Human Onchocerciasis:Modelling the Potential Long-term Consequences of a Vaccination Programme

<div><p>Background</p><p>Currently, the predominant onchocerciasis control strategy in Africa is annual mass drug administration (MDA) with ivermectin. However, there is a consensus among the global health community, supported by mathematical modelling, that onchocerciasis in Africa will not be eliminated within proposed time frameworks in all endemic foci with only annual MDA, and novel and alternative strategies are urgently needed. Furthermore, use of MDA with ivermectin is already compromised in large areas of central Africa co-endemic with <i>Loa loa</i>, and there are areas where suboptimal or atypical responses to ivermectin have been documented. An onchocerciasis vaccine would be highly advantageous in these areas.</p><p>Methodology/Principal Findings</p><p>We used a previously developed onchocerciasis transmission model (EPIONCHO) to investigate the impact of vaccination in areas where loiasis and onchocerciasis are co-endemic and ivermectin is contraindicated. We also explore the potential influence of a vaccination programme on infection resurgence in areas where local elimination has been successfully achieved. Based on the age range included in the Expanded Programme on Immunization (EPI), the vaccine was assumed to target 1 to 5 year olds. Our modelling results indicate that the deployment of an onchocerciasis vaccine would have a beneficial impact in onchocerciasis–loiasis co-endemic areas, markedly reducing microfilarial load in the young (under 20 yr) age groups.</p><p>Conclusions/Significance</p><p>An onchocerciasis prophylactic vaccine would reduce the onchocerciasis disease burden in populations where ivermectin cannot be administered safely. Moreover, a vaccine could substantially decrease the chance of re-emergence of <i>Onchocerca volvulus</i> infection in areas where it is deemed that MDA with ivermectin can be stopped. Therefore, a vaccine would protect the substantial investments made by present and past onchocerciasis control programmes, decreasing the chance of disease recrudescence and offering an important additional tool to mitigate the potentially devastating impact of emerging ivermectin resistance.</p></div

Melanotrope cells of Xenopus laevis express multiple types of high-voltage-activated Ca2+ channels

Item does not contain fulltextPituitary melanotrope cells are neuroendocrine signal transducing cells that translate physiological stimuli into adaptive hormonal responses. In this translation process, Ca2+ channels play essential roles. We have characterised which types of Ca2+ current are present in melanotropes of the amphibian Xenopus laevis, using whole-cell, voltage-clamp, patch-clamp experiments and specific blockers of the various current types. Running an activation current-voltage relationship protocol from a holding potential (HP) of -80 mV/or -110 mV, shows that Xenopus melanotropes possess only high-voltage activated (HVA) Ca2+ currents. Steady-state inactivation protocols reveal that no inactivation occurs at -80 mV, whereas 30% of the current is inactivated at -30 mV. We determined the contribution of individual channel types to the total HVA Ca2+ current, examining the effect of each channel blocker at an HP of -80 mV and -30 mV. At -80 mV, omega-conotoxin GVIA, omega-agatoxin IVA, nifedipine and SNX-482 inhibit Ca2+ currents by 21.8 +/- 4.1%, 26.1 +/- 3.1%, 24.2 +/- 2.4% and 17.9 +/- 4.7%, respectively. At -30 mV, omega-conotoxin GVIA, nifedipine and omega-agatoxin IVA inhibit Ca2+ currents by 33.8 +/- 3.0, 24.2 +/- 2.6 and 16.0 +/- 2.8%, respectively, demonstrating that these blockers substantially inhibit part of the Ca2+ current, independently from the HP. We have previously demonstrated that omega-conotoxin GVIA can block Ca2+ oscillations and steps. We now show that nifedipine and omega-agatoxin IVA do not affect the intracellular Ca2+ dynamics, whereas SNX-482 reduces the Ca2+ step amplitude. We conclude that Xenopus melanotrope cells express all four major types of HVA Ca2+ channel, as well as the resulting currents, but no low-voltage activated channels. The results provide the basis for future studies on the complex regulation of channel-mediated Ca2+ influxes into this neuroendocrine cell type as a function of its role in the animal's adaptation to external challenges

Dopamine D2-receptor activation differentially inhibits N- and R-type Ca2+ channels in Xenopus melanotrope cells.

Contains fulltext : 57824.pdf (publisher's version ) (Closed access)Dopamine inhibits pituitary melanotrope cells of the amphibian Xenopus laevis through activation of a dopamine (D2) receptor that couples to a Gi protein. Activated Gi protein subunits are known to affect voltage-operated Ca2+ currents (ICa). In the present study we investigated which Ca2+ currents are regulated by D2-receptor activation and which Gi protein subunits are involved. Whole-cell voltage-clamp patch-clamp experiments from holding potentials (HPs) of -80 and -30 mV show that 28.6 and 36.9%, respectively, of the total ICa was inhibited by apomorphin, a D2-receptor agonist. The inhibited current had fast activation and inactivation kinetics. From an HP of -80 mV, inhibition of N-type Ca2+ currents with omega-conotoxin GVIA and R-type current by SNX-482 reduced the efficacy of the apomorphin-induced inhibition. From an HP of -30 mV this reduction for omega-conotoxin GVIA was still observed. Blocking L-type current by nifedipine or P/Q-type current by omega-agatoxin IVA did not affect apomorphin-induced inhibition at either HP. Our results imply that D2-receptor activation inhibits both N- and R-type Ca2+ currents. Using a strong depolarizing pre-pulse partially reversed the inhibition of the total current by apomorphin. About 50% of this inhibition was achieved through interaction of Gbeta/gamma proteins, and this part of the inhibited ICa had fast activating and inactivating kinetics. However, the other part of the current inhibited by D2-receptor activation may proceed through Galpha-PKA phosphorylation