Perspectives Invasive Disease and Toxic Shock due to Zoonotic suis: An Emerging Infection in the East? Shiranee Sriskandan*, Josh D. Slater

treptococcus suis (S. suis) is widely of patients were victim to a toxic recognised in the veterinary world shock-like syndrome (TSLS). Indeed, as a cause of rapidly progressive the vast majority of deaths in this Sand fatal in infant , associated outbreak occurred in patients with with , polyarthritis, and, TSLS rather than in patients with occasionally, pneumonia. A more meningitis. To date, streptococcal fulminant bacteraemic infection is toxic shock, per consensus defi nition, seen in neonatal pigs [1,2]. For reasons has been limited to disease caused that are unknown, adult pigs do not by the group A streptococcus, S. succumb to this infection, although pyogenes [6]. Sporadic reports of TSLS they demonstrate asymptomatic due to other (nongroup A) beta- nasopharyngeal carriage (Figure 1), haemolytic streptococci have been and infant piglets become infected reported, though there is potentially after early contact with colonised considerable diagnostic overlap adult females. In many respects, S. between cases of septic shock and suis infection is the porcine version of TSLS [7]. With one exception [8], S. human group B strep disease. Zoonotic suis has not previously been linked to disease due to S. suis does occur TSLS. Tang and colleagues report that sporadically in Western countries, but almost all human cases of TSLS due to is encountered more commonly in S. suis demonstrated an erythematous countries such as Thailand, China, and blanching rash, one of the most specifi c DOI: 10.1371/journal.pmed.0030187.g001 Hong Kong. It affects predominantly features of TSLS, associated with S. suis causes a rapidly progressive and individuals with occupational exposure hypotension and multiorgan failure. fatal sepsis in infant pigs to pigs. In humans, meningitis is the Tang and colleagues provide insight most common presentation (about 80% into the clinical outbreak with regard Sichuan Province have close contact of all cases), though S. suis disease can to the spectrum of clinical disease, with their pigs; humans and animals be associated with other suppurative morbidity, and mortality. They did not often share the same accommodations complications such as pneumonia and identify a clear focus of infection in the arthritis. Mortalities of 5%–10% of TSLS cases, in contrast to the originally cases are reported [2], and S. suis is the described streptococcal toxic shock Funding: The authors received no specifi c funding third most common cause of bacterial syndrome, where soft tissue infection for this article. meningitis in Hong Kong [3]. was most commonly found. Competing Interests: The authors have declared S. suis and Toxic Shock that no competing interests exist. S. suis—The Source? In the current issue of PLoS Medicine, Citation: Sriskandan S, Slater JD (2006) Invasive Epidemiologically, all cases of human disease and toxic shock due to zoonotic Tang and colleagues report on the disease in the recent outbreak were Streptococcus suis: An emerging infection in the East? largest known zoonotic outbreak of PLoS Med 3(5): e187. linked to exposure to pigs, and, , which occurred in Sichuan S. suis although broken skin is reported DOI: 10.1371/journal.pmed.0030187 Province in China in 2005 [4]. The in most cases, the precise route of outbreak, which attracted considerable Copyright: © 2006 Sriskandan and Slater. This is transmission is not further discussed. public and scientifi c interest [5], an open-access article distributed under the terms Other sporadic zoonotic S. suis of the Creative Commons Attribution License, killed 38 out of 204 individuals with which permits unrestricted use, distribution, cases have been linked to accidental the infection and coincided with a and reproduction in any medium, provided the inoculation injuries through lacerations original author and source are credited. major outbreak of disease in pigs. In or inhalation of infected aerosols from addition to its size and the associated Abbreviation: TSLS, toxic shock-like syndrome infected carcasses, though S. suis is high mortality, this outbreak is also found in faeces and fomites of Shiranee Sriskandan is in the Department of unique in that a large proportion Infectious Diseases, Hammersmith Hospital, Imperial infected herds [1,2]. At least some of College London, London, United Kingdom. Josh D. the human cases in an earlier S. suis Slater is at the Royal Veterinary College, Hatfi eld, The Perspectives section is for experts to discuss the outbreak in Sichuan Province in 1998 Hertfordshire, United Kindom. clinical practice or public health implications of a published article that is freely available online. may have been related to ingestion * To whom correspondence should be addressed. of contaminated food [9]. Farmers in E-mail: [email protected]

