Infectious disease. Medical helminthology in the 21st century.
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Animals↗
Biomedical subjects
D G Colley
Publications and source records attributed to D G Colley.
Cellular immune responses of schistosomiasis patients are altered by human immunodeficiency virus type 1 coinfection.
In vitro studies suggest that CD4(+) cells with a T helper 2 (Th2) phenotype better support human immunodeficiency virus type 1 (HIV-1) replication than do cells of the Th1 phenotype. As a result, Th2-type immune responses may be substantially affected by HIV-1 coinfection. To test this hypothesis, a comparison was done of proliferation and cytokine production by peripheral blood mononuclear cells from patients with schistosomiasis who were positive or negative for HIV-1. Patients with schistosomiasis with HIV-1 coinfections had significantly lower interleukin (IL)-4 and IL-10 production than did HIV-1-negative individuals. In contrast, interferon-gamma production levels were similar between the 2 groups. Furthermore, in patients with HIV-1, a decrease in CD4(+) T cells was correlated with an increased Th1:Th2 cytokine production ratio. The effect of praziquantel treatment on proliferation and cytokine responses also differed between HIV-1 infection groups. Thus, HIV-1 infection affects immune response patterns of patients with schistosomiasis.
Adolescent↗
Mouse model for Chagas disease: immunohistochemical distribution of different stages of Trypanosoma cruzi in tissues throughout infection.
Different stages of Trypanosoma cruzi are seen during mammalian infection. Histologic sections of infected hearts have shown amastigotes and, when using immunohistochemistry (IHC), parasite antigens; however, demonstration of trypomastigotes in these tissues has proven elusive. Using a mouse strain that develops chagasic cardiomyopathy (histologically similar to human infection) 70 days after injecting T. cruzi-Brazil strain, we studied the distribution of parasite stages and the extent of inflammation. All organs had varying amounts of mononuclear inflammation by day 10, which peaked between day 20 and day 30, and decreased by day 50. Amastigotes were detected in myocytes, histiocytes, acinar pancreatic cells, astrocytes and ependymal cells by day 10, and the number of amastigotes peaked on day 30. Immunohistochemistry demonstrated trypomastigotes in sinusoids, vessels and interstitial tissues of several organs between day 15 and 50. Abundant parasite antigens (granular staining) were detected in connective tissues throughout the infection. The burden of amastigotes and trypomastigotes during the acute phase seems to correlate with the degree of inflammation and granular staining in the chronic stage.
Animals↗
The effect of treatment of schistosomiasis on blood plasma HIV-1 RNA concentration in coinfected individuals.
OBJECTIVE: To determine whether drug treatment of Schistosomiasis mansoni infection leads to a reduction in plasma HIV-1 RNA concentration in coinfected individuals. METHODS: Stool and plasma samples were obtained prospectively from a cohort of HIV-infected persons (n = 30) in Kisumu, Kenya, before and after treatment of schistosomiasis with praziquantel (mean follow-up, 5.6 months; range 1-15 months). Schistosomal circulating cathodic antigen (CCA) concentrations in plasma were determined by ELISA and fecal egg counts were determined by microscopy. HIV-1 RNA concentrations were measured in pre- and post-treatment plasma samples obtained from the patients whose stool samples remained free of schistosomal eggs for the great majority of the follow-up period. RESULTS: Comparison of pretreatment and follow-up samples revealed that mean +/- SD fecal egg burden was reduced by 96.7% (481.5+/-803.5 versus 16.1+/-24.4 eggs/g feces) and mean plasma CCA concentration decreased by 90.1% (3.22+/-3.26 versus 0.32+/-0.38 microg/ml). In contrast, mean plasma HIV-1 load increased from 3.60+/-0.90 to 3.93+/-0.95 log10 RNA copies/ml (P< 0.001). Although no correlation was found between changes in HIV-1 load and changes in schistosomal burden, there was a significant correlation between changes in plasma HIV load and the time interval between pretreatment and follow-up samples (r = 0.41; P = 0.027). CONCLUSIONS: Treatment of schistosomiasis was not associated with a reduction in plasma HIV-1 load. This study does not, however, exclude the possibility of an adverse effect of helminthic infections on HIV-1 pathogenesis.
Adult↗
Self and nonself stimulatory molecules induce preferential expansion of CD5+ B cells or activated T cells of chagasic patients, respectively.
