Evolutionary history of Salmonella typhi

Abstract

For microbial pathogens, phylogeographic differentiation seems to be relatively common. However, the neutral population structure of Salmonella enterica serovar Typhi reflects the continued existence of ubiquitous haplotypes over millennia. In contrast, clinical use of fluoroquinolones has yielded at least 15 independent gyrA mutations within a decade and stimulated clonal expansion of haplotype H58 in Asia and Africa. Yet, antibiotic-sensitive strains and haplotypes other than H58 still persist despite selection for antibiotic resistance. Neutral evolution in Typhi appears to reflect the asymptomatic carrier state, and adaptive evolution depends on the rapid transmission of phenotypic changes through acute infections.

Fig. 1

Minimal spanning tree of 105 global isolates based on sequence polymorphisms in 199 gene fragments (88,739 base pairs). The tree shows 59 haplotypes (nodes) based on 88 BiPs, the continental sources of which are indicated by colors within pie charts. The numbers along some edges indicate the number of BiPs that separate the nodes that they connect; unlabeled edges reflect single BiPs. The genomes of the CT18 and Ty2 strains have been sequenced (GenBank accession codes AL513382 and AE014613, respectively). z66 refers to a flagellar variant that is common in Indonesia (11).

Fig. 2

Selection for mutations in gyrA versus a neutral population framework in 483 strains. The strains consisted of 105 global isolates (Fig. 1), 59 older isolates from Africa and Vietnam (1958 to 1967) (fig. S4 and Table 1), and 317 isolates from southeast Asia (1984 to 2004) and other sources. (A) Sequence of codons 81 to 89 of gyrA, showing all mutated nucleotides (bold) that were detected within a 489-base pair stretch. Each mutation is designated by the name of the resulting amino acid and codon position (left). NAS, nalidixic acid sensitive. (B) Minimal spanning tree of 85 haplotypes based on 97 BiPs within 55 polymorphic genes. Sizes of circles and arcs reflect numbers of isolates. Strains without mutations in gyrA are shown in white, whereas strains with mutations are indicated by colored arcs that correspond to the colors in (A). The 15 letters indicate independent mutations associated with resistance to nalidixic acid. (C) Time course of isolation of 118 isolates of haplotype H58 or its derivative haplotypes H34, H57, and H60 to H65. These isolates were selected for haplotyping and gyrA genotyping without prior knowledge of their susceptibility to nalidixic acid. Fifty-two other H58 isolates from Vietnam are not included because they were a nonrandom sample of Nal^R bacteria. The apparent increase of Phe83 in 2004 is based on a sample from the Mekong Delta province of Vietnam and may represent an outlier.