686 research outputs found
Regulation of Global Gene Expression in Human Loa loa Infection Is a Function of Chronicity
Infection with the filarial parasite Loa loa causes a parasite-specific downregulation of T cell responses. However, differences exist (clinical and immunologic) between patients born and living in filarial endemic regions (endemics) and those who become infected during travel or short-term residency (expatriates). T cell responses are more depressed in endemics while expatriates have more clinical “allergic-type” symptoms. In this study, we showed that these differences reflect transcriptional differences within the T cell compartment. Using microarrays, we examined global gene expression in both CD4+ and CD8+ T cells of microfilaremic endemic and expatriate patients and found differences not only ex vivo, but also to parasite and, for CD8+ cells, to nonparasite antigens. Functional analysis showed that endemic patients expressed genes linked to inflammatory disease and caspase associated cell death at homeostasis while expatriates tended to have a more activation-induced gene profile at homeostasis and a CD4+ inflammatory response to parasite antigen. Patient groups were similar in their CD4+ response to nonparasite antigen but strongly differed in their CD8+ responses, demonstrating the potential global ramifications of chronic, longstanding infection. Our study describes potential transcriptional mechanisms for the variability seen in patients with different levels of exposure to and chronicity of filarial infection
The significance of guinea worm infection in the immunological diagnosis of onchocerciasis and bancroftian filariasis
Infections with Dracunculus medinensis frequently occur in the same geographical area as infections with Onchocerca volvulus and Wuchereria bancrofti. This study analysed the significance of D. medinensis infections for the specificity and sensitivity of available tests for antibody-based diagnosis of onchocerciasis (using individual recombinant clones OV-10, OV-11 and OV-16, and the OV-7/OV-10/OV-16 tri-cocktail, in an enzyme-linked immunosorbent assay) and for circulating antigen-based diagnosis of bancroftian filariasis (using the TroBio™ and the ICT™ card tests). Some immunological cross-reactivity was observed with all tests. When using individual recombinant O. volvulus antigens, the highest assay indices were obtained for clone OV-10, and the lowest for clone OV-16. Testing the serum responses against the tri-cocktail of recombinant antigens did not notably improve the assay indices. Two of 40 serum samples from individuals with patent dracunculiasis gave a false positive response in the ICT™ test and one of these was also positive in the TropBio™ test. Possible implications of applying these diagnostic assays in areas endemic for dracunculiasis are discusse
Helminth-Tuberculosis Co-infection: An Immunologic Perspective
Over 2 billion people worldwide are infected with helminths (worms). Similarly, infection with Mycobacterium tuberculosis (Mtb) occurs in over a third of the world's population, often with a great degree of geographical overlap with helminth infection. Interestingly, the responses induced by the extracellular helminths and those induced by the intracellular Mtb are often mutually antagonistic and, as a consequence, can result in impaired (or cross-regulated) host responses to either of the infecting pathogens. In this review, we outline the nature of the immune responses induced by infections with helminths and tuberculosis (TB) and then provide data from both experimental models and human studies that illustrate how the immune response engendered by helminth parasites modulates Mtb-specific responses in helminth-TB co-infection
Immunopathogenesis of lymphatic filarial disease
Although two-thirds of the 120 million people infected with lymph-dwelling filarial parasites have subclinical infections, ~ 40 million have lymphedema and/or other pathologic manifestations including hydroceles (and other forms of urogenital disease), episodic adenolymphangitis, tropical pulmonary eosinophilia, lymphedema, and (in its most severe form) elephantiasis. Adult filarial worms reside in the lymphatics and lymph nodes and induce changes that result in dilatation of lymphatics and thickening of the lymphatic vessel walls. Progressive lymphatic damage and pathology results from the summation of the effect of tissue alterations induced by both living and nonliving adult parasites, the host inflammatory response to the parasites and their secreted antigens, the host inflammatory response to the endosymbiont Wolbachia, and those seen as a consequence of secondary bacterial or fungal infections. Inflammatory damage induced by filarial parasites appears to be multifactorial, with endogenous parasite products, Wolbachia, and host immunity all playing important roles. This review will initially examine the prototypical immune responses engendered by the parasite and delineate the regulatory mechanisms elicited to prevent immune-mediated pathology. This will be followed by a discussion of the proposed mechanisms underlying pathogenesis, with the central theme being that pathogenesis is a two-step process - the first initiated by the parasite and host innate immune system and the second propagated mainly by the host’s adaptive immune system and by other factors (including secondary infections)
Development of Onchocerca volvulus in humanized NSG mice and detection of parasite biomarkers in urine and serum.
BACKGROUND: The study of Onchocerca volvulus has been limited by its host range, with only humans and non-human primates shown to be susceptible to the full life cycle infection. Small animal models that support the development of adult parasites have not been identified.