It has previously been demonstrated that Trypanosoma cruzi-derived antigens (TRP) and human parasite-specific antibodies (Id) stimulate proliferation of cells from Chagasic patients. More recently, we have shown that activated T cells and CD5+ B cells are present in elevated levels in the peripheral blood of Chagasic patients. Upon in vitro exposure to these two different types of stimulatory molecules (TRP, Id), we now show that each of these elevated populations respond differentially to TRP or Id. We found that stimulation with TRP led to preferential expansion of activated T cells, while Id preferentially stimulated CD5+ B cells and CD8+ T cells. Moreover, this expansion of CD5+ B cells by Id was even more pronounced in cultures of cells from Chagasic patients with the severe, cardiac form of the disease, as compared to indeterminate patients. CD8+ T cells comprise approximately 50% of the total T cells in cultures stimulated by Id while in TRP-stimulated cultures their frequency is proportionally lower. Since parasite antigens and antiparasite antibodies are always present in the host during the chronic phase of the disease, they may also be involved with differential activation mechanisms of these cell populations in vivo.
Adult↗
T-cell repertoire analysis in acute and chronic human Chagas' disease: differential frequencies of Vbeta5 expressing T cells.
Here, we analysed the use of Vbeta-TCR regions by CD4+ and CD8+ T cells from acute and chronic chagasic patients using flow cytometry. We determined the Vbeta expression in cells freshly isolated from patients, as well as after in vitro stimulation with antigens derived from epimastigote (EPI) or trypomastigote (TRYPO) forms of Trypanosoma cruzi. Analysis of Vbeta-TCR expression of T cells freshly isolated from patients showed a decrease in Vbeta5 expression in the CD4+ T-cell population from acutely infected individuals, whereas CD4+Vbeta5+ T cells were found to be increased in chronic patients with the cardiac, but not indeterminate, clinical form. After culturing peripheral blood mononuclear cells (PBMC) from chronic patients with EPI or TRYPO, we found that both antigenic preparations led to a preferential expansion of CD4+Vbeta5+ T cells. EPI stimulation also led to the expansion of CD8+Vbeta5+ T cells, whereas TRYPO led to the expansion of this cell population only if PBMC were from cardiac and not indeterminate patients. We observed that TRYPO stimulation led to an increase in the frequency of CD4+Vbeta17+ T cells in cultures of PBMC from indeterminate patients, whereas an increase in the frequency of CD8+Vbeta17+ T cells was found upon TRYPO stimulation of PBMC from cardiac patients. Despite this increase in the frequency of Vbeta17+ T-cell populations upon TRYPO stimulation, the same antigenic preparation led to a much higher expansion of Vbeta5+ T cells. These results show a differential expression of Vbeta5-TCR in cells freshly isolated from chagasic patients in different stages of the disease and that parasite-specific antigens stimulate a portion of the T-cell repertoire with preferential usage of Vbeta5-TCR.
Acute Disease↗
Parasitic diseases: opportunities and challenges in the 21st century.
The opportunities and challenges for the study and control of parasitic diseases in the 21st century are both exciting and daunting. Based on the contributions from this field over the last part of the 20th century, we should expect new biologic concepts will continue to come from this discipline to enrich the general area of biomedical research. The general nature of such a broad category of infections is difficult to distill, but they often depend on well-orchestrated, complex life cycles and they often involve chronic, relatively well-balanced host/parasite relationships. Such characteristics force biological systems to their limits, and this may be why studies of these diseases have made fundamental contributions to molecular biology, cell biology and immunology. However, if these findings are to continue apace, parasitologists must capitalize on the new findings being generated though genomics, bioinformatics, proteomics, and genetic manipulations of both host and parasite. Furthermore, they must do so based on sound biological insights and the use of hypothesis-driven studies of these complex systems. A major challenge over the next century will be to capitalize on these new findings and translate them into successful, sustainable strategies for control, elimination and eradication of the parasitic diseases that pose major public health threats to the physical and cognitive development and health of so many people worldwide.
Allergy and Immunology↗
Susceptibility and resistance to Schistosoma mansoni reinfection: parallel cellular and isotypic immunologic assessment.
