Review article
Yersinia enterocolitica: Pathogenesis, virulence and antimicrobial resistanceYersinia enterocolitica: patogénesis, virulencia y resistencia a antibióticos

https://doi.org/10.1016/j.eimc.2011.07.017Get rights and content

Abstract

Yersinia enterocolitica is a heterogeneous group of strains, which are classified into 6 biogroups, and into more than 57 O serogroups. However, the human pathogenic strains most frequently isolated worldwide belong to serogroups O:3, O:5,27, O:8 and O:9. The major route of Y. enterocolitica infection is through contaminated foods or water. The primary pathogenic event is colonization of the intestinal tract where most of the pathologic effects and clinical manifestations occur. Temperature and calcium concentration regulate expression of virulence factors that guide the invading yersiniae and allow them to survive and disseminate. Gastrointestinal infections are usually self-limiting and do not merit antimicrobial therapy. Nonetheless, fluoroquinolones or third generation cephalosporins, the best therapeutic options, are warranted to treat enterocolitis in compromised hosts and in patients with septicemia or invasive infection, in which the mortality can be as high as 50%. A review of the pathogenesis, virulence and antimicrobial resistance is carried out.

Resumen

Y. enterocolitica es un grupo heterogéneo de cepas clasificadas en 6 biogrupos y en más de 57 serogrupos O. Las cepas patógenas humanas más frecuentemente aisladas pertenecen a los serogrupos O:3, O:5,27, O:8 y O:9. La transmisión de la infección es principalmente a través de alimentos o agua contaminados. La etapa esencial de la patogénesis es la colonización del tracto intestinal, donde ocurren la mayoría de los efectos patológicos y manifestaciones clínicas. La temperatura y la concentración de calcio regulan la expresión de los factores de virulencia que guían al patógeno durante la invasión, supervivencia y diseminación. Normalmente las infecciones gastrointestinales son autolimitadas y no necesitan tratamiento antimicrobiano. Las fluoroquinolonas y cefalosporinas de tercera generación son los tratamientos más eficaces en casos de enterocolitis en immunodeprimidos, septicemia o infección invasiva, situaciones en las que la mortalidad puede alcanzar el 50%. Se presenta una revisión de la patogénesis, virulencia y resistencia antimicrobiana.

Introduction

Bacteria of the genus Yersinia cause diseases ranging from enteritis to bubonic plague (Black Death). The initial characterization of this genus was performed in 1894 in Hong Kong. There, Alexandre Emile John Yersin together with Shibasaburo Kitasato identified Yersinia pestis (formerly known as Pasteurella pestis) as the causal agent of the bubonic plague.1 However, the first recognized description of 5 human isolates belonging to Yersinia enterocolitica was made later, in 1939, by Schleifstein and Coleman in the United States.2 Nonetheless, McIver and Pike had already isolated one of these clinical strains in 1934, although they had erroneously identified it under the name Flavobacterium pseudomallei.3

Members of the genus Yersinia are non-spore forming, Gram-negative or Gram-variable, rod-shaped or coccoid cells of 0.5–0.8 μm in width and 1–3 μm in length. All species, with the exception of Y. pestis, are motile at 22–30 °C but not at 37 °C. Motile cells are peritrichously flagellated. Yersiniae grow under aerobic and anaerobic culture conditions between 0 °C and 45 °C, being optimum at 25–28 °C, on non-selective and certain selective media.4

At present, the genus Yersinia includes 11 established species: Y. pestis, Y. pseudotuberculosis, Y. enterocolitica, Y. frederiksenii, Y. intermedia, Y. kristensenii, Y. bercovieri, Y. mollaretii, Y. rohdei, Y. aldovae and Y. ruckeri. Among them only Y. pestis, Y. pseudotuberculosis and certain strains of Y. enterocolitica are of pathogenic importance for humans and certain warm-blooded animals, whereas the other species are of environmental origin and may, at best, act as opportunists. However, Yersinia strains can be isolated from clinical materials and therefore have to be identified at the species level.4

Y. enterocolitica is a heterogeneous group of strains, which are traditionally classified by biotyping into 6 biogroups on the basis of phenotypic characteristics, and by serotyping into more than 57 O serogroups, on the basis of their O (lipopolysaccharide or LPS) surface antigen. Five of the 6 biogroups (1B and 2–5) are regarded as pathogens. However, only a few of these serogroups have been associated with disease in either humans or animals. Strains that belong to serogroups O:3 (biogroup 4), O:5,27 (biogroups 2 and 3), O:8 (biogroup 1B) and O:9 (biogroup 2) are most frequently isolated worldwide from human samples.5 However, the most important Y. enterocolitica serogroup in many European countries is serogroup O:3 followed by O:9, whereas the serogroup O:8 is mainly detected in the United States.1

Y. enterocolitica is widespread in nature, occurring in reservoirs ranging from the intestinal tracts of numerous mammals, avian species, cold-blooded species, and even from terrestrial and aquatic niches. Most environmental isolates are avirulent; however, isolates recovered from porcine sources contain human pathogenic serogroups. In addition, other studies have suggested that dogs, sheep, wild rodents and environmental water may also be a reservoir of pathogenic Y. enterocolitica strains. Human pathogenic strains are usually confined to the intestinal tract and lead to enteritis/diarrhea.6