METHODOLOGY/PRINCIPAL FINDINGS: We hypothesized that highly immunodeficient NSG mice would support the survival and maturation of O. volvulus and alteration of the host microenvironment through the addition of various human cells and tissues would further enhance the level of parasite maturation. NSG mice were humanized with: (1) umbilical cord derived CD34+ stem cells, (2) fetal derived liver, thymus and CD34+ stem cells or (3) primary human skeletal muscle cells. NSG and humanized NSG mice were infected with 100 O. volvulus infective larvae (L3) for 4 to 12 weeks. When necropsies of infected animals were performed, it was observed that parasites survived and developed throughout the infection time course. In each of the different humanized mouse models, worms matured from L3 to advanced fourth stage larvae, with both male and female organ development. In addition, worms increased in length by up to 4-fold. Serum and urine, collected from humanized mice for identification of potential biomarkers of infection, allowed for the identification of 10 O. volvulus-derived proteins found specifically in either the urine or the serum of the humanized O. volvulus-infected NSG mice.
CONCLUSIONS/SIGNIFICANCE: The newly identified mouse models for onchocerciasis will enable the development of O. volvulus specific biomarkers, screening for new therapeutic approaches and potentially studying the human immune response to infection with O. volvulus
Human immune responses to infective stage larval-specific chitinase of filarial parasite, Onchocerca volvulus, Ov-CHI-1.
BACKGROUND: Ov-CHI-1 is a chitinase specifically expressed in the infective stage larvae of the human filarial parasite Onchocerca volvulus. Evidence has show that it could be a vaccine candidate, however, there is no data available regarding the immunological status of people naturally exposed to infective stage larvae and thus provoked by this antigen. METHOD: We analysed the Ov-CHI-1-specific immune response present in four endemic foci of human onchocerciasis (Ecuador, Nigeria, Togo and Cameroon) by enzyme-linked immunosorbent assays and T-cell proliferation assays. RESULTS: In these foci of infection, antibodies to Ov-CHI-1 were found to be present in only 22% of individuals from Ecuador, but were detected in 42–62% of infected individuals in the three foci from West Africa (Nigeria, Togo and Cameroon). There was found to be no relationship between antibody level and age, gender, or infection intensity as indicated by microfilarial density and numbers of skin nodules. The isotype response to Ov-CHI-1 was dominated by the presence of IgG3, IgG1 was present to a lesser extent. Our results show a positive correlation between N- and C-termini of Ov-CHI-1 in their ability to provoke humoral and cellular immune responses in the human. Peripheral blood mononuclear cell (PBMC) proliferative responses to Ov-CHI-1 when assayed, were found to be significantly higher in the individuals from endemic areas and there was a statistically elevated response to Ov-CHI-1 in the infected individuals when compared to putative immune individuals. CONCLUSION: Ov-CHI-1 is an antigen that we have found strongly induces both humoral and cellular immune responses in humans
Heritable Factors Play a Major Role in Determining Host Responses to \u3ci\u3eWuchereria bancrofti\u3c/i\u3e Infection in an Isolated South Pacific Island Population
Background. It is increasingly recognized that host genetic factors may play an important role in determining the outcome of filarial infections. To test this hypothesis in bancroftian lymphatic filariasis, pedigree data were collected twice during an 18-year period from an isolated Polynesian population living on a Pacific island where lymphatic filariasis is endemic. Methods. Using variance-component analysis, we examined the contribution of shared genetic and environmental effects on host clinical and immune responses to filarial infection, along with potential confounding determinants. Results. Sex was found to have a negligible influence on heritability estimates, but shared-household effects accounted for up to 32% of host variability. After accounting for these shared-household effects, heritability estimates suggested that levels of microfilariae and circulating adult worm antigen, as well as host eosinophil and immunoglobulin G antibody responses to larval and adult worm antigens, were highly heritable (range of heritability estimates, 0.15-0.84). Conclusions. These data provide evidence of a key role for genetic factors in determining the host response to filarial infections in humans and emphasize the complexity of the relationships among the host, parasite, and environment
Diagnostic Accuracy of Five Serologic Tests for Strongyloides stercoralis Infection