Cellular and humoral immune responses to Schistosoma mansoni antigen preparations were evaluated in individuals presumed to be susceptible or resistant to reinfection after chemotherapeutic cure. A consistent proliferative increase in the response to soluble egg antigen (SEA) was observed post-treatment in both the susceptible and resistant groups. However, this change was not related to resistance. Isotype studies showed that IgM antibody levels to soluble worm antigen preparation (SWAP) and cercariae antigens were significantly higher in the resistant group than in the susceptible group. Post-treatment, an increase in IgE anti-SWAP and anti-schistosomular tegument (STEG) responses and a decrease in IgG4 anti-SEA and anti-STEG responses were observed in the resistant group. These finding are similar to those we have reported previously for a putative resistant group termed endemic normals, and are compatible with immunologic studies in different endemic areas. Together, these findings indicate that even on the population level, high IgE specificities coupled with low IgG4 specificities correlate well with documented resistance to reinfection.
Adolescent↗
Neonatal exposure to idiotype induces Schistosoma mansoni egg antigen-specific cellular and humoral immune responses.
Exposure of neonatal mice to appropriate, cross-reactive Id (CRI) preparations alters immune responsiveness, ameliorates pathology, and prolongs survival of animals upon subsequent Schistosoma mansoni infection. However, because schistosome infections profoundly affect host immunobiology, which responses are effected by neonatal Id exposure alone and which responses are influenced by infection is unclear. To directly examine the schistosome soluble egg Ag (SEA)-specific immune responses altered by CRI exposure, neonatal mice were injected with CRI-expressing (CRI+) SEA-specific Ab preparations, SEA-specific Abs that did not express CRI (CRI-), or normal mouse Ig. At 9 wk of age, only mice that were neonatally exposed to CRI+ anti-SEA Abs displayed significant SEA-specific IgG serum levels and spleen cell proliferative responses. SEA-stimulated spleen cells from these CRI+-exposed mice also produced IFN-gamma, although not at significantly higher levels than mice receiving CRI- Id or normal mouse Ig. If CRI+-exposed mice were also injected with SEA at 8 wk of age, the 9-wk IFN-gamma responses were significantly higher than those of the other neonatal injection groups. The presence of both CRI and anti-CRI in the sera of animals neonatally injected with CRI, but receiving no exposure to S. mansoni Ags or infection, suggested a functional idiotypic network led to these responses. These data demonstrate that appropriate idiotypic exposure induces B and T cell responsiveness to the Ag recognized by the Id and support the hypothesis that neonatal idiotypic exposure can be an important immunoregulatory factor in schistosomiasis.
Animals↗
Neonatal idiotypic exposure alters subsequent cytokine, pathology, and survival patterns in experimental Schistosoma mansoni infections.
Exposure to maternal idiotypes (Ids) or antigens might predispose a child to develop an immunoregulated, asymptomatic clinical presentation of schistosomiasis. We have used an experimental murine system to address the role of Ids in this immunoregulation. Sera from mice with 8-wk Schistosoma mansoni infection, chronic (20-wk infection) moderate splenomegaly syndrome (MSS), or chronic hypersplenomegaly syndrome (HSS) were passed over an S. mansoni soluble egg antigen (SEA) immunoaffinity column to prepare Ids (8WkId, MSS Id, HSS Id). Newborn mice were injected with 8WkId, MSS Id, HSS Id, or normal mouse immunoglobulin (NoMoIgG) and infected with S. mansoni 8 wk later. Mice exposed to 8WkId or MSS Id as newborns had prolonged survival and decreased morbidity compared with mice that received HSS Id or NoMoIgG. When stimulated with SEA, 8WkId, or MSS Id, spleen cells from mice neonatally injected with 8WkId or MSS Id produced more interferon gamma than spleen cells from mice neonatally injected with HSS Id or NoMoIgG. Furthermore, neonatal exposure to 8WkId or MSS Id, but not NoMoIgG or HSS Id, led to significantly smaller granuloma size and lower hepatic fibrosis levels in infected mice. Together, these results indicate that perinatal exposure to appropriate anti-SEA Ids induces long-term effects on survival, pathology, and immune response patterns in mice subsequently infected with S. mansoni.
Animals↗
Infection-stimulated or perinatally initiated idiotypic interactions can direct differential morbidity and mortality in schistosomiasis.
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Animals↗
Molecular characterisation of a NADH ubiquinone oxidoreductase subunit 5 from Schistosoma mansoni and inhibition of mitochondrial respiratory chain function by testosterone.
