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Increased Prevalence of Leukocytes and Elevated Cytokine Levels in Semen from Schistosoma haematobium—Infected Individuals

  1. Peter D. C. Leutscher1,2,
  2. Mette Pedersen3,
  3. Clairette Raharisolo1,
  4. Jørgen Skov Jensen5,
  5. Steen Hoffmann5,
  6. Ida Lisse6,
  7. Sisse R. Ostrowski3,
  8. Claus M. Reimert2,
  9. Philippe Mauclere1 and
  10. Henrik Ullum3,4
  1. 1Institut Pasteur, Antananarivo, Madagascar
  2. 2Danish Bilharziasis Laboratory, Copenhagen, Denmark
  3. 3Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark
  4. 4Department of Clinical Immunology, Rigshospitalet, Copenhagen, Denmark
  5. 5Department of Pathology, Hvidovre Hospital, Copenhagen, Denmark
  6. 6Department of Bacteriology, Parasitology and Mycology, Statens Serum Institut, Copenhagen, Denmark
  1. Reprints or correspondence: Dr. Peter Leutscher, Danish Bilharziasis Laboratory, Jaegersb, Copenhagen, Denmark (pl{at}bilharziasis.dk).
 
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Abstract

In this study, we investigated the seminal inflammatory response to egg infestation of the urogenital organs in 240 semen-donating men aged 15–49 years living in a Schistosoma haematobium—endemic area of Madagascar. In 29 subjects (12%) with excretion of ⩾5 ova/ejaculate, leukocytospermia (>106 leukocytes/mL) and the presence of seminal lymphocytes and eosinophil leukocytes were each significantly more prevalent than in 74 subjects (31%) who were S. haematobium negative (P < .01). In addition, seminal levels of interleukin (IL)-4, IL-6, IL-10, and tumor necrosis factor-a were significantly higher among seminal egg-excreting subjects than among infection-negative subjects (P < .001). Sexually transmitted infection (STI) with Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium, and/or Trichomonas vaginalis did not act as a confounding factor for the observed associations. At follow-up, 6 months after systematic antischistosomiasis and STI syndrome treatment at baseline, the prevalence of seminal leukocytes decreased significantly among the previously seminal egg—positive subjects. The same tendency was observed for the posttreatment levels of cytokines. Numerous studies have already shown an association between STI-associated genital inflammation and human immunodeficiency virus (HIV) propagation. Therefore, the results of the present study suggest that male urogenital schistosomiasis may constitute a risk factor for HIV transmission, as a result of egginduced inflammation in the semen-producing pelvic organs.

Africa, more than any other continent on the globe, is ravaged by the HIV pandemic, which has resulted in an enormous amount of human suffering and socioeconomic consequences [1]. Epidemiological, clinical, and immunological studies have, in addition to the behavioral element, pointed towards several host, viral, and other biological factors that play a role [2–5].

Sexually transmitted infections (STIs) have, with substantial supporting evidence, been identified as one of the most important risk factors for transmission HIV in sub-Saharan Africa [6–9]. HIV-1 transmission is reflected by the size of the viral inoculum in different types of body fluid, including semen from HIV-1—infected men [4, 10–12]. Gonococcal urethritis has, in this context, been found to be associated with increased seminal viral shedding in HIV-1—infected men, in whom treatment was followed by a significant reduction in the seminal load of HIV-1 RNA [13]. Furthermore, Neisseria gonorrhoeae induces cytokine production as part of genital inflammation, and cytokine production mediates the transport of potentially virus-hosting cells into the genital tract and enhance viral replication [8, 14–16].

Schistosoma haematobium infection has been hypothesized to cause increased viral shedding into the semen of HIV-1—infected men, in a way analogous to STIs, as a result of egg-induced inflammation [17], which, in addition to affecting the bladder, also commonly affects the seminal vesicles and the prostate [18–20]. Feldmeier et al. have raised the complementary hypothesis that egg-induced inflammatory lesions in the epithelial lining of the lower reproductive tract in women, analogous to venereal lesions, are associated with an increased risk of HIV transmission [21]. To provide data validating the hypothesized association between male genital schistosomiasis and HIV transmission, we conducted a study of men living in an area where urogenital schistosomiasis and STIs coexist.

