Browsing by Author "Kwarteng, Alexander"

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    Elevated adaptive immune responses are associated with latent infections of wuchereria bancrofti
    (PLOS, 2012-04) Arndts, Kathrin; Deininger, Susanne; Specht, Sabine; Klarmann, Ute; Mand, Sabine; Adjobimey, Tomabu; Debrah, Alexander Y.; Batsa, Linda; Kwarteng, Alexander; Epp, Christian; Taylor, Mark; Adjei, Ohene; Layland, Laura E.; Hoerauf, Achim
    In order to guarantee the fulfillment of their complex lifecycle, adult filarial nematodes release millions of microfilariae (MF), which are taken up by mosquito vectors. The current strategy to eliminate lymphatic filariasis as a public health problem focuses upon interrupting this transmission through annual mass drug administration (MDA). It remains unclear however, how many rounds of MDA are required to achieve low enough levels of MF to cease transmission. Interestingly, with the development of further diagnostic tools a relatively neglected cohort of asymptomatic (non-lymphedema) amicrofilaremic (latent) individuals has become apparent. Indeed, epidemiological studies have suggested that there are equal numbers of patent (MF+) and latent individuals. Since the latter represent a roadblock for transmission, we studied differences in immune responses of infected asymptomatic male individuals (n = 159) presenting either patent (n = 92 MF+) or latent (n = 67 MF2) manifestations of Wuchereria bancrofti. These individuals were selected on the basis of MF, circulating filarial antigen in plasma and detectable worm nests. Immunological profiles of either Th1/Th17, Th2, regulatory or innate responses were determined after stimulation of freshly isolated PBMCs with either filarial-specific extract or bystander stimuli. In addition, levels of total and filarial-specific antibodies, both IgG subclasses and IgE, were ascertained from plasma. Results from these individuals were compared with those from 22 healthy volunteers from the same endemic area. Interestingly, we observed that in contrast to MF+ patients, latent infected individuals had lower numbers of worm nests and increased adaptive immune responses including antigen-specific IL-5. These data highlight the immunosuppressive status of MF+ individuals, regardless of age or clinical hydrocele and reveal immunological profiles associated with latency and immune-mediated suppression of parasite transmission.
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    Evaluation of Antiwolbachial Treatment in Pathogenesis of Lymphedema Development
    (2010-07-12) Kwarteng, Alexander
    Globally, filarial LE affects more than 16 million individuals. Registered antifilarial drugs do little to mitigate the pathology. Currently, there is no definite drug for treating subjects who develop the pathology because the Global Programme to Eliminate Lymphatic Filariasis (GPELF) relies only on hygiene management practices as the only source of relieve for this group. Antiwolbachial therapy is therefore believed to be the most promising approach for treating lymphedema. To elucidate the efficacy of anti-wolbachial treatment with antibiotics in lymphedema, 180 individuals were recruited from 25 endemic communities of the Nzema East and Ahanta West Districts of the Western Region of Ghana for a double blind placebo-controlled trial. In all, 119 patients were stratified according to circulating filarial antigen (CFA) status, randomized to receive 200mg/d of doxycycline (n=46), 1000mg/d of amoxicillin (n=36) and placebo (n=38) for 42days in a daily observed treatment. Although minimal significant improvements were seen for almost all parameters measured in the CFA-positive treated with doxycycline, there were remarkable improvement in the CFA-negative doxycycline-treated patients particularly in the area of decreased mossy lesions, healed sores, reduced knobs, regressed leg stage, decreased ultrasound measurements (p=0.0001), reduced filarial acute attacks, halt of disease progression, significant reduction in antigenaemia levels (p=<0.00). In the majority of the patients who received 6 weeks doxycycline treatment, there was a highly significant improvement (43.9%) in the leg stage at the end of the study. Although there was halt of disease progression (61.9%) as well as decreased filarial attacks in the amoxicillin treated group, there was no significant improvement in the amoxicillin as well as the placebotreated patients regarding all other parameters assessed. The study suggests that doxycycline as the first therapy for treating lymphedema and recommends its use as individual drug administration.
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    Transcriptomics and Immune Profiles of Asymptomatic Filarial-Infected Individuals
    (2015-08) Kwarteng, Alexander
    Filarial infections caused by Wuchereria bancroftiand Brugiaspecies (lymphatic filariasis (LF)) and Onchocerca volvulus(onchocerciasis) affect almost 200 million individuals worldwide and pose major public health challengesinendemic regions. Indeed, the collective DALYs (disability-adjusted life years) for both infections is 3.3 million. Infections with these thread-like nematodes are chronic and although most individuals develop a regulated state, a portion develop severe forms of pathology. Mass drug administration (MDA) programmes on endemic populations focus on reducing prevalencelevels of people with microfilariae (MF), the worm's offspringin the bloodto less than 1%. Although this has been successful in some areas, studies show that MDA will be required for longer than initially conceived. Thus, there is still a requirement for better drugs or vaccines.W. bancrofti-infected individuals without pathology (asymptomatic) can be subdivided into two groupsthat are patent (MF+) or latent (MF-). Patent infections are associated with an immunologically tolerant phenotype state that favours worm survival and in addition does not provoke overt pathology in the host. Latent infections are characterized by the lack of MF in the periphery, despite the presence of adult worms, and their immune profiles show markers of immune-mediated MF control. In O. volvulusinfection however, the majority of individuals havedermal-residing MFand amicrofilaridermic (a-MF) individuals appear to be the consequences of repeated MDA treatment. Interestingly, recent research revealed that O. volvulusendemic areas,with a lowered infection pressure due to MDA,appear to influencebystander responsesto Plasmodium-derived antigens in community members even if they have not regularlyparticipated in the therapy.Pathology that arises in either filarial infection is associated with dampened regulatory T cell responses (Treg) and IL-10 but elevated Th17 responses. Thus, identifying immune determinants that drive these different infection stateshas the potential to guide the development of improvedanti-filarial drugsand vaccines. In this study, microarray and cellular profiling approaches were used to evaluate gene expression patterns and to revealgenetic pathways specific to W. bancroftior O. volvulusinfection. Individuals with latentLFinfections showed an enhanced gene expressionprofile, including genes involved in Actin Nucleation by ARP-WASP Complex, Rac signaling, Cdc42 signaling, RhoGD1 signaling, eosinophil effector functions and CD28 signaling in T helper cellpathways. Interestingly, the Charcot-Leyden crystal/galectin-10(CLC/Gal-10), an immunosuppressive molecule,was among the top commonly expressed genes in both infections and elevated levels were also detected in plasma.Moreover, compared to healthy volunteers, T cells recovered from W. bancrofti-infected individuals secreted higher levels of CLC/Gal-10and were even higher in MF+ individuals: by complementingtheir elevated Treg responses (Foxp3/IL-10). LatentW. bancrofti-infected individualson the other hand had pronounced Th1, Th2 and Th17 responses. With regards to filarial-specificantibody responses, IgG4, IgE and IgA in plasma were associated with MF+, MF-and endemic normals, respectively. Overall, the transcriptome profiling revealed overlappinggenes in both infections: CLC/Gal-10, ribonuclease RNase A family, 2(RNASE2) and ribosomal protein S4, y-linked 1(RPS4Y1). Thus, the study offersinsightinto filarial-specific genes, signaling pathways and ivimmune determinants, which may be central targets towards the development of new anti-filarial interventions.