Background:The diagnosis of Strongyloides stercoralis (S. stercoralis) infection is hampered by the suboptimal sensitivity of fecal-based tests. Serological methods are believed to be more sensitive, although assessing their accuracy is difficult because of the lack of sensitivity of a fecal-based reference ("gold") standard.Methods:The sensitivity and specificity of 5 serologic tests for S. stercoralis (in-house IFAT, NIE-ELISA and NIE-LIPS and the commercially available Bordier-ELISA and IVD-ELISA) were assessed on 399 cryopreserved serum samples. Accuracy was measured using fecal results as the primary reference standard, but also using a composite reference standard (based on a combination of tests).Results:According to the latter standard, the most sensitive test was IFAT, with 94.6% sensitivity (91.2-96.9), followed by IVD-ELISA (92.3%, 87.7-96.9). The most specific test was NIE-LIPS, with specificity 99.6% (98.9-100), followed by IVD-ELISA (97.4%, 95.5-99.3). NIE-LIPS did not cross-react with any of the specimens from subjects with other parasitic infections. NIE-LIPS and the two commercial ELISAs approach 100% specificity at a cut off level that maintains ≥70% sensitivity.Conclusions:NIE-LIPS is the most accurate serologic test for the diagnosis of S. stercoralis infection. IFAT and each of the ELISA tests are sufficiently accurate, above a given cut off, for diagnosis, prevalence studies and inclusion in clinical trials.Fil: Bisoffi, Zeno. Sacro Cuore Hospital; ItaliaFil: Buonfrate, Dora. Sacro Cuore Hospital; ItaliaFil: Sequi, Marco. Istituto Di Ricerche Farmacologiche Mario Negri; ItaliaFil: Mejia, Rojelio. National Institute Of Allergy And Infectious Diseases; Estados UnidosFil: Cimino, RubĂ©n Oscar. Universidad Nacional de Salta. Sede Regional Orán. Instituto de InvestigaciĂłn de Enfermedades Tropicales; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; ArgentinaFil: Krolewiecki, Alejandro Javier. Universidad Nacional de Salta. Sede Regional Orán. Instituto de InvestigaciĂłn de Enfermedades Tropicales; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; ArgentinaFil: Albonico, Marco. Sacro Cuore Hospital; ItaliaFil: Gobbo, Maria. Sacro Cuore Hospital; ItaliaFil: Bonafini, Stefania. Sacro Cuore Hospital; ItaliaFil: Angheben, Andrea. Sacro Cuore Hospital; ItaliaFil: Requena-Mendez, Ana. Universidad de Barcelona; EspañaFil: Muñoz, JosĂ©. Universidad de Barcelona; EspañaFil: Nutman, Thomas B.. National Institute Of Allergy And Infectious Diseases; Estados Unido
Characterization of glycan determinants that mediate recognition of the major Wuchereria bancrofti circulating antigen by diagnostic antibodies
The Global Program to Eliminate Lymphatic Filariasis (GPELF) relies heavily on a rapid diagnostic test (RDT) to a Wuchereria bancrofti circulating filarial antigen (Wb-CFA) to identify endemic areas and for determining when mass drug administration can stop. The antigen contains a carbohydrate epitope that is recognized by monoclonal antibody AD12. Og4C3, a monoclonal antibody that is used in a commercial ELISA for Wb-CFA recognizes the same moiety. Despite its diagnostic importance, little is known about the structure and function of this AD12 epitope . It is also present on other W. bancrofti glycoproteins and on glycoproteins of other filarial worms, but such antigens are not detected in the sera of individuals with most other filarial infections. We report here functional and biochemical analyses that shed light on the interaction between filarial glycoproteins and AD12 and/or Og4C3. Binding of these monoclonal antibodies to a mammalian glycan array suggests the reactive moiety has structural similarity to terminal β-d-glucuronic acid in a 1-3 linkage to other hexoses. However, sera collected from individuals with patent W. bancrofti infection had very low or undetectable serum antibodies to the GlcA-containing array glycans. Unlike other filarial glycoproteins, the Wb-CFA is relatively resistant to protease digestion by pronase and trypsin and completely resistant to the mucinase O-sialoglycoprotein endopeptidase (OSGE). The protease resistance of the Wb-CFA may contribute to its consistent detection in Wb-infected sera
Immunoglobulin Îş Chain Allotypes (KM) in Onchocerciasis
GM and KM allotypes, powerful tools for genetic characterization of human populations, have been shown to play an important role in genetic predisposition to some infectious diseases. Two diverse racial groups-Afro-Ecuadorians and Amerindians-living in a single restricted geographical area of Ecuador, appear to have different risk factors for acquisition and clinical expression of onchocerciasis, a disease caused by the filarial parasite Onchocerca volvulus. In this study, GM and KM allotypes were determined in 25 Afro-Ecuadorians and 24 Amerindians infected with Onchocerca volvulus (INF) and in putative immune individuals (PI). In Afro-Ecuadorians, the frequency of the homozygous KM 3 phenotype was significantly decreased in INF as compared with the PI group (20 vs. 68%; P = 0.0012), while the frequency of the heterozygous KM 1,3 phenotype was increased in INF as compared with the PI subjects (48 vs 9%; P = 0.0044). These results suggest that in Afro- Ecuadorians KM 3 is associated with a lower relative risk (resistance), whereas KM 1,3 is associated with an increased risk (susceptibility) of onchocerciasis
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