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MATERIALS AND METHODS

Study area, population, and design. This study was conducted in a rural setting in the Ambilobe region in northern Madagascar. Participants were, as part of a community-based study of urogenital schistosomiasis—associated morbidity, recruited from 4 villages (Tanambao, Ambodimanga, Ambodikataka, and Ankatoka) randomly selected from among the 16 villages accommodating the workers and their families in the Sirama sugarcane plantation. The area is endemic for S. haematobium, which is transmitted through the canals used for irrigation of the sugarcane fields and for household, hygienic, and leisure activities. A presurvey by urine examination revealed an S. haematobium prevalence of 53.5% among 298 men in the 4 Sirama villages (range, 46.2%–58.3%). The village of Mataipako was identified outside of the plantation as a study village of lower endemicity, on the basis of an observed S. haematobium prevalence of 28.7% among 172 presurveyed men. Only subjects with confirmed diagnoses of S. haematobium infection in the Sirama villages were enrolled in the baseline study, whereas S. haematobium infection was not a mandatory criterion for enrollment for subjects from Mataipako. The age range criterion for inclusion in the study was 15–49 years. The subjects were examined at baseline and then again after 6 months, by use of an identical examination protocol.

The present study was approved by the Committee of Ethics in the Ministry of Health in Madagascar. Subjects were enrolled in the study only after signed consent was received. The subjects were informed verbally and in writing that participation in the study was on a voluntary basis and that they could withdraw from the study at any given time.

S. haematobium infection and STIs. The mean egg count in 10 mL of urine was determined by filtration of urine samples collected on 2 different days, by use of a Nucleopore membrane (Costar). Total egg excretion levels in ejaculates were measured by a filtration technique, using a Whatman membrane (Whatman International).

Two urethral swabs were obtained from each subject, for culture of N. gonorrhoeae and Trichomonas vaginalis. One swab was kept in liquid nitrogen at −193°C until culture for gonococci could be performed in a reference laboratory (Statens Serum Institute, Copenhagen, Denmark). The second swab was examined on location for the presence of T. vaginalis, by use of the InPouch TV culture system (BioMed Diagnostics). Chlamydia trachomatis and Mycoplasma genitalium were diagnosed in first-voided urine samples, by use of in-house polymerase chain reaction assays in a reference laboratory (Statens Serum Institute). As part of the community-based study of urogenital schistosomiasis—associated morbidity, 643 men and women were tested for HIV antibodies by use of ELISA (Genscreen HIV 1/2, version 2; Bio-Rad) and Western blotting (New Lav Blot 1 and New Lav Blot 2; Bio-Rad); of these, 6 (1%) tested positive.

Seminal leukocyte count. After 3 days of ejaculatory abstinence, an ejaculate was collected in a dry plastic container or in a nonspermicidal condom (Seminal Collection Device; HDC Corporation). Sperm count was performed upon receipt of the sample, by use of a counting chamber (Markler; Sefi- Medical Instruments), as described elsewhere [22]. Total and differential leukocyte counts were performed in 20 microscopy fields (×40) in a Papinocolaou-stained seminal smear from each sample. The concentration of leukocytes was expressed as millions of cells per milliliter of seminal fluid, calculated from their incidence relative to the average number of observed spermatozoa in the microscopy fields and with reference to the sperm count value.

Seminal cytokines. For cytokine analysis, 200 mL of seminal fluid from each sample was stored in a container with liquid nitrogen at −193°C until the specimens could be processed. Seminal plasma was centrifuged from seminal fluid at 700 g for 10 min. The concentrations of interferon (IFN)—γ, tumor necrosis factor (TNF)—α, interleukin (IL)—10, IL-6, IL-4, and IL-2 were measured in the seminal plasma by use of the Cytometric Bead Array (CBA) kit (BD Biosciences) [23].

