Treatment of Schistosoma mansoni infection increases helminth-specific type 2 cytokine responses and HIV-1 loads in coinfected Ugandan adults

BACKGROUND: Studies showing that helminths stimulate type 2 cytokine responses and influence responses to unrelated antigens suggest that helminths may accelerate human immunodeficiency virus type 1 (HIV-1) disease progression in coinfected individuals and that antihelminthic therapy may be beneficial. By the same logic, however, the increase in type 2 cytokines occurring immediately after antischistosomal treatment might increase viral replication and be detrimental. METHODS: To assess the effect of antischistosomal therapy on immune responses and HIV-1 replication, a cohort of 163 Ugandans coinfected with Schistosoma mansoni and HIV-1 was treated with praziquantel. CD4(+) T lymphocyte counts, eosinophil counts, and plasma HIV-1 RNA concentrations were measured before treatment and 1 month and 5 months after treatment. Schistosoma mansoni- and Mycobacterium tuberculosis-specific cytokine responses and serum interleukin (IL)-10 concentrations were analyzed. RESULTS: Transient increases in viral load and sustained decreases in CD4(+) T lymphocyte count were observed, especially in subjects with higher-intensity infections. Despite enhanced posttreatment S. mansoni-specific type 2 responses, no increase in eosinophils or in M. tuberculosis-specific type 2 responses nor any decline in M. tuberculosis-specific interferon (IFN)-gamma responses were seen. A significant decline in circulating IL-10 concentrations was observed. CONCLUSION: Although the mechanisms underlying the increase in viral load after treatment with praziquantel are unclear, these results do not support the hypothesis that treating schistosomiasis is beneficial in the management of HIV-1 disease in Africa.     

Cell-mediated and humoral immune responses in capuchin monkeys infected with Schistosoma japonicum or Schistosoma mansoni

Cell-mediated immune responses, assessed by lymphocyte clonal expansion in vitro, as well as humoral responses, assessed by an enzyme-linked immunosorbent assay (ELISA), were evaluated in capuchin monkeys during a 7-month infection with Schistosoma mansoni or with a Japanese or Philippine strain of Schistosoma japonicum. Although mounting a vigorous antibody response against parasite antigens, the S. mansoni-infected monkeys failed to show lymphocyte proliferation in response to stimulation with soluble adult worm antigen or soluble egg antigen derived from S. mansoni. Monkeys infected with S. japonicum responded to parasite antigens obtained from S. japonicum both by antibody production and lymphocyte blastogenesis. Monkeys infected with S. japonicum (Japanese strain) never developed detectable levels of circulating immune complexes (CIC). On the other hand high levels of CIC appeared at 7 months of infection in the monkeys infected with S. mansoni. The CIC levels exhibited negative correlations with intensity of infection. In studies of antigen species specificity, sera from S. mansoni-infected monkeys showed much higher IgG antibody titers to antigens derived from S. mansoni than to S. japonicum-derived antigens. On the other hand, monkeys infected with S. japonicum had comparable IgG antibody titers to antigens of both schistosome species.     

Isotypic analysis of humoral immune responses in rhesus monkeys to an adult microsomal antigen of Schistosoma mansoni: an indicator of successful treatment

A study was undertaken to examine the potential role of immunodiagnostic methods in determining successful chemotherapy in schistosomiasis. Fifteen rhesus monkeys were infected with 1,500 Schistosoma mansoni (Puerto Rico strain) cercariae, and 10 of the monkeys were then treated with a curative dose of praziquantel 13 weeks after infection. Five monkeys remained untreated. One monkey was not successfully cured, as confirmed by the presence of both male and female worms at the time of perfusion. Serum samples were longitudinally collected and specific Ig isotypes were quantified with an adult microsomal antigen of S. mansoni using the FAST-ELISA. Specific isotypes were detected with monoclonal antibodies specific for each human Ig isotype, followed by a peroxidase-conjugated anti-mouse Ig. Longitudinally, all monkeys showed similar isotype patterns. Isotypes increased for the first nine weeks following infection, and then began to decrease. Ten to 14 days following treatment, all isotypes increased. The Ig isotype responses of all monkeys followed classic patterns of isotype expression. A ratio of pretreatment (week 13) IgG1 absorbance values to post-treatment IgG1 absorbance values was generated for each monkey. All successfully treated monkeys, determined to be worm-free by perfusion, had IgG1 ratios at week 53 greater than 2.4 (range 2.4-181). The untreated monkeys and the single monkey that was a treatment failure had IgG1 ratios less than 2.1 (range 0.09-2.05) for the same time period.     

