Functional insights from proteome-wide structural modeling of Treponema pallidum subspecies pallidum, the causative agent of syphilis.

BACKGROUND: Syphilis continues to be a major global health threat with 11 million new infections each year, and a global burden of 36 million cases. The causative agent of syphilis, Treponema pallidum subspecies pallidum, is a highly virulent bacterium, however the molecular mechanisms underlying T. pallidum pathogenesis remain to be definitively identified. This is due to the fact that T. pallidum is currently uncultivatable, inherently fragile and thus difficult to work with, and phylogenetically distinct with no conventional virulence factor homologs found in other pathogens. In fact, approximately 30% of its predicted protein-coding genes have no known orthologs or assigned functions. Here we employed a structural bioinformatics approach using Phyre2-based tertiary structure modeling to improve our understanding of T. pallidum protein function on a proteome-wide scale. RESULTS: Phyre2-based tertiary structure modeling generated high-confidence predictions for 80% of the T. pallidum proteome (780/978 predicted proteins). Tertiary structure modeling also inferred the same function as primary structure-based annotations from genome sequencing pipelines for 525/605 proteins (87%), which represents 54% (525/978) of all T. pallidum proteins. Of the 175 T. pallidum proteins modeled with high confidence that were not assigned functions in the previously annotated published proteome, 167 (95%) were able to be assigned predicted functions. Twenty-one of the 175 hypothetical proteins modeled with high confidence were also predicted to exhibit significant structural similarity with proteins experimentally confirmed to be required for virulence in other pathogens. CONCLUSIONS: Phyre2-based structural modeling is a powerful bioinformatics tool that has provided insight into the potential structure and function of the majority of T. pallidum proteins and helped validate the primary structure-based annotation of more than 50% of all T. pallidum proteins with high confidence. This work represents the first T. pallidum proteome-wide structural modeling study and is one of few studies to apply this approach for the functional annotation of a whole proteome.

Is Screening for Chlamydia and Gonorrhea in Men Who Have Sex With Men Associated With Reduction of the Prevalence of these Infections? A Systematic Review of Observational Studies.

BACKGROUND: Neisseria gonorrhoeae (gonorrhea) could become untreatable in the near future. Indeed, while the treatment of symptomatic gonorrhea in core groups, such men who have sex with men (MSM), is crucial for gonorrhea control programs, screening for and treating asymptomatic gonorrhea/Chlamydia trachomatis(chlamydia) in MSM may contribute to antibiotic resistance in gonorrhea. In this systematic review, we aim to assess if there is evidence that screening MSM for gonorrhea/chlamydia is associated with a decline in the prevalence of these infections. METHODS: We conducted a systematic review in PubMed and Web of Science for relevant studies including uncontrolled observational studies and reported the results following the PRISMA guidelines. The change in estimated prevalences for chlamydia and gonorrhea across the different time points for 3 anatomical sites (oral, urethral and anal) were collected and examined. RESULTS: Twelve studies met our entry criteria. We were able to statistically assess the change in prevalence in 10 of 12 studies. In 3 studies, there was a significant increase in chlamydia prevalence, whereas for gonorrhea, 2 studies reported a significant increase and 2 others a decrease. Our review provides little evidence that screening for gonorrhea and chlamydia in MSM has an effect on the prevalence of these infections. No evidence was found that more frequent screening reduces prevalence more effectively than annual screening. CONCLUSIONS: Our study was not able to provide evidence that screening for chlamydia and gonorrhea lowers the prevalence of these infections in MSM. Randomized controlled trials are required to assess the risks and benefits of gonorrhea/chlamydia screening in high- and low-risk MSM.

The Prevalence of Syphilis from the Early HIV Period is Correlated With Peak HIV Prevalence at a Country Level.

BACKGROUND: Could we have predicted national peak HIV based on syphilis prevalence in the 1990s? Earlier studies have shown positive correlations between various sexually transmitted infections at different population levels. In this article, we test the hypothesis that there was a residual variation in the national prevalence rates of syphilis and that these rates could predict subsequent peak HIV prevalence rates. METHODS: This analysis uses linear regression to evaluate the country-level relationship between antenatal syphilis prevalence (1990-1999) and peak HIV prevalence. Antenatal syphilis data were taken from an Institute for Health Metrics and Evaluation database on the prevalence of syphilis in low-risk populations. Peak HIV prevalence was calculated based on data taken from the Global Health Observatory Data Repository of the World Health Organization. RESULTS: A moderately strong association is found for the 76 countries with data available (R = 0.53, P < 0.001). The association was weakened but remained significantly positive when we adjusted for the type of syphilis testing used. CONCLUSIONS: Syphilis prevalence in the 1990s predicted approximately 53% of the variation in peak HIV prevalence. Populations with generalized HIV epidemics had a higher prevalence of syphilis in the pre-HIV period. This finding provides additional rationale to carefully monitor sexual behavior, sexual networks, and sexually transmitted infection incidence in these populations.

