New Variant of Multidrug-Resistant Salmonella enterica Serovar Typhimurium Associated with Invasive Disease in Immunocompromised Patients in Vietnam

Abstract

Nontyphoidal Salmonella (NTS), particularly Salmonella enterica serovar Typhimurium, is among the leading etiologic agents of bacterial enterocolitis globally and a well-characterized cause of invasive disease (iNTS) in sub-Saharan Africa. In contrast, S Typhimurium is poorly defined in Southeast Asia, a known hot spot for zoonotic disease with a recently described burden of iNTS disease. Here, we aimed to add insight into the epidemiology and potential impact of zoonotic transfer and antimicrobial resistance (AMR) in S Typhimurium associated with iNTS and enterocolitis in Vietnam. We performed whole-genome sequencing and phylogenetic reconstruction on 85 human (enterocolitis, carriage, and iNTS) and 113 animal S Typhimurium isolates isolated in Vietnam. We found limited evidence for the zoonotic transmission of S Typhimurium. However, we describe a chain of events where a pandemic monophasic variant of S Typhimurium (serovar I:4,[5],12:i:- sequence type 34 [ST34]) has been introduced into Vietnam, reacquired a phase 2 flagellum, and acquired an IncHI2 multidrug-resistant plasmid. Notably, these novel biphasic ST34 S Typhimurium variants were significantly associated with iNTS in Vietnamese HIV-infected patients. Our study represents the first characterization of novel iNTS organisms isolated outside sub-Saharan Africa and outlines a new pathway for the emergence of alternative Salmonella variants into susceptible human populations.IMPORTANCESalmonella Typhimurium is a major diarrheal pathogen and associated with invasive nontyphoid Salmonella (iNTS) disease in vulnerable populations. We present the first characterization of iNTS organisms in Southeast Asia and describe a different evolutionary trajectory from that of organisms causing iNTS in sub-Saharan Africa. In Vietnam, the globally distributed monophasic variant of Salmonella Typhimurium, the serovar I:4,[5],12:i:- ST34 clone, has reacquired a phase 2 flagellum and gained a multidrug-resistant plasmid to become associated with iNTS disease in HIV-infected patients. We document distinct communities of S Typhimurium and I:4,[5],12:i:- in animals and humans in Vietnam, despite the greater mixing of these host populations here. These data highlight the importance of whole-genome sequencing surveillance in a One Health context in understanding the evolution and spread of resistant bacterial infections.

Keywords: Salmonella Typhimurium; antimicrobial resistance; genomics; invasive salmonellosis.

FIG 1

Maximum-likelihood phylogeny of 198 Salmonella Typhimurium/S. I:4,[5],12:i:− isolates from Vietnam. Reads were mapped to reference S. Typhimurium SL1344, with host species, multilocus sequence type (ST), and BAPS cluster (in red) marked. The scale bar represents the number of nonrecombinogenic single nucleotide polymorphisms per branch.

FIG 2

Maximum-likelihood phylogeny of 418 Salmonella Typhimurium/S. I:4,[5],12:i:− isolates from Vietnam and other countries. Reads were mapped to reference monophasic S. Typhimurium variant S. I:4,[5],12:i:− SO4698-09, with country of origin, ST34 subgroup, HIV status, flagellar status, and presence or absence of antimicrobial resistance determinants mapped against the phylogeny. The blue box indicates the multidrug-resistant (MDR) ST34 subgroup. The scale bar represents the number of nonrecombinogenic single nucleotide polymorphisms per branch.

FIG 3

Multigenome comparison of the second flagellar region of Salmonella Typhimurium SL1344, isolate VNB151 from Vietnam, and monophasic S. Typhimurium variant S. I:4,[5],12:i:− SO4698-09. Arrows represent coding sequences for SL1344 and predicted coding sequences for VNB151 and SO4698-09; gray blocks indicate regions of genetic similarity between genomes. Minor differences in annotated coding sequences in regions with gray blocks reflect the predicted nature of the VNB151 and SO4698-09 annotation.