To validate the method on seminal plasma, samples were spiked with cytokines from the CBA kit, reaching final concentrations of 650, 312, 156, 40, 20, 10, 5, 2.5, 1.25, 0.6, and 0.3 pg/mL. Furthermore. seminal plasma was spiked to a concentration of 666 pg/mL and was subsequently diluted 2-fold to reach a concentration of 0.3 pg/mL (data not shown). Both the spiking assay and the dilution assay showed good discrimination in both the upper and the lower concentration range. The cytokine- specific detection limits were calculated from the average fluorescence of 15 negative samples from the standard curve, multiplied by 3 times the SD, and were as follows: IFN-γ, 8.0 pg/mL; TNF-α, 0.4 pg/mL; IL-10, 2.0 pg/mL; IL-6, 1.2 pg/mL; IL-4, 2.8 pg/mL; and IL-2, 0.8 pg/mL. Cytokine concentrations >5 pg/mL were calculated using CBA software (BD Biosciences). Cytokine concentrations <5 pg/mL were calculated using values between concentrations of 0 and 5 pg/mL on the linear curve of the plot of concentration against fluorescence.

Specificity was tested by the addition of anti—TNF-α and anti—IL-6 to spiked (400 pg/mL) and nonspiked seminal plasma. This procedure completely inhibited the relevant fluorescence signal of all of the samples (data not shown). To test for the influence of the sample collection procedure on the outcome of the seminal cytokine level measurement under the given field-study conditions, spiked (400 pg/mL) and nonspiked samples were left for 8 h at room temperature. This storage had only minimal effect on the cytokines (data not shown).

Treatment. Each subject was offered the following treatment with oral agents against schistosomiasis and STIs: praziquantel (40 mg/kg) as a single dose and 100 mg of doxycycline twice per day for 7 days (or, alternatively, 1 g of azithromycine as a single dose), in combination with 500 mg of ciprofloxacin and 2 g of metronidazole (both as single doses). The partner(s) of each subject was also offered STI syndrome treatment in accordance with existing recommendations.

Statistics. Data were analyzed using EpiInfo (version 6.02; Centers for Disease Control and Prevention). Differences in proportions were tested by χ2 or Fisher's exact test. The means from different groups at baseline were compared by Kruskall-Wallis test (Mann-Whitney U test), and means from the same group at baseline and at follow-up were compared by Wilcoxon's signed rank test. Correlation between seminal cytokine levels was tested by nonparametric Spearman's test.

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RESULTS

A complete data set was obtained from 240 subjects at baseline: 126 subjects in the Sirama villages and 114 in Mataipako. The median age of the study subjects was 31 years. At the 6-month follow-up, 160 subjects (67%) from the baseline study sample were reinvestigated.

S. haematobium infection. At baseline, urogenital schistosomiasis was diagnosed in 166 (69%) of 240 subjects (table 1). S. haematobium ova were detected in urine from 160 subjects (67%) and in semen from 67 subjects (28%). Moderate to high levels of egg excretion, defined as ⩾50 ova/10 mL in urine and as ⩾5 ova/ejaculate, were observed in 28 subjects (12%) and in 29 subjects (12%), respectively. In the Sirama villages, moderate to high egg levels of excretion in urine and in semen were significantly more prevalent in subjects aged 15–39 years than in subjects aged 40–49 years: 22%–38% versus 5%, respectively, for urine (P = .03) and 26%–38% versus 5%, respectively, for semen (P = .02) (table 2). In Mataipako, ova were detected in urine from 34 subjects (30%) and in semen from 21 subjects (18%), and the prevalences of moderate to high levels of egg excretion were 6% and 0%, respectively.

Table 1.
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Table 1.

Distribution of Schistosoma haematobium infection and sexually transmitted infections in the study population at baseline and at the 6-months-posttreatment follow-up.

At follow-up, the overall S. haematobium infection prevalence had declined significantly, to 18% (P < 10−6) (table 1). None of the 16 subjects with ova detected in urine at follow-up had moderate to high levels of egg excretion, compared with 3 (23%) of the 13 subjects with seminal egg excretion. Of 29 subjects who received diagnoses of S. haematobium infection at follow-up, 11 (38%) were found to be egg positive in semen only.

STIs. STIs were diagnosed at baseline in 43 subjects (18%) (table 1). The overall STI prevalences in the Sirama villages and in Mataipako were similar (17% and 19%, respectively), and the age-specific prevalences also did not differ significantly (table 2). At follow-up, the STI prevalence had declined to 7% (P < .001).