PLoS Medicine | www.plosmedicine.org 0595 May 2006 | Volume 3 | Issue 5 | e187 and animals are slaughtered at home. North American strains [14]. Isolates Furthermore, it is common practice for from the 2005 outbreak in Sichuan diseased animals to be slaughtered and Province were compared at a molecular eaten. Thus, in addition to inoculation level with a European serotype-2 strain and airborne transmission from (P1/7) and with a handful of isolates infected pigs, foodborne transmission from the earlier outbreak in Sichuan by infected pork may have also Province in 1998. contributed to the recent outbreak. The isolates from the recent Chinese outbreak carried genes for all of the S. suis DOI: 10.1371/journal.pmed.0030187.g002 Phenotype of Virulent known virulence-associated factors, Isolates: Lack of Superantigenicity? Figure 1. Scanning Electron Microscopy of akin to European invasive strains. S. suis Having identifi ed S. suis as the Diplococci in a Sheet of Mucus on the However, Tang and colleagues report causative agent of the 2005 outbreak, Surface of the Nasopharyngeal Epithelium that the serotype-2 strain associated from a the authors went on to provide an with the recent outbreak is quite (Photo: Josh D. Slater) initial phenotypic and molecular different to other invasive type-2 analysis of the S. suis strains involved in isolates with regard to the capsular isolates from the current outbreak clinical disease. Bacterial superantigen polysaccharide synthesis gene cluster with those causing invasive disease production, with consequent and restriction fragment length in other countries, in addition to a overstimulation of immunological polymorphism pattern. Intriguingly, comparison with colonising isolates. cascades, is believed to underlie the the recent isolates are indistinguishable Being the natural host, the pig is catastrophic features of toxic shock from the isolates that caused the earlier clearly a superior model for study of [10]. However, little is known about S. 1998 outbreak in China that killed 14 suis, and mouse models have proved the superantigenicity of S. suis, and out of 25 human patients [9]. Thus, unreliable [12]. Future refi nement and when Tang and colleagues tested S. there appears to be good evidence that standardisation of S. suis models should suis isolates for mitogenic activity, a the strains from the Chinese outbreaks include the use of -free piglets hallmark of superantigen production, are epidemiologically distinct from and the administration of an inoculum they found none. In the absence of other invasive S. suis strains. via the nasopharyngeal route, in order superantigens, alternative virulence to better reproduce natural infection. S. suis mechanisms might account for Emerging Infections in Pigs are normally sensitive to the effects endothelial leakage and the features Humans: A Need for Coordinated of superantigens [13], although they of TSLS, such as M protein–fi brinogen and Cooperative Research have not been reported to develop the interactions and activation of the infection is of major economic rash characteristic of human TSLS. S. suis coagulation system [10,11]. More and veterinary importance in the detailed analysis of the strains farming world, and should now be on associated with the outbreak is required Comparison of Chinese Outbreak the list of differential diagnoses when to eliminate a role for superantigens; Isolates with Other Virulent Strains clinicians encounter patients with this includes molecular analysis and To compare the S. suis isolates of the unexplained sepsis who have a history study of T cell subset changes induced Chinese outbreak with European of exposure to pigs. Eradication of by exposure to secreted products of invasive isolates, molecular analysis S. suis from the pig population is not these strains. The genome sequences of was undertaken by the investigating currently feasible, even though S. suis two S. suis strains are currently available team. S. suis is an alpha-haemolytic, or appears fully sensitive to . for study (see http:⁄⁄www.sanger.ac.uk/ nonhaemolytic, group D streptococcus, Antibiotic treatment in pigs is rarely Projects/S_suis and http:⁄⁄genome. which is normally sensitive to successful, probably because of jgi-psf.org/draft_microbes/strsu/strsu. in vitro. Strains associated with virulent poor antibiotic penetration of the home.html), and although regions disease do produce a number of porcine tonsillar tissues, which act as bearing some similarity to S. pyogenes M extracellular proteins, such as a 110- a source of infection [16]. Resistance protein and superantigen genes can be kDa extracellular factor, a 136-kDa to macrolides, lincosamides, and identifi ed, functional analysis is needed muramidase-released protein, and a tetracycline is common, limiting efforts to fully characterise these features. thiol-activated haemolysin (suilysin), to clear tonsillar carriage. Development although none alone are suffi cient S. suis of a vaccine targeted against the In Vivo Study of Virulence for full virulence [14]. The capsular most virulent or prevalent strains One of the key questions arising from polysaccharide, as for other streptococci, might be one possible way to prevent this report is whether a new, highly appears crucial to resistance to colonisation of female pigs and to virulent strain of S. suis has emerged in opsonophagocytosis [15]. There are protect those working with pigs [17]. China? Tang and colleagues explored 35 known capsular serotypes, though Better characterisation of activities virulence using a neonatal piglet capsular serotype 2—the type associated that increase risk of S. suis acquisition model of infection. Consistent with its with the 2005 outbreak in China—is and faster diagnostic tests to identify causative role, the S. suis strain from the most common in most parts of outbreaks in pigs will lead to adaptation the recent outbreak caused disease, the world. Even within this serotype, of practices that incur unnecessary whereas a known avirulent S. suis strain there is heterogeneity, and European exposure to infected carcasses. did not. Future studies might be best strains appear more likely to produce The emergence of any new zoonotic served by a comparison of invasive virulence-associated exoproteins than infectious disease associated with high

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