Take three, test one: a cross-sectional study to evaluate the molecular detection of Chlamydia trachomatis and Neisseria gonorrhoeae in pooled pharyngeal, anorectal and urine samples versus single-site testing among men who have sex with men in Belgium.

Objectives: To investigate the efficacy of performing a pooling strategy of triple-anatomical site samples (pharyngeal, anorectal and urine samples) for simultaneous Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) nucleic acid amplification detection.Methods: A total of 117 specimen sets (pharyngeal, anorectal and urine) were collected from 98 men between 2014 and 2016. Double sampling of pharyngeal, anorectal and urine samples allowed for pooled and unpooled analyses using a multiplex Abbott Real Time CT/NG assay, together with confirmatory PCR testing in case of CT/NG positivity. Clinical and demographic data were analyzed.Results: The positivity rate for the triple-site pooled testing for CT and NG was 8.5% (10/117) and 6.8%, (8/117), respectively, compared to the single-site testing total positivity rate, which was 9.4% (11/117) and 4.3% (5/117) for CT and NG, respectively. Pooled analysis missed one CT-positive urine sample and one CT-positive anorectal sample could not be confirmed. In addition, less PCR inhibition was reported for the pooled sample (PS) testing and ERV-3 qPCR testing revealed ineffective sampling of self-collected anorectal swabs in two cases. No pharyngeal samples were positive for CT, nor were any urine samples positive for NG.Conclusion: This small study showed that PS testing is a possible testing strategy for screening high-risk men who have sex with men attending pre-exposure prophylaxis (PrEP) clinics. However, due to the low positivity rate of CT/NG in this study, larger evaluations are needed to confirm the effectiveness of CT/NG screening with multiple-site PS nucleic acid amplification test (NAAT) screening practices.

The Global Epidemiology of Syphilis in the Past Century - A Systematic Review Based on Antenatal Syphilis Prevalence.

BACKGROUND: How can we explain the uneven decline of syphilis around the world following the introduction of penicillin? In this paper we use antenatal syphilis prevalence (ASP) to investigate how syphilis prevalence varied worldwide in the past century, and what risk factors correlate with this variance. METHODS: 1) A systematic review using PubMed and Google Scholar was conducted to identify countries with published data relating to ASP estimates from before 1952 until the present. Eleven countries were identified (Canada, Denmark, Finland, India, Japan, Norway, Singapore, South Africa, United States of America (USA), United Kingdom (UK) and Zimbabwe). The ASP epidemic curve for each population was depicted graphically. In South Africa and the USA, results are reported separately for the black and white populations. 2) National antenatal syphilis prevalence estimates for 1990 to 1999 and 2008 were taken from an Institute for Health Metrics and Evaluation database on the prevalence of syphilis in low risk populations compiled for the Global Burden of Diseases study and from a recent review paper respectively. National ASPs were depicted graphically and regional median ASPs were calculated for both time periods. 3) Linear regression was used to test for an association between ASP in 1990-1999 and 2008 and four risk factors (efficacy of syphilis screening/treatment, health expenditure, GDP per capita and circumcision prevalence). WHO world regions were included as potential explanatory variables. RESULTS: In most populations, ASP dropped to under 1% before 1960. In Zimbabwe and black South Africans, ASP was high in the pre-penicillin period, dropped in the post-penicillin period, but then plateaued at around 6% until the end of the 20th century when ASP dropped to just above 1%. In black Americans, ASP declined in the post penicillin period, but plateaued at 3-5% thereafter. ASP was statistically significantly higher in sub-Saharan Africa in 1990-1999 and 2008 than in the other world regions (P < 0.001). On multivariate analysis in both time periods, ASP was only associated with residence in sub-Saharan Africa. CONCLUSIONS: Further research is necessary to elucidate the reasons for the higher prevalence of syphilis in sub-Saharan Africa.

Strong Country Level Correlation between Syphilis and HSV-2 Prevalence.