Table 2.
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Table 2.

Comparison of Schistosoma haematobium egg excretion in urine and in semen, sexually transmitted infections, and seminal leukocytes, between the Sirama villages and Mataipako, according to age.

Seminal leukocytes and cytokines. Leukocytospermia, defined as >106 leukocytes/mL, was detected at baseline in 42 subjects (18%)—27 (21%) in the Sirama villages and 15 (13%) in Mataipako—but the difference did not reach a significant level (table 2). Lymphocytes in semen were more frequently observed in the Sirama villages than in Mataipako (30% vs. 18%, respectively; P < .02), whereas the prevalence of eosinophil leukocytes was the same in the 2 locations. With regard to age-dependent differences in S. haematobium infection intensity in the Sirama villages, the prevalence of leukocytospermia and seminal lymphocytes was significantly higher in subjects aged 15–39 years than in those aged 40–49 years: for leukocytospermia, 21%–38% versus 8%, respectively (P < .05), and for presence of lymphocytes, 34%–38% versus 11%, respectively (P < .01).

In the comparison between the seminal leukocyte findings at baseline and those for the 160 subjects at follow-up, the prevalence of leukocytospermia did not change significantly, whereas the prevalence of lymphocyte-positive smears decreased from 24% at baseline to 4% at follow-up (P < 10−5). A significant decrease was also observed for the eosinophil leukocyte—positive smears, from 13% to 6% (P < .03).

Complete baseline and follow-up seminal cytokine data were obtained from 116 subjects (47%) in the study group. Of the 6 cytokines being investigated, IL-6 was detected most often, in 115 (99%) of the baseline ejaculates, followed by TNF-α in 89 (77%), IFN-γ in 31 (27%), IL-10 in 25 (22%), IL-2 in 8 (7%), and IL-4 in 5 (4%). In the correlation analysis between the 6 cytokines, TNF-α, IL-10, and IL-6 were each correlated with one another: IL-6/TNF-α, r = 0.67; IL-6/IL-10, r = 0.52; and TNF-α/IL-10, r = 0.50 (P < .001). Compared with baseline values, the overall prevalence of detectable seminal cytokines remained unaltered at follow-up, whereas there was a nonsignificant tendency toward a decrease in the geometric mean levels.

Bivariate analyses. In the comparison of the 74 (31%) S. haematobium infection-negative subjects with the 137 subjects (57%) with low levels of seminal egg excretion (0–4 ova/ejaculate) and with the 29 subjects (12%) with moderate to high levels of seminal egg excretion (⩾5 ova/ejaculate), it was observed that leukocytospermia was significantly less prevalent in the infection-negative group: 8%, versus 18% in the group with low levels of egg excretion (P < .05) and 38% in the group with moderate to high levels of egg excretion (P < .01) (table 3). Lymphocytes and eosinophil leukocytes were also detected in significantly higher proportions in the group with moderate to high levels of egg excretion than in the infection-negative group (P < .001 and P < .01, respectively). STIs were diagnosed in the same proportions among all 3 groups.

Table 3.
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Table 3.

Seminal leukocyte and sexually transmitted infection data according to Schistosoma haematobium infection status, among the 240 study subjects at baseline.

Of the 116 subjects with complete cytokine data, 45 (39%) were from among the 74 S. haematobium infection—negative subjects, 59 (51%) were from among the 137 subjects with low levels of seminal egg excretion, and 12 (10%) were from among the 29 subjects with moderate to high levels of seminal egg excretion (table 4). As was observed for the seminal leukocytes, the difference was most significant in the comparison between infection-negative subjects and subjects with moderate to high levels of egg excretion. The prevalence of detectable IL-10 was 75% in the egg-positive group, compared with 13% in the infection-negative group (P < .0001). Of the 5 subjects with seminal IL-4 detected, all belonged to the group of the 12 subjects with egg excretion (P < .0001). Geometric mean levels of IFN-γ, TNF-α, and IL-6 were also significantly higher in the group with moderate to high levels of egg excretion. In the same group of subjects with complete cytokine data, no significant differences were found in geometric mean cytokine levels or in the prevalence of detectable seminal cytokines, leukocytospermia, lymphocytes, and eosinophil leukocytes in the comparison between subjects with diagnoses of STIs and those without diagnoses of STIs (data not shown). In the correlation analysis of seminal egg count, leukocyte count, and cytokine level, the following correlations were observed: egg count/lymphocytes, rp0.53 (P < .001); egg count/IFN-γ level, r = 0.37 (P < .05); egg count/IL-10 level, r = 0.59 (P < 0.01), egg count/IL-4 level, r = 0.63 (P < .001), leukocytes/ IFN-γ level, r = 0.65 (P < .001); leukocytes/TNF-α level, r = 0.56 (P < .001); leukocytes/IL-10 level, r = 0.57 (P < .001); and leukocytes/IL-6 level, r = 0.68 (P < .001).

