Treponema pallidum genome sequencing from six continents reveals variability in vaccine candidate genes and dominance of Nichols clade strains in Madagascar

Abstract

In spite of its immutable susceptibility to penicillin, Treponema pallidum (T. pallidum) subsp. pallidum continues to cause millions of cases of syphilis each year worldwide, resulting in significant morbidity and mortality and underscoring the urgency of developing an effective vaccine to curtail the spread of the infection. Several technical challenges, including absence of an in vitro culture system until very recently, have hampered efforts to catalog the diversity of strains collected worldwide. Here, we provide near-complete genomes from 196 T. pallidum strains–including 191 T. pallidum subsp. pallidum–sequenced directly from patient samples collected from 8 countries and 6 continents. Maximum likelihood phylogeny revealed that samples from most sites were predominantly SS14 clade. However, 99% (84/85) of the samples from Madagascar formed two of the five distinct Nichols subclades. Although recombination was uncommon in the evolution of modern circulating strains, we found multiple putative recombination events between T. pallidum subsp. pallidum and subsp. endemicum, shaping the genomes of several subclades. Temporal analysis dated the most recent common ancestor of Nichols and SS14 clades to 1717 (95% HPD: 1543–1869), in agreement with other recent studies. Rates of SNP accumulation varied significantly among subclades, particularly among different Nichols subclades, and was associated in the Nichols A subclade with a C394F substitution in TP0380, a ERCC3-like DNA repair helicase. Our data highlight the role played by variation in genes encoding putative surface-exposed outer membrane proteins in defining separate lineages, and provide a critical resource for the design of broadly protective syphilis vaccines targeting surface antigens.

B-cell epitope mapping of TprC and TprD variants ofTreponema pallidumsubspecies

“…pertenue, as recently demonstrated in Papua New Guinea (15). Foci of bejel have been reported in the last two decades, mostly in the Near East and Sahelian Africa (16)(17)(18)(19), and bejel strains have recently reported to be transmitted sexually (20).…”

Whole genome sequences of Treponema pallidum subsp. endemicum isolated from Cuban patients: The non-clonal character of isolates suggests a persistent human infection rather than a single outbreak

“…Assuming that the mutation rate is similar in TEN as in TPA and TPE, the estimated 22.8 to 117.4 nucleotide differences between individual TEN strains detected in Cuba suggest at least several hundreds of years of separate evolution in the human population and, therefore, the long-term existence of the different TEN strains in the Cuban or related population. On the other hand, several studies presented higher treponemal mutation rates, e.g., 3,02 x 10 −7 [ 7 ] or 6,6 x 10 −7 [ 40 ] per nucleotide site per year, which would suggest several decades of separate evolution considering the lowest nucleotide difference of 22.8 nt.…”

“…While bejel is a disease typically associated with dry arid areas such as the Sahel and the Middle East [ 2 ], it has also been found in Canada [ 4 ], France [ 5 ], Japan [ 6 , 7 ], and Cuba [ 8 ]. Cases in Canada and France were explained by bejel being imported from endemic areas, Senegal and Pakistan, respectively [ 4 , 5 ].…”

High-throughput nanopore sequencing of Treponema pallidum tandem repeat genes arp and tp0470 reveals clade-specific patterns and recapitulates global whole genome phylogeny

“…All human samples were collected and deidentified following protocols established at each institution. All IRB information from samples collected in Japan; Italy; Ireland; Maryland, USA; Madagascar; Peru; Papua New Guinea, and Nanjing, China has been previously published (Hopkins et al, 2004;Lukehart et al, 2004;Van Damme et al, 2009;Hook III et al, 2010;Marra et al, 2010;Lieberman et al, 2021)…”