Clinical Laboratory Response to a Mock Outbreak of Invasive Bacterial Infections: A Preparedness Study.

Olsen RJ1, Fittipaldi N2, Kachroo P3, Sanson MA4, Long SW3, Como-Sabetti KJ5, Valson C3, Cantu C3, Lynfield R5, Van Beneden C6, Beres SB3, Musser JM3.

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Abstract

Large, hospital-based clinical laboratories must be prepared to rapidly investigate potential infectious disease outbreaks. To challenge the ability of our molecular diagnostics laboratory to use whole genome sequencing in a potential outbreak scenario and identify impediments, we studied 84 invasive serotype emm59 group A Streptococcus (GAS) strains collected in the United States. We performed a rapid-response exercise to the mock outbreak scenario using whole genome sequencing, genome-wide transcript analysis and mouse virulence studies. Protocol changes installed in response to lessons learned were tested in a second iteration. The initial investigation was completed in 9 days. Whole genome sequencing showed that the invasive infections were caused by multiple subclones of epidemic emm59 GAS likely spread to the United States from Canada. The phylogenetic tree showed a strong temporal-spatial structure with diversity in mobile genetic element content, features useful for identifying closely related strains and possible transmission events. The genome data informed the epidemiology, identifying multiple patients who likely acquired the organisms through direct person-to-person transmission. Transcriptome analysis unexpectedly revealed significantly altered expression of genes encoding a two-component regulator and the hyaluronic acid capsule virulence factor. Mouse infection studies confirmed a high-virulence capacity of these emm59 organisms. Whole genome sequencing, coupled with transcriptome analysis and animal virulence studies, can be rapidly performed in a clinical environment to effectively contribute to patient care decisions and public health maneuvers.