Complementary DNA, encoding the mitochondrial enzyme NADH-ubiquinone oxidoreductase subunit 5 (SmND5) of the human parasite Schistosoma mansoni was isolated by screening a S. mansoni cDNA library with a human androgen receptor (hAR) cDNA probe. The complete nucleotide and deduced aminoacid sequences of SmND5 were determined. Southern blot analysis revealed the occurrence of a single copy gene for SmND5 and by means of RT-PCR, it was shown that sex- and stage-specific expression of SmND5 occurred. In order to establish a functional relationship between the mitochondrial enzyme and the androgen receptor, the effects of testosterone were compared to those of classical respiratory chain inhibitors, using adult schistosome and beef heart submitochondrial particles. Physiological concentrations of testosterone were able to inhibit the maintenance of proton gradient across the mitochondrial membranes, as well as ATP synthesis. The steroid was found to be cytotoxic to the larvae, but not to adult schistosomes. A model is proposed to explain the observed in vivo testosterone-related differences in worm burdens, in experimental chronic infections.
Amino Acid Sequence↗
Clinical forms of human Schistosoma mansoni infection are associated with differential activation of T-cell subsets and costimulatory molecules.
The current study has compared the activation status and the expression of the CD28 molecule on circulating CD4+ and CD8+ lymphocytes from patients with different clinical forms of schistosomiasis. The data show that patients with acute schistosomiasis have an increase on the mean percentage of CD4+ HLA-DR+ cells, whereas chronic asymptomatic patients exhibit an increased mean percentage of CD8+ HLA-DR+ cells. Patients with the hepatosplenic disease showed an increase in both CD4+ HLA-DR+ and CD8+ HLA-DR+ cells. Despite the high levels of CD8+ HLA-DR+ cells in hepatosplenic patients, they presented a decreased ratio of CD8+ CD28+/CD8+ cells. These findings of a different percentage of circulating CD8+ CD28+ cells might explain the different in vitro cellular reactivity of asymptomatic and hepatosplenic patients and the defects in the cytokine secretion patterns reported in individuals with hepatosplenic schistosomiasis.
Acute Disease↗
Schistosomiasis vaccine:research to development.
In this article, Robert Bergquist and Dan Colley deal with the consolidated, international efforts to generate a schistosomiasis vaccine; in particular, they summarize the deliberations of a series of meetings, held in Cairo, Egypt, 21-25 May 1997, with the aim of reviewing the current status of affairs in this respect in order to make recommendations for the future course of schistosomiasis vaccine development.
Journal Article↗
Cytokine mRNA levels in the hearts of inbred mice that develop different degrees of cardiomyopathy during infection with Trypanosoma cruzi.
Profiles of cytokine mRNA expression were examined by semiquantitative RT-PCR in the hearts of DBA/2 (pathopermissive) and B10.D2 (pathoresistant) mice during infection with the Brazil strain of Trypanosoma cruzi. The levels and time-course profiles of IFNgamma, IL-1beta and IL-10 mRNA expression were similar in each strain. TNFalpha, iNOs, and IL-13 mRNA expression peaked at comparable levels and times after infection in each strain, but declined more rapidly in B10.D2 than in DBA/2 mice. Peak IL-2 mRNA levels were also similar between the two strains, but occurred earlier in DBA/2 than in B10.D2 mice. Levels of IL-4, IL-6 and IL-12 mRNA were significantly higher in DBA/2 than in B10.D2 mice from day 10 through day 50 of infection. With the exception of IL-1beta, which was expressed constitutively in both strains, the levels of mRNA of all other cytokines examined reached their peak no later than day 20 and declined significantly by day 50 after infection. The inflammatory infiltrate paralleled the latter cytokines; starting at day 10 in DBA/2 mice and at day 15 in the B10.D2 s, peaking between days 20 and 30 in both strains, decreasing to minimal levels by day 50 in the pathoresistant mice, but maintaining a mild amount through day 70 in the pathopermissive strain. The inflammation was composed mostly of lymphocytes and histiocytes throughout the entire process. These data demonstrate differences in the profiles of cytokine mRNA that may be related to the differential degree of cardiac pathology that develops in these two strains of mice upon infection with T. cruzi.
Age Factors↗
Cytokine profiles during experimental Chagas' disease.
