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Pathogens (Basel, Switzerland) Mar 2024Despite several decades of mass drug administration and elimination-related activities, human onchocerciasis still represents a major parasitic threat in endemic...
Despite several decades of mass drug administration and elimination-related activities, human onchocerciasis still represents a major parasitic threat in endemic regions. Among the challenges encountered by the elimination program is the lack of a suitable diagnostic tool that is accurate and non-invasive. Currently used methods are either invasive or not suitable for monitoring large numbers of patients. Herein, we describe the identification and characterization of heat shock protein 70 (HSP70) as a novel diagnostic biomarker for human onchocerciasis, which can directly be detected in urine samples of infected patients. This nematode-specific antigen was identified through LC-MS after differential SDS-PAGE using urine-derived protein extracts from -infected patients in Cameroon. Polyclonal antibodies generated in rabbits after cloning and expression of HSP70 in reliably differentiated between urine samples from infected- and uninfected patients in a hypoendemic area of human onchocerciasis. These results provide an excellent basis for further development of a non-invasive and scalable diagnostic assay for human onchocerciasis using urine samples. Such a urine-based diagnostic assay will be of major importance for the elimination program of human onchcerciasis in endemic countries.
PubMed: 38668248
DOI: 10.3390/pathogens13040293 -
Frontiers in Tropical Diseases Apr 2024Mouse models of human filarial infections are not only urgently needed to investigate the biology of the nematodes and their modulation of the host's immunity, but will...
INTRODUCTION
Mouse models of human filarial infections are not only urgently needed to investigate the biology of the nematodes and their modulation of the host's immunity, but will also provide a platform to screen and test novel anti-filarial drugs. Recently, murine infection models have been stablished using immunocompromised mouse strains, whereas murine infections have not been implemented until now.
METHODS
Therefore, we aim to establish experimental infections using the immunocompromised mouse strains RAG2IL-2Rγ (lack B, T and natural killer cells), IL-4Rα/IL-5 (impaired IL-4/5 signalling and eosinophil activation) and NOD.Cg-PrkdcIl2rg l/SzJ (NOD scid gamma, NSG) BALB/c mice (lack mature lymphocytes) through subcutaneous (s.c.) or intraperitoneal (i.p.) inoculation of infective stage 3 larvae (L3) isolated from engorged vectors.
RESULTS
In total, 145 immunocompromised mice have been inoculated with 3,250 , 3,337 , and 2,720 L3 to comparatively analyse which immunocompromised mouse strain is susceptible to human filarial infections. Whereas, no and L3 could be recovered upon 2-63 days post-inoculation, a 62-66% L3 recovery rate could be achieved in the different mouse strains. Gender of mice, type of inoculation (s.c. or i.p.) or time point of analysis (2-63 days post inoculation) did not interfere with the success of L3 recovery. In addition, administration of the immune suppressants hydrocortisone, prednisolone and cyclophosphamide did not restore L3 recovery rates.
DISCUSSION
These findings show that RAG2IL-2RgBALB/c and C57BL/6, IL-4Rα/IL-5 BALB/c and NSG mice were not susceptible to and L3 inoculation using the applied methods, whereas infection could be maintained. Further studies should investigate if humanized immunocompromised mice might be susceptible to . and .
PubMed: 38655273
DOI: 10.3389/fitd.2024.1293632 -
Parasitology Research Apr 2024Onchocerciasis is a devastating skin and eye disease that afflicts about 21 million people, most of whom live in sub-Saharan Africa. Its control with the...
