Genome-wide Analysis of Salmonellaenterica serovar Typhi in Humanized Mice Reveals Key Virulence Features.

Joyce E Karlinsey
Taylor A Stepien
Matthew Mayho
Larissa A Singletary
Lacey K Bingham-Ramos
Michael A Brehm
Dale L Greiner
Leonard D. Shultz, The Jackson Laboratory
Larry A Gallagher
Matt Bawn
Robert A Kingsley
Stephen J Libby
Ferric C Fang

Abstract

Salmonella enterica serovar Typhi causes typhoid fever only in humans. Murine infection with S. Typhimurium is used as a typhoid model, but its relevance to human typhoid is limited. Non-obese diabetic-scid IL2rγnull mice engrafted with human hematopoietic stem cells (hu-SRC-SCID) are susceptible to lethal S. Typhi infection. In this study, we use a high-density S. Typhi transposon library in hu-SRC-SCID mice to identify virulence loci using transposon-directed insertion site sequencing (TraDIS). Vi capsule, lipopolysaccharide (LPS), and aromatic amino acid biosynthesis were essential for virulence, along with the siderophore salmochelin. However, in contrast to the murine S. Typhimurium model, neither the PhoPQ two-component system nor the SPI-2 pathogenicity island was required for lethal S. Typhi infection, nor was the CdtB typhoid toxin. These observations highlight major differences in the pathogenesis of typhoid and non-typhoidal Salmonella infections and demonstrate the utility of humanized mice for understanding the pathogenesis of a human-specific pathogen.