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The second World Neglected Tropical Diseases (NTDs) Day was celebrated on 30 January 2021. To mark the occasion, the World Health Organization (WHO) launched its roadmap for NTDs for the period 2021 to 2030, which is aimed at increasing prevention and control of these too-long neglected diseases. Described here is a global overview on past achievements, current challenges, and future prospects for the WHO NTDs roadmap 2021–2030.

Abstract The incidence of syphilis has risen worldwide in the last decade in spite of being an easily treated infection. The causative agent of this sexually transmitted disease is the bacterium Treponema pallidum subspecies pallidum (TPA), very closely related to subsp. pertenue (TPE) and endemicum (TEN), responsible for the human treponematoses yaws and bejel, respectively. Although much focus has been placed on the question of the spatial and temporary origins of TPA, the processes driving the evolution and epidemiological spread of TPA since its divergence from TPE and TEN are not well understood. Here, we investigate the effects of recombination and selection as forces of genetic diversity and differentiation acting during the evolution of T. pallidum subspecies. Using a custom-tailored procedure, named phylogenetic incongruence method, with 75 complete genome sequences, we found strong evidence for recombination among the T. pallidum subspecies, involving 12 genes and 21 events. In most cases, only one recombination event per gene was detected and all but one event corresponded to intersubspecies transfers, from TPE/TEN to TPA. We found a clear signal of natural selection acting on the recombinant genes, which is more intense in their recombinant regions. The phylogenetic location of the recombination events detected and the functional role of the genes with signals of positive selection suggest that these evolutionary processes had a key role in the evolution and recent expansion of the syphilis bacteria and significant implications for the selection of vaccine candidates and the design of a broadly protective syphilis vaccine.

The origins of treponemal diseases have long remained unknown, especially considering the sudden onset of the first syphilis epidemic in the late 15th century in Europe and its hypothesized arrival from the Americas with Columbus’ expeditions 1 , 2 . Recently, ancient DNA evidence has revealed various treponemal infections circulating in early modern Europe and colonial-era Mexico 3 – 6 . However, there has been to our knowledge no genomic evidence of treponematosis recovered from either the Americas or the Old World that can be reliably dated to the time before the first trans-Atlantic contacts. Here, we present treponemal genomes from nearly 2,000-year-old human remains from Brazil. We reconstruct four ancient genomes of a prehistoric treponemal pathogen, most closely related to the bejel-causing agent Treponema pallidum endemicum . Contradicting the modern day geographical niche of bejel in the arid regions of the world, the results call into question the previous palaeopathological characterization of treponeme subspecies and showcase their adaptive potential. A high-coverage genome is used to improve molecular clock date estimations, placing the divergence of modern T. pallidum subspecies firmly in pre-Columbian times. Overall, our study demonstrates the opportunities within archaeogenetics to uncover key events in pathogen evolution and emergence, paving the way to new hypotheses on the origin and spread of treponematoses. Reconstruction of four Treponema pallidum genomes associated with human remains from around 2,000 years ago suggests that T. pallidum existed in the Americas and diverged to its modern subspecies before the fifteenth century European contact with the Americas.

Yaws affects children in tropical regions, while syphilis primarily affects sexually active adults worldwide. Despite various campaigns towards the eradication of yaws and elimination of syphilis, these two diseases are still present in Ghana. The aetiological agents of both diseases, two Treponema pallidum subspecies, are genetically similar. This study aimed to assess the prevalence of these treponematoses and the occurrence of pathogens causing similar skin lesions in the Ashanti region of Ghana. A point-of-care test was used to determine the seroprevalence of the treponematoses. Both yaws and syphilis were identified in the Ashanti region of Ghana. Multiplex PCR was used to identify treponemes and other pathogens that cause similar skin lesions. The results indicated that the seroprevalences of T . pallidum in individuals with yaws-like and syphilis-like lesions were 17.2% and 10.8%, respectively. Multiplex PCR results showed that 9.1%, 1.8% and 0.9% of yaws-like lesions were positive for Haemophilus ducreyi , herpes simplex virus-1 (HSV-1) and T . pallidum respectively. Among syphilis-like lesions, 28.3% were positive for herpes simplex virus -2 (HSV-2) by PCR. To our knowledge, this is the first time HSV-I and HSV-2 have been reported from yaws-like and syphilis-like lesions, respectively, in Ghana. The presence of other organisms apart from T . pallidum in yaws-like and syphilis-like lesions could impede the total healing of these lesions and the full recovery of patients. This may complicate efforts to achieve yaws eradication by 2030 and the elimination of syphilis and warrants updated empirical treatment guidelines for skin ulcer diseases.

In ancient human compact bone tissue, we can present the identified marker proteins of Treponema pallidum , the lipoproteins 47 kDa, 17 kDa and 15 kDa in three adult individuals from Austria (thirteenth–seventeenth century CE), and in a 5 to 6-years-old child from Germany (seventeenth–nineteenth century CE). These three identified lipoproteins are also used to diagnose syphilis in current medicine. The individuals selected for this study predominantly exhibit the macroscopic and microscopic features of treponemal disease. However, the result of the proteomic analysis can confirm the diagnosis of treponematosis without any doubt. The extracellular matrix (ECM) proteins in well-preserved ancient human compact bone are still tightly bound to hydroxyapatite and/or collagen. With our solubilization technique, the entrapped ECM proteins are solubilized and identified with special antibodies in Western blot. Our techniques open up more possibilities to diagnose also other infectious diseases and tumors in humans who lived many thousands years ago.