Onchocerciasis is a devastating skin and eye disease that afflicts about 21 million people, most of whom live in sub-Saharan Africa. Its control with the microfilaricidal drug ivermectin is limited, thus necessitating the development of preclinical animal models to aid in the discovery of a macrofilaricide. Previously, we found that Onchocerca ochengi (the closest relative of the human O. volvulus) worm masses survive better in hamsters than in gerbils. The aim of this study was to compare the survival of O. ochengi adult male worms and their susceptibility to flubendazole (FBZ, a macrofilaricide) in gerbils and hamsters. The animals were intraperitoneally implanted with O. ochengi male worms, treated with FBZ, and sacrificed 35 days post-implantation. Unlike gerbils which had some worms moving freely in the peritoneum and some in newly formed nodules (neo-nodules), all the worms in the hamsters were found in neo-nodules. FBZ significantly decreased worm burden, motility, and viability in gerbils whereas it had no significant effect in hamsters. These results highlight a major difference in how O. ochengi adult male worms are sustained and affected by FBZ in gerbils compared to hamsters. Understanding the difference between these two models is important in the development of effective macrofilaricides for onchocerciasis.
Topics: Adult; Animals; Cricetinae; Humans; Male; Onchocerca; Gerbillinae; Onchocerciasis; Mebendazole
PubMed: 38634933
DOI: 10.1007/s00436-024-08207-z -
Open Research Europe 2023Maridi County is an onchocerciasis-endemic area in South Sudan. Annual community-directed treatment with ivermectin (CDTi) was instituted in Maridi since the early...
BACKGROUND
Maridi County is an onchocerciasis-endemic area in South Sudan. Annual community-directed treatment with ivermectin (CDTi) was instituted in Maridi since the early 2000s, but with low coverage. In 2021, the CDTi programme was strengthened to a six-monthly programme. Additionally, the community-based vector control strategy "Slash and Clear" has been implemented since 2019 at the Maridi Dam, the only blackfly breeding site in the area. This study assessed the effect of these reinforced onchocerciasis elimination interventions on the seroprevalence among young children, an indicator of ongoing transmission.
METHODS
Baseline and follow-up serosurveys were conducted in Maridi in 2019 (prior to strengthening onchocerciasis elimination efforts) and 2023, respectively. During both surveys, children aged three to nine years were recruited from five study sites situated at different distances from the Maridi Dam. Ov16 antibodies were detected via rapid diagnostic tests (RDTs) using whole blood obtained by finger-pricking the participants. Baseline and follow-up Ov16 prevalence rates were calculated and compared.
RESULTS
In 2019, the Ov16 seroprevalence among children aged three to nine years was 24.5% compared to 30.6% in 2023 (p=0.22). Both surveys found a particularly high Ov16 seroprevalence in the study site closest to the Maridi Dam (35.0% in 2019 and 44.0% in 2023, p=0.52). The Ov16 seroprevalence had a non-significant decreasing trend in the three-year-old children, from 12.5% (3/24) in 2019 to 8.8% (3/34) in 2023 (p=0.65).
CONCLUSION
The persistent Ov16 RDT seropositivity among three-year-old children in 2023 indicates ongoing transmission. Therefore, further strengthening of the onchocerciasis elimination programme is required. The study highlights the utility of RDTs in monitoring onchocerciasis transmission in highly endemic settings.
PubMed: 38617116
DOI: 10.12688/openreseurope.16093.2 -
Pathogens (Basel, Switzerland) Mar 2024Onchocerciasis, or river blindness, has historically been one of the most important causes of blindness worldwide, and a major cause of socio-economic disruption,... (Review)
Review
Onchocerciasis, or river blindness, has historically been one of the most important causes of blindness worldwide, and a major cause of socio-economic disruption, particularly in sub-Saharan Africa. Its importance as a cause of morbidity and an impediment to economic development in some of the poorest countries in the world motivated the international community to implement several programs to control or eliminate this scourge. Initially, these involved reducing transmission of the causative agent through controlling the vector population. When ivermectin was found to be a very effective drug for treating onchocerciasis, the strategy shifted to mass drug administration (MDA) of endemic communities. In some countries, both vector control and ivermectin MDA have been used together. However, traditional vector control methods involve treating rivers in which the black fly vectors breed with insecticides, a process which is expensive, requires trained personnel to administer, and can be ecologically harmful. In this review, we discuss recent research into alternatives to riverine insecticide treatment, which are inexpensive, ecologically less harmful, and can be implemented by the affected communities themselves. These can dramatically reduce vector densities and, when combined with ivermectin MDA, can accelerate the time to elimination when compared to MDA alone.
