Of Mice, Cattle, and Humans: The Immunology and Treatment of River Blindness

Allen, Judith E.; Adjei, Ohene; Bain, O.; Hoerauf, Achim; Hoffmann, W. H.; Makepeace, Benjamin L.; Schulz‐Key, H.; Tanya, Vincent N.; Trees, A. J.; Wanji, Samuel; Taylor, David W.

doi:10.1371/journal.pntd.0000217

Cited by 105 publications

(111 citation statements)

References 80 publications

(100 reference statements)

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“…7). After reaching the adult stage, adult female worms each live within their own intradermal nodules, primarily on the ventral aspect and hind legs of the cow (2,230), and males migrate from nodule to nodule (231). Nodules begin to appear at 180 days p.i., and microfilaridermia onset occurs between 279 and 532 days p.i.…”

Section: Onchocerca Ochengimentioning

confidence: 99%

“…These agents cause genital diseases (typically hydrocele) in approximately 25 million and lymphedema/elephantiasis in approximately 15 million people (1). Onchocerca volvulus, which causes river blindness and skin disease, is estimated to infect 37 million people and is responsible for blindness or visual disturbance in approximately half a million people (2,3). Other filarial infections that cause disease in humans include Loa loa, certain Mansonella species, and, occasionally, Dirofilaria (4).…”

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confidence: 99%

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A Comprehensive, Model-Based Review of Vaccine and Repeat Infection Trials for Filariasis

et al. 2013

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SUMMARY Filarial worms cause highly morbid diseases such as elephantiasis and river blindness. Since the 1940s, researchers have conducted vaccine trials in 27 different animal models of filariasis. Although no vaccine trial in a permissive model of filariasis has provided sterilizing immunity, great strides have been made toward developing vaccines that could block transmission, decrease pathological sequelae, or decrease susceptibility to infection. In this review, we have organized, to the best of our ability, all published filaria vaccine trials and reviewed them in the context of the animal models used. Additionally, we provide information on the life cycle, disease phenotype, concomitant immunity, and natural immunity during primary and secondary infections for 24 different filaria models.

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Section: Onchocerca Ochengimentioning

confidence: 99%

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confidence: 99%

A Comprehensive, Model-Based Review of Vaccine and Repeat Infection Trials for Filariasis

et al. 2013

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“…Infection of mice with Litomosoides sigmodontis can be used to model most features of immune response and immune modulation observed in human filarial infections (17,18). L. sigmodontis third-stage larvae (L3) are transmitted to their natural host, the cotton rat (Sigmodon hispidus), by the bite of infected mites (Ornithonyssus bacoti).…”

mentioning

confidence: 99%

Pathogenic Nematodes Suppress Humoral Responses to Third-Party Antigens In Vivo by IL-10–Mediated Interference with Th Cell Function

Hartmann

Haben

Fleischer

et al. 2011

The Journal of Immunology

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One third of the human population is infected with helminth parasites. To promote their longevity and to limit pathology, helminths have developed several strategies to suppress the immune response of their host. As this immune suppression also acts on unrelated third-party Ags, a preexisting helminth infection may interfere with vaccination efficacy. In this study, we show that natural infection with Litomosoides sigmodontis suppressed the humoral response to thymus-dependent but not to thymus-independent model Ags in C57BL/6 mice. Thereby, we provide evidence that reduced humoral responses were mediated by interference with Th cell function rather than by direct suppression of B cells in L. sigmodontis-infected mice. We directly demonstrate suppression of Ag-specific proliferation in OVA-specific Th cells after adoptive transfer into L. sigmodontis-infected mice that led to equally reduced production of OVA-specific IgG. Transferred Th cells displayed increased frequencies of Foxp3+ after in vivo stimulation within infected but not within naive mice. Helminth-mediated suppression was induced by established L. sigmodontis infections but was completely independent of the individual worm burden. Using DEREG mice, we rule out a central role for host-derived regulatory T cells in the suppression of transferred Th cell proliferation. In contrast, we show that L. sigmodontis-induced, host-derived IL-10 mediated Foxp3 induction in transferred Th cells and significantly contributed to the observed Th cell hypoproliferation within infected mice.

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“…One NTD for which there is pressing urgency for a therapeutic revolution is onchocerciasis, or river blindness, a leading cause of blindness in the developing world (5,6). The infection is caused by the filarial parasitic nematode Onchocerca volvulus that is transmitted to humans by the blackfly (Simulium spp.)…”

mentioning

confidence: 99%

Repositioning of an existing drug for the neglected tropical disease Onchocerciasis

Gloeckner

Garner

Mersha

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Onchocerciasis, or river blindness, is a neglected tropical disease caused by the filarial nematode Onchocerca volvulus that affects more than 37 million people, mainly in third world countries. Currently, the only approved drug available for mass treatment is ivermectin, however, drug resistance is beginning to emerge, thus, new therapeutic targets and agents are desperately needed to treat and cure this devastating disease. Chitin metabolism plays a central role in invertebrate biology due to the critical structural function of chitin for the organism. Taken together with its absence in mammals, targeting chitin is an appealing therapeutic avenue. Importantly, the chitinase OvCHT1 from O. volvulus was recently discovered, however, its exact role in the worm’s metabolism remains unknown. A screening effort against OvCHT1 was conducted using the Johns Hopkins Clinical Compound Library that contains over 1,500 existing drugs. Closantel, a veterinary anthelmintic with known proton ionophore activities, was identified as a potent and specific inhibitor of filarial chitinases, an activity not previously reported for this compound. Notably, closantel was found also to completely inhibit molting of O. volvulus infective L3 stage larvae. Closantel appears to target two important biochemical processes essential to filarial parasites. To begin to unravel closantel’s effects, a retro-fragment-based study was used to define structural elements critical for closantel’s chitinase inhibitor function. As resources towards the development of new agents that target neglected tropical diseases are scant, the finding of an existing drug with impact against O. volvulus provides promise in the hunt for new therapies against river blindness.

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Of Mice, Cattle, and Humans: The Immunology and Treatment of River Blindness

Cited by 105 publications

References 80 publications

A Comprehensive, Model-Based Review of Vaccine and Repeat Infection Trials for Filariasis

A Comprehensive, Model-Based Review of Vaccine and Repeat Infection Trials for Filariasis

Pathogenic Nematodes Suppress Humoral Responses to Third-Party Antigens In Vivo by IL-10–Mediated Interference with Th Cell Function

Repositioning of an existing drug for the neglected tropical disease Onchocerciasis

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