Increases in human T helper 2 cytokine responses to Schistosoma mansoni worm and worm-tegument antigens are induced by treatment with praziquantel

Levels of Schistosoma mansoni-induced interleukin (IL)-4 and IL-5 and posttreatment levels of immunoglobulin E recognizing the parasite's tegument (Teg) correlate with human resistance to subsequent reinfection after treatment. We measured changes in whole-blood cytokine production in response to soluble egg antigen (SEA), soluble worm antigen (SWA), or Teg after treatment with praziquantel (PZQ) in a cohort of 187 individuals living near Lake Albert, Uganda. Levels of SWA-induced IL-4, IL-5, IL-10, and IL-13 increased after treatment with PZQ, and the greatest relative increases were seen in the responses to Teg. Mean levels of Teg-specific IL-5 and IL-10 increased ~10-15-fold, and mean levels of IL-13 increased ~5-fold. Correlations between the changes in cytokines suggested that their production was positively coregulated by tegumentally derived antigens. Levels of SEA-, SWA-, and Teg-induced interferon- gamma were not significantly changed by treatment, and, with the exception of IL-10, which increased slightly, responses to SEA also remained largely unchanged. The changes in cytokines were not strongly influenced by age or intensity of infection and were not accompanied by corresponding increases in the numbers of circulating eosinophils or lymphocytes.     

Increased blastogenic responses to worm antigen and loss of adherent suppressor cell activity after treatment for human infection with Schistosoma mansoni

Fifteen Egyptian subjects infected with Schistosoma mansoni were evaluated parasitologically, clinically, and immunologically; treated with praziquantel; and reevaluated nine months later. Fecal egg counts were 97% lower after therapy; seven subjects no longer excreted eggs, as determined by Kato thick smears. Optimal [3H]thymidine incorporation induced by soluble adult worm antigenic preparation (SWAP) in peripheral blood mononuclear cells (PBMCs) increased significantly, from 4,041 +/- 434 (mean change in cpm +/- SE) before treatment to 11,232 +/- 3,414 after treatment (P less than .0005). The relation between dose of antigen and response also shifted; the SWAP concentration producing optimal responses was 30.0 micrograms/ml before and 1.0 microgram/ml after therapy. Before treatment, depletion of adherent cells from PBMCs in six subjects resulted in enhancement of responses to SWAP from 5,575 +/- 1,210 to 14,719 +/- 8,190 (P less than .025). However, in these same individuals after treatment, PBMC and nonadherent lymphocyte responses were similar (22,917 +/- 6,505 and 21,239 +/- 6,122). These studies indicate loss of activity of adherent suppressor cells after treatment of chronic infection with S. mansoni. Waning of cellular regulatory mechanisms as the parasite load decreases may contribute to restoration of blastogenic responses.     

Caribbean female patients with type 2 diabetes mellitus have lower serum levels of adiponectin than nondiabetic subjects

BACKGROUND: Previous studies in other populations suggest that low levels of serum adiponectin may be a cardiovascular risk factor. We aimed to determine the baseline concentration of serum adiponectin and its relationship with selected biochemical risk factors for coronary artery disease (CAD) in a cross-section of Caribbean patients with type 2 diabetes. METHODS: Anthropometric indices and fasting plasma concentrations of glucose, insulin, adiponectin, triglyceride, and total and HDL cholesterol were measured in 56 type 2 diabetic patients and 33 nondiabetic subjects. Insulin resistance (IR) was determined using the homeostatic model assessment (HOMA) method. RESULTS: Consistent with previous reports, Caribbean type 2 diabetic patients had significantly lower fasting serum adiponectin levels and higher mean levels of glucose, triglyceride and IR than the nondiabetic subjects (all, p < 0.01). The nondiabetic female subjects had significantly higher serum adiponectin levels than did the female diabetics or nondiabetic males (p < 0.01). Serum adiponectin level was negatively correlated with triglyceride or LDL cholesterol and positively related with HDL cholesterol among nondiabetic subjects, and the latter relationship persisted after adjusting for the effects of age, sex and BMI (r = 0.70, p < 0.01). CONCLUSION: Similar to reports from other populations, Caribbean patients with type 2 diabetes, particularly the females, have lower levels of serum adiponectin than their nondiabetic counterparts and this is an additional CVD risk factor for the patients.     

