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. 2024 Jan 11;12(1):e0346623.
doi: 10.1128/spectrum.03466-23. Epub 2023 Dec 14.

Evaluation of a minimal array of Treponema pallidum antigens as biomarkers for syphilis diagnosis, infection staging, and response to treatment

Austin M Haynes  1 , Kelika A Konda  2   3 , Emily Romeis  1 , Janet Siebert  4 , Silver K Vargas  3 , Michael Reyes Diaz  2 , Amber Phan  1 , Carlos F Caceres  2 , Lorenzo Giacani  1   5 , Jeffrey D Klausner  6
Affiliations

Evaluation of a minimal array of Treponema pallidum antigens as biomarkers for syphilis diagnosis, infection staging, and response to treatment

Austin M Haynes et al. Microbiol Spectr. .

Abstract

This manuscript explores the host humoral response to selected antigens of the syphilis agent during infection to evaluate their potential use as diagnostic tests and markers for treatment.

Keywords: Treponema pallidum; protein array; serodiagnosis; staging; syphilis; treatment response.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig 1
Fig 1
Correlation in baseline sera between immunodominant antigens and additional proteins in the array. (A) Pearson correlation coefficients showing that at baseline, Tp0163, Tp0768, and Tp0954 reactivity correlates with that of the immunodominant Tp0435 and Tp0574 antigens. A coefficient value ≥0.47 was used as the cut-off. (B) Baseline primary sera reactivity to Tp435, Tp0574, Tp0163, Tp0769, and Tp0954 plotted as individual values with mean ± standard deviation. Except for Tp0954 and Tp0574 (P = 0.99), the reactivity of Tp0163, Tp0954, and Tp0769 is significantly different from that of the immunodominant antigens.
Fig 2
Fig 2
Baseline reactivity to selected T. pallidum antigens. Antigens to which a significant difference in reactivity was detected in baseline sera (collected at diagnosis and prior to treatment) using stage (A, B), HIV status (C–E), and syphilis history (F–I) as covariates. In panels (A and B), the P-value indicates that there is a significant difference across the means of the four groups analyzed. Groups lean toward statistically significant differences in means (P < 0.1) if they do not share a letter. I, primary syphilis; II, secondary syphilis; EL, early latent; LL, late latent; U: latency of unknown duration; Pos, HIV-positive patients; Neg: HIV-negative patients; H, patients with history of syphilis; NH, patients with no history of syphilis. The horizontal bar indicates the mean absorbance value. Analyses in panels (A, B) were performed with 118 samples. Analyses in panels (C–E) were performed with 120 samples. Analysis in panels (F–I) was performed with 93 samples.
Fig 3
Fig 3
Correlation between reactivity of Tp0769 at baseline and decrease in RPR titer and between changes in Tp0769 at time point 2 (tp2) post-treatment and decrease in RPR titer. (A) Higher baseline levels of Tp0769 are associated with a higher RPR titer. Correlation P-value =0.02. (B) Decrease in Tp0769 post-treatment is associated with the decrease of RPR titer. Dotted lines represent a fitted regression model (antigen~decrease in RPR dilution). N at baseline = 64; N with change = 51. For the RPR titers, 0–6 values represent 1:1–1:64.
Fig 4
Fig 4
Longitudinal reactivity to selected T. pallidum antigens without considering covariates. Antigens to which sera reactivity decreased significantly post-treatment. Time points 0, 1, and 2 include baseline sera (tp0) and convalescent sera collected at 3 months [time point 2 (tp2)] and 6 months [time point 3 (tp3)] post-treatment. Values are displayed by stage to minimize overplotting. Antigens are reported in gene number order. In the tables associated to each figure panel, the “Est” column reports the mean reactivity for all samples at baseline (tp0 row) and the amount by which antigen reactivity declined at tp2 and tp3 compared to baseline. Asterisks indicate significance with Bonferroni-adjusted P-values ≤0.001 (***), ≤0.01 (**), and ≤0.05 (*). A total of 66 samples were analyzed for tp0, 51 samples for tp2, and 44 people at tp3, as not all tp3 patients provided a sample at 3 months post-treatment. The steepest declines were seen for Tp0769 (D) and Tp0117 (A).
Fig 5
Fig 5
Correlation between changes in serum reactivity over time between immunodominant antigens and additional proteins in the array. Pearson correlation coefficients showing that the decrease in reactivity in Tp0769 correlates strongly with a decrease in reactivity in Tp0117/TprC, Tp0621/TprJ.5′, and Tp1031/TprL. A coefficient value ≥0.47 was used as the cut-off.
Fig 6
Fig 6
Longitudinal reactivity to selected T. pallidum antigens including covariates. Antigens to which sera reactivity decreased significantly post-treatment (Fig. 3) were further analyzed using syphilis history (A–C), stage (D), and HIV status. The models shown were significantly better than models using time alone. Time points 0, 1, and 2 include baseline sera (tp0) and convalescent sera collected at 3 (tp2) and 6 (tp3) months post-treatment. Antigens are reported in the gene number order. In the tables associated with each figure panel, the “Est” column reports the mean reactivity for samples in each group at baseline (tp0 row) and the amount by which antigen reactivity declined at tp2 and tp3 compared to baseline. Asterisks indicate significance with Bonferroni-adjusted P-values ≤0.001 (***), ≤0.01 (**), and ≤0.05 (*). No significant differences were seen when HIV status was used as a covariant. A total of 66 samples were analyzed for tp0, 51 samples for tp2, and 44 people at tp3, as not all tp3 patients provided a sample at tp2 post-treatment.
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