Several recent studies have focused on the identification, functional analysis, and structural characterization of outer membrane proteins (OMPs) of Treponema pallidum ( Tp ). The Tp species encompasses the highly related pallidum , pertenue , and endemicum subspecies of this pathogen, known to be the causative agents of syphilis, yaws, and bejel, respectively. These studies highlighted the importance of identifying surface-exposed OMP regions and the identification of B-cell epitopes that could be protective and used in vaccine development efforts. We previously reported that the TprC and TprD OMPs of Tp are predicted to contain external loops scattered throughout the entire length of the proteins, several of which show a low degree of sequence variability among strains and subspecies. In this study, these models were corroborated using AlphaFold2, a state-of-the-art protein structure modeling software. Here, we identified B-cell epitopes across the full-length TprC and TprD variants using the Geysan pepscan mapping approach with antisera from rabbits infected with syphilis, yaws, and bejel strains and from animals immunized with refolded recombinant TprC proteins from three syphilis strains. Our results show that the humoral response is primarily directed to sequences predicted to be on surface-exposed loops of TprC and TprD proteins, and that the magnitude of the humoral response to individual epitopes differs among animals infected with various syphilis strains and Tp subspecies. Rather than exhibiting strain-specificity, antisera showed various degrees of cross-reactivity with variant sequences from other strains. The data support the further exploration of TprC and TprD as vaccine candidates.

Background Treponema pallidum subspecies pertenue and Haemophilus ducreyi cause skin ulcers in impoverished communities. Historical serologic records from Ghana focus on T. pallidum , omitting potential H. ducreyi cases. The objective of this study was to investigate, for the first time, the presence and distribution of T. p .subsp. pertenue and/or H. ducreyi in skin lesions in two previously unstudied areas in Western North Region of Ghana. Methods We conducted observational cross-sectional surveys and screened skin lesions in the Aowin municipality and Suaman district in Western North Region, Ghana. Suspected yaws cases were tested for 1) treponemal and non-treponemal antibodies using a finger-prick blood test and 2) Treponema pallidum and H. ducreyi DNA in lesion swabs using polymerase chain reaction (PCR). GPS coordinates were recorded for all tests administered near patients’ schools or residences. Results Of the 11,917 individuals examined, 1,699 patients with suspected yaws consented to testing. In the Aowin municipality, the seroprevalence of current treponemal infections was 10.8%, while the prevalence of yaws and H. ducreyi , confirmed by PCR, was 2.3% and 4.3%, respectively. High RPR titers correlated with active yaws infection. However, T. pallidum DNA was confirmed in lesions with low RPR titers (≤1:4). Communities with high seropositivity rates were more likely to have PCR-confirmed yaws cases. No evidence of resistance to azithromycin was observed in T. p. subsp. pertenue isolates. Dual infections with H. ducreyi were uncommon. No treponemal-positive cases were identified in the Suaman district. Conclusions Serological surveillance without molecular testing may undermine efforts to interrupt yaws transmission. More comprehensive community surveillance detecting yaws and H. ducreyi infections is critical in developing strategies to achieve the WHOs yaws eradication goal.

Background Spirochetal organisms of the Treponema genus are responsible for causing Treponematoses. Pathogenic treponemes is a Gram-negative, motile, spirochete pathogen that causes syphilis in human. Treponema pallidum subsp. endemicum (TEN) causes endemic syphilis (bejel); T. pallidum subsp. pallidum (TPA) causes venereal syphilis; T. pallidum subsp. pertenue (TPE) causes yaws; and T. pallidum subsp. Ccarateum causes pinta. Out of these four high morbidity diseases, venereal syphilis is mediated by sexual contact; the other three diseases are transmitted by close personal contact. The global distribution of syphilis is alarming and there is an increasing need of proper treatment and preventive measures. Unfortunately, effective measures are limited. Results Here, the genome sequences of 53  T. pallidum strains isolated from different parts of the world and a diverse range of hosts were comparatively analysed using pan-genomic strategy. Phylogenomic, pan-genomic, core genomic and singleton analysis disclosed the close connection among all strains of the pathogen T. pallidum , its clonal behaviour and showed increases in the sizes of the pan-genome. Based on the genome plasticity analysis of the subsets containing the subspecies T pallidum subsp. pallidum , T. pallidum subsp. endemicum and T. pallidum subsp. pertenue , we found differences in the presence/absence of pathogenicity islands (PAIs) and genomic islands (GIs) on subsp.-based study. Conclusions In summary, we identified four pathogenicity islands (PAIs), eight genomic islands (GIs) in subsp. pallidum , whereas subsp. endemicum has three PAIs and seven GIs and subsp. pertenue harbours three PAIs and eight GIs. Concerning the presence of genes in PAIs and GIs, we found some genes related to lipid and amino acid biosynthesis that were only present in the subsp. of T. pallidum, compared to T. pallidum subsp. endemicum and T. pallidum subsp. pertenue .

Ulrich von Hutten (1488–1523), a renowned sixteenth-century German humanist, documented the symptoms of the epidemic that swept through Europe starting around 1495, commonly known as the French Disease. While it has traditionally been associated with venereal syphilis, Dutch tropical physician Willem F. R. Essed proposed in 1933, largely unnoticed to this day, that this new disease might instead be tropical yaws. This study establishes a clear link between Hutten’s reported symptoms and yaws, especially in its secondary and tertiary stages. The skeleton discovered in 1968 on Ufnau Island in Lake Zurich where Hutten died and was buried, exhibits distinct bone manifestations of ancient treponematosis with a pattern more consistent with yaws than syphilis. Furthermore, the correspondence between Hutten’s main symptoms and the lesions observable on the 1968 skeleton further confirms the identification of these human remains. The historical evidence of yaws significantly contributes to our understanding of this early modern epidemic.