A DNA-prime/protein-boost vaccination regimen enhances Th2 immune responses but not protection following Schistosoma mansoni infection

DNA immunization represents a promising vaccine strategy that has been reasonably successful, and will likely play an even greater role in vaccine development as these vaccines continue to be improved. We have developed a partially protective DNA vaccine against schistosome infection based on a 23-kDa integral membrane protein, Sm23. The focus of this study was to compare immunogenicity and efficacy of vaccination regimens utilizing Sm23 DNA vaccine alone vs. regimens that utilized both Sm23 DNA and Sm23 in recombinant protein form. We found that priming and boosting with the Sm23 DNA construct (Sm23-pcDNA) resulted in a significant level of protection against challenge infection (36-44%). In contrast, altering this protocol by changing the boost from Sm23 DNA to boosting with recombinant Sm23 protein (rSm23) formulated in aluminium hydroxide (alum) failed to induce a significant reduction in worm burdens. Similarly, mice primed and boosted with the rSm23 in alum also did not develop significant levels of protection against challenge infection. We hypothesize that the differences in the ability to drive protective immunity using the DNA prime-DNA boost strategy and the inability to do so when recombinant Sm23 in alum was substituted for Sm23 DNA is due to driving of different immune responses. In support of this, we found that mice primed and boosted with Sm23-pcDNA had Th1-type immune responses characterized by low anti-Sm23 IgG1 : IgG2a antibody isotype ratios, whereas mice boosted with rSm23 had higher IgG1 : IgG2a ratios. In addition, priming and boosting with rSm23 elicited mainly IgG1 antibodies with no detectable IgG2a, indicative of a polarized Th2-type immune response. Thus, similar to our earlier work, the results of this study show that protective vaccination using Sm23 is associated with a Th1 immune response, and efficacy is diminished using protocols that diminish this Th1 bias. In our study, this was likely due to the use of the Th2-driving adjuvant alum, and future studies are planned where we will compare the protective efficacy of rSm23 administered with Th1-type adjuvants.     

Human infant respiratory syncytial virus (RSV)-specific type 1 and 2 cytokine responses ex vivo during primary RSV infection

BACKGROUND: Respiratory syncytial virus (RSV) infection is the most common respiratory viral infection resulting in hospitalizations in infants worldwide. Illness severity is likely multifactorial; however, unlike other viral infections, both type 1 and type 2 cytokine responses have been implicated in severe disease. METHODS: We measured RSV-specific cytokine responses ex vivo during primary RSV infection in the blood of 18 infants with polymerase chain reaction-confirmed RSV infection. To focus on primary RSV infection, subjects were all<9 months old. RSV-specific cytokine responses were measured at 3 time points during acute primary RSV infection and at 1 memory time point 3-6 months later. RESULTS: RSV-specific interferon (IFN)- gamma responses were detected in 10 of 18 of infants. Infants with mild disease had higher RSV-specific IFN- gamma memory responses than did those with moderate or severe disease. No consistent correlations between RSV-specific IFN- gamma responses and corticosteroid administration were observed. RSV-specific interleukin (IL)-4 or IL-5 responses to primary RSV infection were detectable in 5 of 18 and 8 of 15 infants, respectively. CONCLUSIONS: During primary RSV infection, many infants demonstrated RSV-specific IFN- gamma responses. The strongest IL-4 and IL-5 responses were detected in 3 infants with severe disease, suggesting that type 2 responses may contribute to the pathogenesis of severe disease.     