PubMed: 38535611
DOI: 10.3390/pathogens13030268 -
The American Journal of Tropical... May 2024Current WHO guidelines for onchocerciasis elimination provide requirements for stopping mass drug administration of ivermectin and the verification of elimination of...
Current WHO guidelines for onchocerciasis elimination provide requirements for stopping mass drug administration of ivermectin and the verification of elimination of transmission. These guidelines also recommend post-elimination surveillance (PES) based on entomological surveys. Serological markers in humans could complement entomological PES once the longevity of anti-OV-16 antibody responses is better understood. In 2014-2015 we evaluated ELISA anti-OV-16 IgG4 antibody persistence among previously seropositive people from the central endemic zone of Guatemala. The country stopped all onchocerciasis program interventions in 2012 and was verified by WHO as having eliminated transmission of onchocerciasis in 2016. A total of 246 participants with prior OV-16 ELISA results from 2003, 2006, 2007, or 2009 were enrolled in a follow-up study. Of these, 77 people were previously OV-16 seropositive and 169 were previously seronegative. By 2014 and 2015, 56 (72.7%) previously seropositive individuals had sero-reverted, whereas all previous negatives remained seronegative. The progression of antibody responses over time was estimated using a mixed-effects linear regression model, using data from seropositive participants who had sero-reverted. The temporal variation showed a mean activity unit decay of 0.20 per year (95% credible interval [CrI]: 0.17, 0.23), corresponding to an estimated antibody response half-life of 3.3 years (95% CrI: 2.7, 4.1). These findings indicate that the majority of seropositive people will sero-revert over time.
Topics: Humans; Guatemala; Onchocerciasis; Immunoglobulin G; Male; Female; Adult; Antibodies, Helminth; Middle Aged; Ivermectin; Disease Eradication; Endemic Diseases; Animals; Onchocerca volvulus; Young Adult; Adolescent; Enzyme-Linked Immunosorbent Assay; Mass Drug Administration
PubMed: 38507804
DOI: 10.4269/ajtmh.23-0473 -
Parasites & Vectors Mar 2024After ivermectin became available, diethylcarbamazine (DEC) use was discontinued because of severe adverse reactions, including ocular reactions, in individuals with... (Randomized Controlled Trial)
Randomized Controlled Trial
Onchocerca volvulus microfilariae in the anterior chambers of the eye and ocular adverse events after a single dose of 8 mg moxidectin or 150 µg/kg ivermectin: results of a randomized double-blind Phase 3 trial in the Democratic Republic of the Congo, Ghana and Liberia.
BACKGROUND
After ivermectin became available, diethylcarbamazine (DEC) use was discontinued because of severe adverse reactions, including ocular reactions, in individuals with high Onchocerca volvulus microfilaridermia (microfilariae/mg skin, SmfD). Assuming long-term ivermectin use led to < 5 SmfD with little or no eye involvement, DEC + ivermectin + albendazole treatment a few months after ivermectin was proposed. In 2018, the US FDA approved moxidectin for treatment of O. volvulus infection. The Phase 3 study evaluated SmfD, microfilariae in the anterior chamber (mfAC) and adverse events (AEs) in ivermectin-naïve individuals with ≥ 10 SmfD after 8 mg moxidectin (n = 978) or 150 µg/kg ivermectin (n = 494) treatment.
METHODS
We analyzed the data from 1463 participants with both eyes evaluated using six (0, 1-5, 6-10, 11-20, 21-40, > 40) mfAC and three pre-treatment (< 20, 20 to < 50, ≥ 50) and post-treatment (0, > 0-5, > 5) SmfD categories. A linear mixed model evaluated factors and covariates impacting mfAC levels. Ocular AEs were summarized by type and start post-treatment. Logistic models evaluated factors and covariates impacting the risk for ocular AEs.