Clinical identification of Y. enterocolitica strains is achieved after growth of stool samples on MacConkey plates, as well as on CIN Agar (Cefsulodin, Irgasan, Novobiocin), also known as Yersinia Selective Agar. Plates are incubated for 24 h at 37 °C and identification of colonies is performed according to macroscopic characteristics. Y. enterocolitica has slower lactose fermentation and slower growth in comparison with other enteric bacterial species normally present in fecal samples. Therefore, the pinpoint and colorless colonies grown on MacConkey plates make identification a difficult task against the background of the more rapidly growing bacteria.1 Consequently, the use of selective media such as the CIN Agar, which is a differential medium that inhibits growth of normal enteric organisms, provides improved direct recovery of this pathogen from feces. The characteristic translucent and sharp-bordered colonies, showing a deep-red center due to mannitol fermentation, are usually referred to as bull's eyes colonies and allow easy identification.7

In addition, there are specific biochemical properties which corroborate its identification. The most significant traits are the following: Y. enterocolitica strains are motile at 25 °C but not at 37 °C, produce urease, lack oxidase activity and do not produce either gas or hydrogen sulphide on Kligler's Iron Agar.1

In order to distinguish between pathogenic and non-pathogenic strains, further approaches can be undertaken. Serogroup analysis can be performed using specific antisera for typing pathogenic strains. According to the geographical distribution of the serogroups, this methodology is particularly important in Europe or Japan to detect serogroups O:3 and O:9. On the other hand, this serological diagnostic method has been minimally used in the United States to detect serogroup O:8 because of the absence of sufficient guidelines for interpretation of agglutinin titers.1, 8

When antisera are not available, assessment of virulence traits is an alternative methodology and generally identifies expression of plasmid-encoded virulence factors by means of simple phenotypic tests. Pathogenic strains are usually positive for autoagglutination at 37 °C, calcium dependence for growth at 37 °C, Congo red binding, and resistance to the bactericidal effects of serum.9, 10, 11 However, absence of pyrazinamidase production and lack of salicin fermentation and esculin hydrolysis are traits of pathogenic yersiniae independently associated with the presence of the virulence plasmid.12

Nowadays, MALDI-TOF mass spectrometry analysis has been incorporated as a straightforward, rapid, accurate and inexpensive tool to identify bacteria according to specific protein profiles. Therefore, it is currently displacing the former biochemical and phenotypic characterization in an increasing number of clinical microbiology laboratories.13, 14

Section snippets

Pathogenesis model

The usual route of acquisition of this pathogen is through contaminated foods or water.15, 16 The primary event of Y. enterocolitica pathogenesis is colonization of the intestinal tract, particularly the distal small intestine (terminal ileum) and proximal colon. Accordingly, most of the pathologic effects and, hence, clinical manifestations occur at this location.1 There, virulent yersiniae must traverse the intestinal lumen, attach to and penetrate the mucus barrier overlying the mucosal

Virulence factors

The virulence factors characterized in Y. enterocolitica are located within the chromosome and also on a 70 kb virulence plasmid designated pYV which is only detected in virulent strains. These virulence properties, particularly the plasmid-encoded genes, guide the invading Yersinia pathogen and enable bacteria to survive inside the human host.1, 24, 25

Regulation of virulence

All pathogenic Y. enterocolitica strains, both low and high-pathogenicity isolates, show a thermally responsive adaptation process which aids the transition from the environment to the adverse conditions inside of the human host. The rapidity of this process in surviving yersiniae cells determines the clinical outcome, as well as the incubation period.1 Thus, regulation of virulence genes plays a key role in the successful accommodation for the increase in temperature to 37 °C when infecting

Clinical relevance

Among the different biotypes and throughout the gastrointestinal tract, Y. enterocolitica biotype 1B (mainly associated in the clinical setting with serotype O:8) is known as highly pathogenic and usually produces the most catastrophic events. However, serogroups O:3 and O:9 (belonging to biotypes 4 and 2, respectively), which are the most common causes of yersiniae infections worldwide, are less destructive.1 Since iron appears to play a crucial role in the pathogenesis of Yersinia, one of the

Antimicrobial treatment and resistance

The great majority of the gastrointestinal infections are self-limiting and confined to the gut and do not merit antimicrobial therapy in an immunocompetent host. However, antimicrobial therapy is warranted to treat enterocolitis in compromised hosts and in patients with septicemia or invasive infection, in which the mortality can be as high as 50%. Despite antibiotic susceptibility patterns varying among serogroups, the organism is usually susceptible in vitro to aminoglycosides,

Concluding remarks

Infections caused by the pathogen Y. enterocolitica following the ingestion of contaminated foods or water, generally do not transcend the gastrointestinal tract and the underlying lymphoid tissues (PP and MLN). Nonetheless, there are particular situations in which these bacteria can circumvent the host defense mechanisms and cause systemic infection, reaching extra-intestinal sites such as the liver and the spleen. Otherwise, an alternative less frequent, although serious route, of infection

Funding

This study has been supported by the Spanish Ministry of Health (FIS 08/0195 to JV), by 2009 SGR 1256 from the Departament de Universitats, Recerca i Societat de la Informació de la Generalitat de Catalunya, and by the Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III, Spanish Network for the Research in Infectious Disease (REIPI 06/0008). This work has also been supported by funding from the European Community (AntiPathoGN contract HEALTH-F3-2008-223101; TROCAR contract

Conflict of interest

The authors declare no conflicts of interest related to this study.

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