People infected with Trypanosoma cruzi remain so for life, yet only 30-40% of these individuals develop characteristic chagasic cardiomyopathies. Similarly, when infected with the Brazilian strain of T. cruzi, DBA/2 mice develop severe cardiac damage while B10.D2 mice do not. To better understand the immunological parameters that may be involved in the disease process, we have used this murine model (DBA/2 vs B10.D2) and compared the changes in cytokine production during the course of infection with T cruzi. Concanavalin A (Con A) stimulation of spleen cells harvested during the acute phase (day 30) resulted in similarly high levels of IFN-gamma in both mouse strains. However, the amount of IFN-gamma in supernatants from cultures of B10.D2 spleen cells initiated during the chronic phase (day 72) was at subacute levels, whereas secretion by chronic DBA/2 spleen cells remained high. In addition, Con A-stimulated spleen cells from acute DBA/2 mice produced approximately twice as much IL-10 and significantly more IL-4 than cells from B10.D2 mice. IL-4 secretion remained low by cells from chronic B10.D2 mice, but when using cells from chronic DBA/2 mice, levels continued to increase beyond the already high levels secreted by cells harvested during the acute phase. Proliferative responses to Con A stimulation by spleen cells from DBA/2 mice were significantly higher than those from B10.D2 mice in both the acute and chronic phases. These data suggest that enhanced responses in DBA/2 mice, which may be related to a higher parasite burden, a lack of down-regulation, and/or the onset of autoimmune phenomena, correlate with the more severe cardiomyopathy seen in pathopermissive mice.
Animals↗
Studies on schistosomiasis in western Kenya: II. Efficacy of praziquantel for treatment of schistosomiasis in persons coinfected with human immunodeficiency virus-1.
Praziquantel is the drug of choice for schistosomiasis chemotherapy. Although the exact mechanism of how praziquantel kills schistosomes remains poorly understood, the immune response of the host is an important factor in drug efficacy. It is thus possible that disease states of humans that lead to immunodeficiencies, such as infection with human immunodeficiency virus-1 (HIV-1), may render praziquantel less effective in treating schistosomiasis. To test this hypothesis, persons with high levels of Schistosoma mansoni infection who were or were not also infected with HIV-1 were treated with a standard regimen of praziquantel and monitored by quantitative fecal examination and plasma circulating cathodic antigen. Both groups responded to praziquantel therapy equally and individuals with low percentages (< 20%) of CD4+ T cells did not differ from individuals with higher CD4 cell percentages. These data demonstrate that persons with HIV-1 infection can be treated effectively for schistosomiasis with praziquantel.
Animals↗
Polymerase chain reaction amplification of three different Trypanosoma cruzi DNA sequences from human chagasic cardiac tissue.
Chagas' disease is caused by the hemoflagellate protozoan Trypanosoma cruzi. The most common, serious manifestation of Chagas' disease is a progressive inflammatory cardiomyopathy, which occurs decades after primary infection. The inability to consistently demonstrate T. cruzi by histologic techniques in inflammatory cardiac lesions has suggested that the parasites' persistence may not be required for the pathology of the chronic phase. In this report we further analyze the persistence and localization of T. cruzi DNA in the hearts of seven patients with chronic chagasic cardiomyopathy, along with four indeterminate patients and seven control patients seronegative for T. cruzi infection. In the seven patients with chronic chagasic cardiomyopathy, we extracted DNA from selected inflammatory foci-positive (IFP) and inflammatory foci-negative (IFN) areas of' hematoxylin and eosin-stained cardiac tissue. We then used polymerase chain reaction methodology to amplify three different T. cruzi sequences (a minicircle sequence [MCS], a satellite repetitive sequence [RS], and, a low copy number sequence within the gene coding for a flagellar protein [FPS]). The MCS was detected in approximately 100% of both the IFP and IFN areas analyzed. The RS was detected in 37.5% and 23% of the IFP and IFN areas, respectively (difference not statistically significant; P > 0.10, degrees of freedom = 1, G test of independence = 1.9522). The FPS was rarely detected (2%), and was only present in DNA extracted from IFP areas. The MCS was also detected in most indeterminate cases (none of whom had inflammatory lesions) although with a markedly diminished amplification signal relative to cardiomyopathy cases. The MCS was not amplified from the cardiac tissues from seronegative controls. These results suggest that the quantity of T. cruzi DNA persisting in hearts of patients with Chagas' disease correlates with cardiomyopathy, but may not be preferentially associated with inflammatory foci.
Animals↗