RESULTS
Moxidectin and ivermectin had the same effect on mfAC levels. These increased from pre-treatment to Day 4 and Month 1 in 20% and 16% of participants, respectively. Six and 12 months post-treatment, mfAC were detected in ≈5% and ≈3% of participants, respectively. Ocular Mazzotti reactions occurred in 12.4% of moxidectin- and 10.2% of ivermectin-treated participants without difference in type or severity. The risk for ≥ 1 ocular Mazzotti reaction increased for women (OR 1.537, 95% CI 1.096-2.157) and with mfAC levels pre- and 4 days post-treatment (OR 0: > 10 mfAC 2.704, 95% CI 1.27-5.749 and 1.619, 95% CI 0.80-3.280, respectively).
CONCLUSIONS
The impact of SmfD and mfAC levels before and early after treatment on ocular AEs needs to be better understood before making decisions on the risk-benefit of strategies including DEC. Such decisions should take into account interindividual variability in SmfD, mfAC levels and treatment response and risks to even a small percentage of individuals.
Topics: Animals; Female; Humans; Anterior Chamber; Democratic Republic of the Congo; Double-Blind Method; Ghana; Intestinal Volvulus; Ivermectin; Liberia; Macrolides; Microfilariae; Onchocerca; Onchocerca volvulus; Onchocerciasis; Male
PubMed: 38491528
DOI: 10.1186/s13071-023-06087-3 -
F1000Research 2023A high prevalence of onchocerciasis-associated epilepsy (OAE) has been observed in onchocerciasis-endemic areas with high ongoing transmission. However, the...
BACKGROUND
A high prevalence of onchocerciasis-associated epilepsy (OAE) has been observed in onchocerciasis-endemic areas with high ongoing transmission. However, the pathogenesis of OAE remains to be elucidated. We hypothesise that the virome could be involved in inducing epilepsy. With this study, we aim to describe the virome and identify potential neurotropic viruses linked to OAE.
METHODS
In Maridi County, an onchocerciasis endemic area in South Sudan with a high prevalence of OAE, we will conduct an exploratory case-control study enrolling 40 persons aged 12 years and above with palpable onchocerciasis nodules. Cases will be participants with OAE (n=20), who will be age- and village-matched with controls without epilepsy (n=20). For each study participant, two skin snips at the iliac crest will be obtained to collect microfilariae, and one nodulectomy will be performed to obtain adult worms. A viral metagenomic study will be conducted on microfilariae and adult worms, and the virome of persons with and without OAE will be compared. The number, size, and localisation of onchocerciasis nodules in persons with and without OAE will be described. Moreover, the pre- and post-nodulectomy frequency of seizures in persons with OAE will be compared.
ETHICS AND DISSEMINATION
The protocol has been approved by the Ethics Committee of the University of Antwerp and the Ministry of Health of South Sudan. Findings will be disseminated nationally and internationally via meetings and peer-reviewed publications.
REGISTRATION
ClinicalTrials.gov registration NCT05868551 ( https://clinicaltrials.gov/study/NCT05868551).
PROTOCOL VERSION
1.1, dated 09/05/2023.
Topics: Adult; Animals; Humans; Onchocerciasis; Onchocerca volvulus; Case-Control Studies; Intestinal Volvulus; Epilepsy; Microfilariae
PubMed: 38439783
DOI: 10.12688/f1000research.138774.1 -
Parasite Epidemiology and Control May 2024Loiasis is an endemic filarial infection in the rainforest zone of West and Central Africa. Repeated annual community-directed treatment with ivermectin (CDTI) delivered...
BACKGROUND
Loiasis is an endemic filarial infection in the rainforest zone of West and Central Africa. Repeated annual community-directed treatment with ivermectin (CDTI) delivered for several years to control onchocerciasis has been shown to reduce the prevalence and intensity of Loiasis in some co-endemic areas. However, the impact of these multiple rounds of CDTI on entomological indicators of loiasis transmission is not known, and was therefore assessed in this study in areas with contrasting histories of CDTI.
METHODS
The study was conducted in the East, North-west and South-west 1 CDTI project sites of Cameroon. Two communities per CDTI project were selected for fly collection and dissection. Ivermectin treatment coverage was documented in these areas, and this was correlated to infection and infective rates. A total of 7029 female were collected from 6 communities of the 3 CDTI projects (East, North-west, and South-west 1) and from 2 communities in a non-CDTI district (East).
