Baldwin AT et al. (2016) J Cell Sci "Unique and redundant -catenin regulatory roles of two Dishevelled paralogs during C. elegans asymmetric cell division."

Phillips BT, Clemons AM, Baldwin AT

[J Cell Sci, 2016]

The Wnt/-catenin signaling pathway is utilized across metazoans. However, the mechanism of signal transduction, especially dissociation of the -catenin destruction complex by Dishevelled proteins, remains controversial. Here we describe the function of the Dishevelled paralogs DSH-2 and MIG-5 in the Wnt/-catenin Asymmetry (WA) pathway in Caenorhabditis elegans, where WA drives asymmetric cell divisions throughout development. We find that DSH-2 and MIG-5 redundantly regulate cell fate in hypodermal seam cells. Similarly, both DSH-2 and MIG-5 are required for negative regulation of SYS-1/-catenin localization, but MIG-5 has a stronger effect on polarity of SYS-1 localization. We show that MIG-5 controls cortical APR-1/APC localization. DSH-2 and MIG-5 both regulate the localization of WRM-1/-catenin, acting together as negative regulators of WRM-1 nuclear localization. Finally, we demonstrate that overexpression of DSH-2 or MIG-5 in seam cells leads to stabilization of SYS-1 in the anterior seam daughter, solidifying the Dishevelleds as positive regulators of SYS-1/-catenin. Overall, we have further defined the role of Dishevelled in the WA signaling pathway, and demonstrated that DSH-2 and MIG-5 regulate cell fate, -catenin nuclear levels and polarity of -catenin regulation.

Terhell AJ et al. (2002) Parasitology "Regulation of anti-filarial IgE by infection pressure."

Mangali A, Yazdanbakhsh M, Van Oortmarssen GJ, Terhell AJ, Stolk WA, Haarbrink M

[Parasitology, 2002]

In lymphatic filariasis, specific IgG4 responses to the parasite and their relationship with infection have been studied extensively, but only a few studies have concentrated on anti-filarial and total IgE. Here we have investigated the role of filarial infection pressure on production of IgE by considering length of exposure (age), filarial endemicity and parasitological status. Antibody levels were determined in 366 individuals, who were resident in 3 villages in South-Sulawesi, Indonesia, with varying degrees of filarial transmission intensity, as indicated by the prevalence of Brugia malayi microfilaraemia (0.7%, 9% and 32%, respectively). Anti-filarial IgE levels were significantly lower in the low transmission village than in the areas with intermediate and high filarial transmission; however, in the latter village a remarkable suppression of specific IgE was found. Microfilaria-positive individuals showed elevated levels of total IgE, but suppression of specific IgE, which has been reported before. Taken together, these observations suggest that 2 opposing mechanisms regulate anti-parasite IgE expression: increasing experience of filarial infection stimulates specific IgE, but antibody levels become specifically suppressed when microfilariae or adult worms develop. Using a simple mathematical model, we illustrate how anti-filarial IgE increases with parasite antigen up to a threshold level, but levels off and becomes down-regulated after the threshold is exceeded.

Hamley JID et al. (2020) J Infect Dis "Structural Uncertainty in Onchocerciasis Transmission Models Influences the Estimation of Elimination Thresholds and Selection of Age Groups for Seromonitoring."

Coffeng LE, Milton P, de Vlas SJ, Stolk WA, Basanez MG, Walker M, Hamley JID

[J Infect Dis, 2020]

BACKGROUND: The World Health Organization recommends monitoring Onchocerca volvulus Ov16 serology in children aged <10 years for stopping mass ivermectin administration. Transmission models can help to identify the most informative age groups for serological monitoring and investigate the discriminatory power of serology-based elimination thresholds. Model predictions depend on assumed age-exposure patterns and transmission efficiency at low infection levels. METHODS: The individual-based transmission model, EPIONCHO-IBM, was used to assess (1) the most informative age groups for serological monitoring using receiver operating characteristic curves for different elimination thresholds under various age-dependent exposure assumptions, including those of ONCHOSIM (another widely used model), and (2) the influence of within-human density-dependent parasite establishment (included in EPIONCHO-IBM but not ONCHOSIM) on positive predictive values for different serological thresholds. RESULTS: When assuming EPIONCHO-IBM exposure patterns, children aged <10 years are the most informative for seromonitoring; when assuming ONCHOSIM exposure patterns, 5-14 year olds are the most informative (as published elsewhere). Omitting density-dependent parasite establishment results in more lenient seroprevalence thresholds, even for higher baseline infection prevalence and shorter treatment durations. CONCLUSIONS: Selecting appropriate seromonitoring age groups depends critically on age-dependent exposure patterns. The role of density dependence on elimination thresholds largely explains differing EPIONCHO-IBM and ONCHOSIM elimination predictions.

Akhoon BA et al. (2018) Exp Gerontol "Withanolide A extends the lifespan in human EGFR-driven cancerous Caenorhabditis elegans."