Background. Syphilis is curable but Herpes Simplex Virus-2 (HSV-2) is not. As a result, the prevalence of syphilis but not HSV-2 may be influenced by the efficacy of national STI screening and treatment capacity. If the prevalence of syphilis and HSV-2 is found to be correlated, then this makes it more likely that something other than differential STI treatment is responsible for variations in the prevalence of both HSV-2 and syphilis. Methods. Simple linear regression was used to evaluate the relationship between national antenatal syphilis prevalence and HSV-2 prevalence in women in two time periods: 1990-1999 and 2008. Adjustments were performed for the laboratory syphilis testing algorithm used and the prevalence of circumcision. Results. The prevalence of syphilis was positively correlated with that of HSV-2 for both time periods (adjusted correlations, 20-24-year-olds: 1990-99: R (2) = 0.54, P < 0.001; 2008: R (2) = 0.41, P < 0.001 and 40-44-year-olds: 1990-99: R (2) = 0.42, P < 0.001; 2008: R (2) = 0.49, P < 0.001). Conclusion. The prevalence of syphilis and HSV-2 is positively correlated. This could be due to a common set of risk factors underpinning both STIs.

The changing relationship between bacterial STIs and HIV prevalence in South Africa - an ecological study.

Prevalence estimates of various bacterial sexually transmitted infections in South Africa have declined considerably since the mid-1990s. Syphilis among pregnant women, for example, declined from 10.8% in 1998 to 2.8% in 2001. We used Pearson's correlation coefficients to estimate the association between the prevalence of syphilis/male urethral discharge/male genital ulcers and the peak HIV prevalence at a district and provincial level in the early and late phases of the HIV epidemic in South Africa. Prevalence estimates of syphilis, male urethral discharge and male genital ulcers during the period preceding the peak HIV prevalence were all positively correlated with the peak HIV prevalence at a provincial level (Pearson's correlation coefficient [r] = 0.83, p = 0.006; r = 0.66, p = 0.052; r = 0.79, 0.011, respectively). These relationships all switched to a negative association later in the HIV epidemic at a provincial level (r = -0.53, p = 0.14; r = -0.73, p = 0.130; r = -0.54, p = 0.027, respectively). AIDS mortality may have played an important role in the decline of bacterial sexually transmitted infections such as syphilis in this region. Consequently, the relatively recent scale-up of antiretroviral therapy may result in a resurgence of syphilis and other sexually transmitted infections as observed in high-income countries.

Who Knows Their Partner's HIV Status? Results From a Nationally Representative Survey in Uganda.

OBJECTIVE: We examine the extent to which Ugandans accurately know their HIV status and that of their partners. METHODS: The 2011 Uganda AIDS Indicator Survey (UAIS) was a nationally representative study of 15-59 year olds that tested 21,366 individuals for HIV. We compared self-reported HIV status with UAIS-determined HIV status for respondents. We were able to link 3285 couples in the survey, and in this group, we compared the reported HIV status of partners with that determined by UAIS. Multiple logistic regression analysis was used to identify factors associated with inaccurate knowledge of HIV status. RESULTS: An estimated 55.8% of adult Ugandans reported having had an HIV test. Of 1495 HIV-infected Ugandans, 59.1% were unaware of their HIV infection. Among 3285 linked couples in this analysis, 273 couples (8.3%) had at least 1 infected partner, with 96 couples (2.9%) having both members infected and the remaining 177 couples (5.4%) being HIV discordant. This meant that 369 persons in the linked couple group had an HIV-infected partner. One hundred ten (29.8%) of this group knew that their partner was HIV infected. In multiple logistic regression analysis, accurately knowing that ones partner was HIV infected was strongly associated with couple HIV testing [adjusted odds ratio (AOR): 4.3, 95% confidence interval (CI): 2.2 to 8.4] and reporting oneself to be HIV positive versus reporting HIV negative (AOR: 7.3, 95% CI: 3.8 to 14.3) or HIV status unknown (AOR: 30.6, 95% CI: 3.8 to 263.4). CONCLUSIONS: Respondents may be reporting the HIV status of their partners based on their own HIV status. Campaigns to inform people about the prevalence of serodiscordance in conjunction with further promotion of couple counseling may help increase the proportion of Ugandans who know their own HIV status and that of their partners.

The Prevalence of HIV by Ethnic Group Is Correlated with HSV-2 and Syphilis Prevalence in Kenya, South Africa, the United Kingdom, and the United States.

