Panton-Valentine leucocidin is the key determinant of Staphylococcus aureus pyomyositis in a bacterial GWAS.

Bernadette C Young ,Sona Soeng,Songly Hor,Vuthy Sar,Rachel Bousfield,Rory Bowden,Nicole Stoesser,Varun Kumar,Sarah G Earle,Leanne Barker,Paul Turner,Katherine R W Emary ,David Wyllie ,Emma K Nickerson ,Nicholas P J Day ,Nicholas Sanderson ,Daniel J Wilson ,Pinaki Sar ,Christopher M Parry ,Derrick W Crook ,Catrin E Moore

doi:10.7554/elife.42486

Abstract

Pyomyositis is a severe bacterial infection of skeletal muscle, commonly affecting children in tropical regions, predominantly caused by Staphylococcus aureus. To understand the contribution of bacterial genomic factors to pyomyositis, we conducted a genome-wide association study of S. aureus cultured from 101 children with pyomyositis and 417 children with asymptomatic nasal carriage attending the Angkor Hospital for Children, Cambodia. We found a strong relationship between bacterial genetic variation and pyomyositis, with estimated heritability 63.8% (95% CI 49.2-78.4%). The presence of the Panton-Valentine leucocidin (PVL) locus increased the odds of pyomyositis 130-fold (p=10-17.9). The signal of association mapped both to the PVL-coding sequence and to the sequence immediately upstream. Together these regions explained over 99.9% of heritability (95% CI 93.5-100%). Our results establish staphylococcal pyomyositis, like tetanus and diphtheria, as critically dependent on a single toxin and demonstrate the potential for association studies to identify specific bacterial genes promoting severe human disease.

Highlights

Microbial genome sequencing and bacterial genome-wide association studies (GWAS) present new opportunities to discover bacterial genes involved in the pathogenesis of serious infections (Sheppard et al, 2013; Chewapreecha et al, 2014; Earle et al, 2016; Lees et al, 2016; Falush, 2016; Power et al, 2017)
We estimated the overall heritability of case/control status to be 63.8% in the sample, reflecting the strong relationship between bacterial genetic variation and case/control status
We found a strong association between pyomyositis, a highly distinctive tropical infection of skeletal muscle in children, and Panton-Valentine leukocidin, a bacterial toxin commonly carried by bacteriophages

Summary

Introduction

Microbial genome sequencing and bacterial genome-wide association studies (GWAS) present new opportunities to discover bacterial genes involved in the pathogenesis of serious infections (Sheppard et al, 2013; Chewapreecha et al, 2014; Earle et al, 2016; Lees et al, 2016; Falush, 2016; Power et al, 2017). Pyomyositis is a severe infection of skeletal muscle most commonly seen in children in the tropics (Chauhan et al, 2004; Verma, 2016; Bickels et al, 2002). In up to 90% of cases, it is caused by a single bacterial pathogen, Staphylococcus aureus (S. aureus) (Chauhan et al, 2004; Verma, 2016; Bickels et al, 2002; Moriarty et al, 2015). There is evidence that some S. aureus strains have heightened propensity to cause pyomyositis – the incidence in the USA doubled during an epidemic of community-associated methicillin resistant S. aureus (CA-MRSA) (Pannaraj et al, 2006) – but molecular genetic investigation of S. aureus from pyomyositis has been limited (Borges et al, 2012)

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Results

Conclusion