Table 4.
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Table 4.

Seminal cytokine results according to Schistosoma haematobium infection status among 116 examined subjects.

Of the 29 subjects with moderate to high levels of seminal egg excretion observed at baseline, 22 (76%) were reexamined at follow-up. The number of subjects with leukocytospermia and differential leukocytes in this group decreased frombaseline to follow-up: leukocytospermia, from 9 subjects to 3 subjects (P = .10); lymphocytes, from 12 subjects to 1 subject (P < .001); and eosinophil leukocytes, from 9 subjects to 1 subject (P < .02). IL-4 was not detected in any of the 12 ejaculates collected at follow-up (P < .02), and the geometric mean levels of IFN-γ and IL-6 decreased significantly, to 16.9 pg/mL (P < .02) and 106.3 pg/mL (P < .05), respectively. The same tendency, although nonsignificant, was observed for TNF-α (11.9 pg/mL) and IL-10 (6.3 pg/mL) at follow-up.

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DISCUSSION

It seems plausible that urogenital schistosomiasis may be a contributing factor in HIV transmission from a dually infected man to his partner. This study has shown that S. haematobium egg excretion in semen is associated with the presence of neutrophils, lymphocytes, and eosinophil leukocytes. In addition, seminal egg count was correlated with seminal lymphocyte count. Elevated numbers of polymorphonuclear leukocytes in semen are invariably accompanied by increased levels of macrophages and CD4+ lymphocytes, which are the primary HIV host cells [24], and, consequently, HIV is more readily cultured from the semen of seropositive men with leukocytospermia [13]. Eosinophil leukocytes can also express CD4 protein and CD4 receptors for HIV-1 [25, 26], since they may act as host cells for the virus [27–29]. As part of the host's immune response to schistosomiasis, activated eosinophil leukocytes secrete, among different mediators, eosinophilic cationic protein (ECP) [30]. Measurable seminal ECP is a reliable indicator of egg-induced eosinophil leukocyte-rich genital inflammation, since it is found in high concentrations in the presence of seminal S. haematobium ova [17].

A postmortem study of schistosomiasis-infected individuals showed that S. haematobium ova were deposited as frequently in the seminal vesicles as in the bladder wall [18]. However, the egg counts per field were highest in the bladder. The prostate was less frequently affected and had lower egg counts per field than the other pelvic organs. The same study also demonstrated that inflammatory lesions were directly associated with the presence of S. haematobium ova in the seminal vesicles and, to a lesser extent, in prostate tissue. However, it was also observed that the presence of even a few ova provokes marked inflammation, although the reverse situation, in which dense ova deposition is associated with limited inflammation, may occur as well. The variation in the level of egg-induced inflammation from person to person could be explained by many factors, including patient history of infection and treatment, the level of immune status, and genetic susceptibility [31–33].

The presence of S. haematobium ova in semen was also associated with an increased prevalence of detectable levels of IL- 4 and IL-10 in semen and with significantly higher levels of IFN-γ, TNF-α, and IL-6. Furthermore, both seminal egg count and leukocyte count were correlated with cytokine level.