Cellular immune responses of a Senegalese community recently exposed to Schistosoma mansoni: correlations of infection level with age and inflammatory cytokine production by soluble egg antigen-specific cells

A recently reported epidemic of Schistosoma mansoni infection in Senegal provided an opportunity to study the dynamics of the development of immunity to human schistosomiasis. We report here on the cell-mediated immune response in a population of 99 females and 95 males, with particular emphasis on the relationship between intensity of infection and age. We found that the intensity of infection correlated negatively with age in females but not in males. In men and women, both Th1- and Th2-type cytokines were detected upon in vitro stimulation of PBMCs with soluble egg antigen (SEA) or soluble adult worm antigens (SWAP). In the female group, SEA-induced PBMC proliferation was associated with the production of IFN-gamma, IL-2 and IL-5, all of which correlated negatively with intensity of infection. Most cytokine production correlated positively with age. Spontaneous production of TNF-alpha, IL-6 and IL-10 was higher in the infected population than in an uninfected control group. Our results suggest that immunity to infection could be more pronounced in the female population and associated with a Th0/1 + 2 pattern of cytokine secretion mediated by soluble egg antigen (SEA).     

Urinary neopterin concentrations in rhesus monkeys after infection with simian immunodeficiency virus (SIVmac 251)

Two rhesus monkeys were infected with SIVmac 251. Elevated urinary neopterin concentrations were observed as the first sign of infection. Virus-specific antibodies were detected 14 days after infection, when neopterin concentrations were already decreasing. The neopterin levels of one animal remained elevated and the virus was repeatedly isolated. Urinary or serum neopterin concentrations appear to be early markers for SIV infection and viremia in rhesus monkeys.     

Factors associated with Schistosoma mansoni infection 5 years after selective treatment in a low endemic area in Brazil.

Five years after a single dose treatment, prevalence, intensity and morbidity of schistosomiasis mansoni were evaluated in Agua Branca, a low endemic community in the South East Brazil (cure rate 94%). At community level, prevalence showed a decrease from 38.9 to 24.5% and the intensity of infection dropped from 119.5 to 38.9 eggs per g of faeces (epg). However, after the exclusion of immigrants, newborn children and individuals that had left the area after the first evaluation, the prevalence among the treated and followed population was not significantly affected. Multivariate analysis showed that the 10-29 age group and water contact for agricultural purposes were independently associated with the presence of infection on post treatment evaluation [OR 3.9 and 5.09, respectively]. A previous treatment among subjects older than 15 years was inversely associated [OR 0.58]. The authors wish to draw attention to the fact that mobility may lead to a serious bias in evaluating the impact of the control programme.     

Ultrasonographical investigation of periportal fibrosis in children with Schistosoma mansoni infection: reversibility of morbidity seven months after treatment with praziquantel

Five hundred thirty six Sudanese schoolchildren with Schistosoma mansoni infection were treated at random with either 20 mg or 40 mg/kg praziquantel. Seven months later 420 children could be reinvestigated by ultrasonography. Reduction of egg excretion and reversibility of sonographically-proven periportal fibrosis (PF) was not significantly different in the two groups. Schistosoma mansoni-induced PF grade II decreased from 22.9% to 6.7% and grade III from 5.2% to 1.6%. An increased prevalence of PF grade I, from 10% to 29.8% of the investigated patients, was observed. This increase was caused partly by a downshifting of patients who had PF II (n = 45) and PF III (n = 8) before therapy, but also by patients who developed PF I in the seven months after therapy (n = 56). The overall percentage of patients with PF before and after treatment was 38.1%. Of 420 children, 17.4% increased in their PF grade, 55% remained at the same level and 27.6% improved. Children younger than 11 years of age had a higher rate of complete reversibility than older ones. The percentage of patients with hepatomegaly decreased significantly (11.6% to 6.9%; p = 0.001). The rate of splenomegaly remained unchanged. It was concluded that within seven months therapy with praziquantel resulted in a considerable qualitative improvement of PF in Sudanese schoolchildren with S. mansoni infection.