Rathor L, Pandey R, Akhoon BA

[Exp Gerontol, 2018]

The conserved EGFR pathway is linked with multiple cancers in humans including breast, ovarian, and lung carcinoma. Withanolide A, one of the major withanolidal active compounds isolated from the Withania somnifera, extends lifespan and ameliorates stress resistance in wild-type C. elegans by targeting the Insulin/IGF-1 signaling pathway. Up-regulation of IGF1 can transactivate EGFR which inturn reduces longevity and promotes tumor development in an organism. We examined the effects of Withanolide A on the lifespan of a human EGFR-driven C. elegans transgenic model exhibiting the multivulva (Muv) phenotype. The results showed that WA extends the lifespan of both wild human EGFR-driven C. elegans model (human wild-type tyrosine kinase) as well as models bearing single (L858R), and double mutations (T790M-L858R). The lifespan extension observed in these transgenic strains was 20.35, 24.21 and 21.27%, respectively. Moreover, the reduced fat levels were noticed in both wild-type N2 worms and transgenic strains. These observations support the heathspan promoting effect of WA as lipid-rich diet has been reported to promote tumor development. In view of the fact that most of the well known FDA approved drugs such as gefitinib fail to inhibit the EGFR-associated cancers because of these mutations, the present findings show the potential of Withanolide A as a foreseen future nutraceutical to improve the average survival of cancer patients.

Lont YL et al. (2017) PLoS Negl Trop Dis "Modelling Anti-Ov16 IgG4 Antibody Prevalence as an Indicator for Evaluation and Decision Making in Onchocerciasis Elimination Programmes."

Domingo GJ, Golden A, Coffeng LE, de Los Santos T, Lont YL, de Vlas SJ, Stolk WA

[PLoS Negl Trop Dis, 2017]

BACKGROUND: Onchocerciasis is targeted for elimination in Africa through annual or biannual ivermectin mass drug administration (MDA). An immunodiagnostic test, based on the detection of human IgG4 antibodies in the blood to the Onchocerca volvulus-specific antigen Ov16, is one of the recommended tools for determining whether transmission is interrupted and mass treatment can stop. For different transmission settings, the relationship between post-MDA Ov16 antibody prevalence in children (measured 1 year after the last round of MDA) and the duration and coverage of MDA, the mf prevalence in the population, and the probability that onchocerciasis is eventually eliminated is explored through mathematical modelling. METHODOLOGY: The ONCHOSIM model was extended with new output on the Ov16 antibody serostatus of individuals. Seroconversion was assumed to be triggered by the first worm establishing in the host, with seroconversion occurring either before maturation, after maturation or only after the start of mf production. We are mainly interested in seroconversion rates in children, and for now ignore the possibility of seroreversion to simplify the model. PRINCIPAL FINDINGS: Yearly repeated MDA leads to a strong reduction in the in the parasite acquisition rate in humans. This reduces the seroconversion rate in newborns and young children, while those who seroconverted before the start of control remain antibody positive. Both the microfiladermia prevalence in the population aged 5 years and above and the Ov16 antibody prevalence in children under 10 declined with increasing duration of MDA. The association between either of these indicators and the model-predicted probability of elimination was not influenced much by the assumed treatment coverage levels, but was found to depend on baseline endemicity levels, assumptions regarding the trigger of seroconversion, and diagnostic test characteristics (sensitivity and specificity). CONCLUSIONS: Better understanding of the dynamics of Ov16 antibody responses is required for accurate interpretation of seroprevalence data and more precise estimation of endpoint for MDA. Our study demonstrates that this endpoint will be dependent on baseline endemicity levels, which should be taken into account in guidelines for defining when to stop MDA.

Vinkeles Melchers NVS et al. (2019) Clin Infect Dis "Projected number of people with onchocerciasis-loiasis co-infection in Africa, 1995 to 2025."

Vinkeles Melchers NVS, Coffeng LE, Tekle AH, Boussinesq M, Stolk WA, Remme JH, Pion SDS, Wanji S, Zoure HGM, Pedrique B

[Clin Infect Dis, 2019]

BACKGROUND: Onchocerciasis elimination through mass drug administration (MDA) is hampered by co-endemicity of Loa loa in Africa, as people with high L. loa microfilariae (mf) density can develop serious adverse events (SAEs) after ivermectin treatment. We assessed the geographical overlap of onchocerciasis and loiasis prevalence and estimated the number of co-infected individuals at risk of post-ivermectin SAEs in West and Central Africa from 1995 to 2025. METHODS: Focussing on regions with suspected loiasis transmission in 14 African countries, we overlaid pre-control maps of loiasis and onchocerciasis prevalence to calculate pre-control prevalence of co-infection by 5x5 km pixel, distinguishing different categories of L. loa mf intensity. Using statistical and mathematical models, we predicted the prevalence of both infections and co-infection for 2015 and 2025, accounting for the impact of MDA with ivermectin. RESULTS: The number of people infected with onchocerciasis was predicted to decline from almost 19 million in 1995 to 4 million in 2025. Of these, 137,000 people were estimated to also have L. loa hypermicrofilaraemia (20,000 L. loa mf/mL) in 1995, declining to 31,000 in 2025. In 2025, 92.8% of co-infected cases with loiasis hypermicrofilaraemia are predicted to live in hypoendemic areas currently not targeted for MDA. CONCLUSIONS: Loiasis co-infection is a major concern for onchocerciasis elimination in Africa. We predict that under current strategies, at least 31,000 co-infected people will still require treatment for onchocerciasis in 2025 while being at risk of SAEs, justifying continued efforts in research and development for safer drugs and control strategies.