The retained ova in the host tissue evokes a delayed-hypersensitivity granulomatous T cell—mediated immune responsemediated by soluble egg antigens, resulting in an accumulation of eosinophils, macrophages, and lymphocytes and thus forming the classic Schistosoma granuloma [34]. The cytokines involved in the formation of granuloma in schistosomiasis infection include TNF-α, IL-2, IL-4, and IL-5, whereas IFN-γ, IL-10, and IL-12 are known for their immune modulating role [35–38].

The results we obtained at the 6-months-posttreatment follow- up have added support to the conclusion that semen containing S. haematobium ova is associated with the presence of inflammatory cells and immunological mediators. After the therapeutic clearance of urogenital schistosomiasis, the prevalence of leukocytospermia declined significantly, as did the prevalence of detectable IL-4 in semen. Moreover, a clear—and, in some cases, significant—tendency for a decrease in cytokine levels was observed at follow-up.

Experimental studies indicate that various cytokines, including IFN-γ, TNF-α, and IL-4, produced by inflammatory and immunocompetent cells attracted to genital infection amplify the local immune response in the epithelial and mucosal cells in the urethra, prostate, and seminal vesicles [24, 39]. Of the 6 cytokines investigated in the present study, TNF-α and IL-6 are associated with a stimulatory effect on HIV-1 replication in monocytederived macrophages and T cells, and IL-10 is associated with an inhibitory effect [40, 41]. These inflammatory cytokines, along with other soluble mediators [42], may be expected to increase the transport of HIV-1—harboring cells into the genital tract and to enhance the rate of viral replication and viral release into the semen. Cytokines, which are characteristically associated with most inflammatory lesions, have been shown to induce latently infected T cells and macrophages to produce large amounts of HIV-1 [43]. Alternatively, urethral inflammation itself could be responsible for an increased migration of cell-free HIV-1 from the blood to the seminal plasma [13].

STIs did not act as confounding variables for the observed associations between seminal egg excretion and leukocytospermia, and STIs were not found to be associated with elevated levels of seminal cytokines. In this regard, previous studies of N. gonorrhoeae immunopathology have demonstrated that this organism induces an increased secretion of TNF-α, IL-4, IL-6, and IL-10 in the genital tract [8, 14–16]. Our study sample of STI-infected subjects may have been too small to demonstrate a similar association.

Recently, interest in the detrimental influence of parasitic diseases on the natural history and transmission of HIV infection has increased [44–46]. So far, no studies have been able to demonstrate an exacerbating effect of schistosomiasis on the course of HIV-1 infection [47, 48], whereas it has been established that the latter condition affects the immune response patterns of patients with schistosomiasis [49–51]. From a therapeutic perspective, it has been shown that the effect of praziquantel treatment on schistosomiasis infection is similar among patients with HIV infection and those without HIV infection [52].

Epidemiological studies of schistosomiasis in endemic communities have demonstrated an age-associated distribution, with the highest prevalence and intensity of infection found among children and young adults [53]. The same tendency toward age dependence was observed in the present study, in which egg excretion in urine, as well as that in semen, was higher in subjects aged 15–39 years than in older subjects. This observation leads to the speculation that young men coinfected with urogenital schistosomiasis and HIV pose a potential additional risk burden in the transmission and propagation of HIV in S. haematobium—endemic areas, since young men in general have already been identified as a particular target group in global HIV/STI control strategies, because of their sexual risk behavior. Accordingly, urogenital schistosomiasis, because of egg-induced inflammatory lesions in the reproductive tract, may also be considered to be an additional risk factor for contracting HIV infection in young women living in settings where S. haematobium and HIV/STIs coexist [21]. If this hypothesis regarding urogenital schistosomiasis and its alleged associations with HIV-1 transmission are proven correct in clinical studies, antischistosomiasis treatment could constitute another important preventive tool in the control of HIV-1 transmission in the major part of sub-Saharan Africa.

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Acknowledgments

Benjamin Scheel Jørgensen is acknowledged for excellent technical assistance, and Dr. Charles Laubscher is acknowledged for his careful review of the manuscript.

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Footnotes

  • Financial support: Danish Council of Development Research, Danida (postdoctoral research fellowship to P.D.C.L.).

  • Received July 7, 2004.
  • Accepted November 24, 2004.
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  1. J Infect Dis. (2005) 191 (10): 1639-1647. doi: 10.1086/429334
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