Background. This paper investigates two issues: do ethnic/racial groups with high HIV prevalences also have higher prevalences of other STIs? and is HIV prevalence by ethnic group correlated with the prevalence of circumcision, concurrency, or having more than one partner in the preceding year? Methods. We used Spearman's correlation to estimate the association between the prevalence of HIV per ethnic/racial group and HSV-2, syphilis, symptoms of an STI, having more than one partner in the past year, concurrency, and circumcision in Kenya, South Africa, the United Kingdom, and the United States. Results. We found that in each country HSV-2, syphilis, and symptomatic STIs were positively correlated with HIV prevalence (HSV-2: Kenya rho = 0.50, P = 0.207; South Africa rho-1, P = 0.000; USA rho-1, P = 0.000, Syphilis: Kenya rho = 0.33, P = 0.420; South Africa rho-1, P = 0.000; USA rho-1, P = 0.000, and STI symptoms: Kenya rho = 0.92, P = 0.001; South Africa rho-1, P = 0.000; UK rho = 0.87, P = 0.058; USA rho-1, P = 0.000). The prevalence of circumcision was only negatively associated with HIV prevalence in Kenya. Both having more than one partner in the previous year and concurrency were positively associated with HIV prevalence in all countries (concurrency: Kenya rho = 0.79, P = 0.036; South Africa rho-1, P = 0.000; UK 0.87, P = 0.058; USA rho-1, P = 0.000 and multiple partners: Kenya rho = 0.82, P = 0.023; South Africa rho-1, P = 0.000; UK rho = 0.87, P = 0.058; USA rho-1, P = 0.000). Not all associations were statistically significant. Conclusion. Further attention needs to be directed to what determines higher rates of partner change and concurrency in communities with high STI prevalence.

What underpins the decline in syphilis in Southern and Eastern Africa? An exploratory ecological analysis.

BACKGROUND: AIDS mortality played an important role in the decline in syphilis prevalence in the USA, but its effect on the dramatic reduction in syphilis prevalence in Southern and Eastern Africa has not been explored. In this ecological study, we investigated the extent to which the relationship between syphilis and HIV prevalence at a population level varied between the early and late periods of the HIV epidemic. METHODS: We performed linear regression analysis to measure the association between the national prevalence of syphilis and the peak-HIV prevalence in the early and late phases of the HIV epidemic in 11 countries of Southern and Eastern Africa. RESULTS: Our analysis showed a strong positive association between peak-HIV prevalence and syphilis prevalence early in the HIV epidemic (R(2)=0.59; p=0.006). Although only of borderline statistical significance, this linear relationship between HIV prevalence and syphilis prevalence switched to a negative direction late in the HIV epidemic (R(2)=0.32; p=0.07). CONCLUSIONS: AIDS mortality may have played an important role in the decline in syphilis in this region. Consequently, with AIDS deaths declining in Sub-Saharan Africa, vigilant surveillance of syphilis prevalence will be necessary to detect a potential re-emergence, as has occurred in high-income countries, and to render a timely public health response.

Male circumcision and sexual risk behaviors may contribute to considerable ethnic disparities in HIV prevalence in Kenya: an ecological analysis.

BACKGROUND: HIV prevalence varies between 0.8 and 20.2% in Kenya's various ethnic groups. The reasons underlying these variations have not been evaluated before. METHODS: We used data from seven national surveys spanning the period 1989 to 2008 to compare the prevalence of a range of risk factors in Kenya's ethnic groups. Spearman's and linear regression were used to assess the relationship between HIV prevalence and each variable by ethnic group. RESULTS: The ethnic groups exhibited significant differences in a number of HIV related risk factors. Although the highest HIV prevalence group (the Luo) had the highest rates of HIV testing (Men 2008 survey: 56.8%, 95% CI 51.0-62.5%) and condom usage at last sex (Men 2008∶28.6%, 95% CI 19.6-37.6%), they had the lowest prevalence of circumcision (20.9%, 95% CI 15.9-26.0) the highest prevalence of sex with a non-married, non-cohabiting partner (Men: 40.2%, 95% CI 33.2-47.1%) and pre-marital sex (Men 2008∶73.9%, 95% CI 67.5-80.3%) and the youngest mean age of debut for women (1989 SURVEY: 15.7 years old, 95% CI 15.2-16.2). At a provincial level there was an association between the prevalence of HIV and male concurrency (Spearman's rho = 0.79, P = 0.04). Ethnic groups with higher HIV prevalence were more likely to report condom use (Men 2008 survey: R2 = 0.62, P = 0.01) and having been for HIV testing (Men 2008 survey: R2 = 0.47, P = 0.04). CONCLUSION: In addition to differences in male circumcision prevalence, variation in sexual behavior may contribute to the large variations in HIV prevalence in Kenya's ethnic groups. To complement the prevention benefits of the medical male circumcision roll-out in several parts of Kenya, interventions to reduce risky sexual behavior should continue to be promoted.