RESULTS
biting densities and parous rates were significantly reduced in the North-west and South-west sites post-CDTI, while in the East, biting densities were similar in non-CDTI and CDTI sites, with higher parous rates observed in the non-CDTI site. Infection and infective rates in the East non-CDTI site were 4.4% and 1.8% respectively, as compared to 3.3% and 1.3% in the CDTI site after 10 ivermectin rounds (there were no baseline data for the latter). In the North-west site, significant reductions in infection and infective rates from 10.2% and 4.2% respectively, to 3.5% and 1.2 (after 9 rounds of ivermectin treatment), were recorded following CDTI. In the South-west, infection rate significantly increased from 1.74% to 2.8% and infective rate remained statistically unchanged after 14 rounds of CDTI (0.45% - 0.40%). Similar trends in Mean Head L3 were observed except in the East site where this indicator was similar in both CDTI and control sites. Only in the North-west site did monthly transmission potentials decrease significantly.
CONCLUSION
This study demonstrated that the impact of repeated annual treatment with ivermectin for the control of onchocerciasis using community directed delivery approach on the entomological indicators of loiasis varies with bioecological zones. Community directed treatment with ivermectin induced a significant reduction in the entomological indicators of loiasis in the North-West project site which lies in forest savanna area. A non-significant decrease was observed in the East project site and in contrast, a significant increase was observed in the South-West 1 project site which both lies in the rainforest zones.
PubMed: 38405181
DOI: 10.1016/j.parepi.2024.e00343 -
Pharmaceutics Feb 2024Onchocerciasis and lymphatic filariasis are two neglected tropical diseases caused by filarial nematodes that utilize insect vectors for transmission to their human...
Onchocerciasis and lymphatic filariasis are two neglected tropical diseases caused by filarial nematodes that utilize insect vectors for transmission to their human hosts. Current control strategies are based on annual or biannual mass drug administration (MDA) of the drugs Ivermectin or Ivermectin plus Albendazole, respectively. These drug regimens kill the first-stage larvae of filarial worms (i.e., microfilariae) and interrupt the transmission of infections. MDA programs for these microfilaricidal drugs must be given over the lifetime of the filarial adult worms, which can reach 15 years in the case of . This is problematic because of suboptimal responses to ivermectin in various endemic regions and inefficient reduction of transmission even after decades of MDA. There is an urgent need for the development of novel alternative treatments to support the 2030 elimination goals of onchocerciasis and lymphatic filariasis. One successful approach has been to target , obligatory endosymbiotic bacteria on which filarial worms are dependent for their survival and reproduction within the human host. A 4-6-week antibiotic therapy with doxycycline, for example, resulted in the loss of that subsequently led to extensive apoptosis of somatic cells, germline, embryos, and microfilariae, as well as inhibition of fourth-stage larval development. However, this long-course regimen has limited use in MDA programs. As an alternative approach to the use of bacteriostatic antibiotics, in this study, we focused on autophagy-inducing compounds, which we hypothesized could disturb various pathways involved in the interdependency between and filarial worms. We demonstrated that several such compounds, including Niclosamide, an FDA-approved drug, Niclosamide ethanolamine (NEN), and Rottlerin, a natural product derived from Kamala trees, significantly reduced the levels of in vitro. Moreover, when these compounds were used in vivo to treat -infected gerbils, Niclosamide and NEN significantly decreased adult worm survival, reduced the release of microfilariae, and decreased embryonic development depending on the regimen and dose used. All three drugs given orally significantly reduced loads and induced an increase in levels of lysosome-associated membrane protein in worms from treated animals, suggesting that Niclosamide, NEN, and Rottlerin were effective in causing drug-induced autophagy in these filarial worms. These repurposed drugs provide a new avenue for the clearance of adult worms in filarial infections.
PubMed: 38399310
DOI: 10.3390/pharmaceutics16020256