Downloaded by guest on September 26, 2021 a particularly worrisome development genome sequences of clades 1 and 3 a theoretical factor that could influ- because antibiotic usage is contraindi- strains. In contrast, the recent increase ence clinical outcome. Although the cated for this pathogen. No specific in the rate and severity of Clostridium molecular information presented in therapeutic regimens have been devel- difficile-associated disease in North their study does not give any obvious oped for E. coli O157:H7, although America has been associated with a new insights into preventing transmission of supportive care guidelines have been strain characterized by a deletion in a E. coli O157:H7 infection, a task that improved so that mortality rates are low putative negative regulator of toxins A is greatly complicated by the very low Ͻ (5). Manning et al.’s conclusion that this and B (6). Our incomplete understand- infectious dose ( 100 colony-forming emergent subpopulation of a more viru- ing of the pathogenesis of disease units), Manning et al. note the critical lent clade has acquired critical virulence caused by E. coli O157:H7 and the lack importance of further investigation of factors that contribute to more severe of a suitable animal model contribute to the bovine reservoir, agricultural prac- disease is certainly consistent with the the difficulty in explaining the potential tices in areas where livestock and pro- data, although the present study does increased virulence of clade 8 strains. duce fields coexist, and other factors involved in the transmission of disease. not identify what the critical virulence Although Manning et al.’s conclusion The work of Manning et al. (2) re- factor(s) may be. Clade 8 strains were that clade 8 strains has acquired criti- minds us that evolution of microbial more likely to have both the stx2 and cal factors that contribute to more agents is an ongoing process. E. coli stx2c genes when compared with other severe disease could be borne out in O157:H7 is the most notorious of sev- stx2c-positive clades, but Manning et al. future studies, it should be noted that eral different types of pathogenic E. coli conclude that the toxin–gene combina- pathogen virulence factors represent that are ‘‘relentlessly evolving’’ (7). This tion alone does not account for the vari- only part of the equation in attempting study demonstrates the power of current ation in hospitalization and HUS rates to understand the outcome of infec- molecular techniques, where the entire by clade. Even the determination of the tion. Differences in the frequency of genome sequence of a bacterial patho- complete genome sequence of the clade HUS between outbreaks could also be gen can be determined to investigate a 8 spinach isolate did not reveal an obvi- a function of host factors such as im- specific disease outbreak, but it also ous explanation for increased virulence, munity, age, and gastric acidity and demonstrates the limitations of such although a number of differences were also the concentration of the organism techniques in relating the sequence in- noted between the clade 8 genome se- in the food.