Chemotherapy against onchocerciasis and lymphatic filariasis has been discussed mainly within the framework of mass drug administration with diethylcarbamazine, ivermectin and albendazole. Although ...strong reductions in infection prevalence were achieved, the regimes for these drugs do not fully cover needs of individual patients who seek treatment because of symptoms. Chemotherapy against filarial Wolbachia endosymbionts with doxycycline showed higher antiparasitic efficacy in onchocerciasis and lymphatic filariasis and also improved disease. This review details the recent indications for this new treatment, focussing on regimes for individual drug administration.
A regimen of 6-week/100 mg doxycycline per day sterilized adult female Onchocerca volvulus. Two hundred milligrams doxycycline per day for 4 or 6 weeks revealed 50 and 60% macrofilaricidal effects, respectively. Reduction of 80-90% of adult worms was observed in bancroftian filariasis with 200 mg/day doxycycline for 4 or 6 weeks. The latter regimen showed reduction of lymph vessel dilation and of hydrocele. Lymphoedema progression was halted and reversed in early stages.
Different options for antiwolbachial individual drug administration are summarized here. With improving health systems in endemic countries, individuals will demand best-possible treatment and accelerate a shift from mass drug administration-only approaches to integrated approaches combining both mass drug administration and individual drug administration. Treatment may be further improved by new antibiotics detected in high-throughput settings.
Lymphatic filariasis and onchocerciasis Taylor, Mark J, Prof; Hoerauf, Achim, Prof; Bockarie, Moses, Prof
The Lancet (British edition),
10/2010, Volume:
376, Issue:
9747
Journal Article
Peer reviewed
Summary Lymphatic filariasis and onchocerciasis are parasitic helminth diseases that constitute a serious public health issue in tropical regions. The filarial nematodes that cause these diseases are ...transmitted by blood-feeding insects and produce chronic and long-term infection through suppression of host immunity. Disease pathogenesis is linked to host inflammation invoked by the death of the parasite, causing hydrocoele, lymphoedema, and elephantiasis in lymphatic filariasis, and skin disease and blindness in onchocerciasis. Most filarial species that infect people co-exist in mutualistic symbiosis with Wolbachia bacteria, which are essential for growth, development, and survival of their nematode hosts. These endosymbionts contribute to inflammatory disease pathogenesis and are a target for doxycycline therapy, which delivers macrofilaricidal activity, improves pathological outcomes, and is effective as monotherapy. Drugs to treat filariasis include diethylcarbamazine, ivermectin, and albendazole, which are used mostly in combination to reduce microfilariae in blood (lymphatic filariasis) and skin (onchocerciasis). Global programmes for control and elimination have been developed to provide sustained delivery of drugs to affected communities to interrupt transmission of disease and ultimately eliminate this burden on public health.
Filariae are vector-borne parasitic nematodes that are endemic worldwide, in tropical and subtropical regions. Important human filariae spp. include
Onchocerca volvulus
,
Wuchereria bancrofti
and
...Brugia
spp., and
Loa loa
and
Mansonella
spp. causing onchocerciasis (river blindness), lymphatic filariasis (lymphedema and hydrocele), loiasis (eye worm), and mansonelliasis, respectively. It is estimated that over 1 billion individuals live in endemic regions where filarial diseases are a public health concern contributing to significant disability adjusted life years (DALYs). Thus, efforts to control and eliminate filarial diseases were already launched by the WHO in the 1970s, especially against lymphatic filariasis and onchocerciasis, and are mainly based on mass drug administration (MDA) of microfilaricidal drugs (ivermectin, diethylcarbamazine, albendazole) to filarial endemic areas accompanied with vector control strategies with the goal to reduce the transmission. With the United Nations Sustainable Development Goals (SDGs), it was decided to eliminate transmission of onchocerciasis and stop lymphatic filariasis as a public health problem by 2030. It was also requested that novel drugs and treatment strategies be developed. Mouse models provide an important platform for anti-filarial drug research in a preclinical setting. This review presents an overview about the
Litomosoides sigmodontis
and
Acanthocheilonema viteae
filarial mouse models and their role in immunological research as well as preclinical studies about novel anti-filarial drugs and treatment strategies.
Lymphatic filariasis presents a complex spectrum of clinical manifestations ranging from asymptomatic microfilariaemic (MF+) to chronic pathology (CP), including lymphedema and elephantiasis. ...Emerging evidence suggests a link between the physiopathology of filarial infections and antibody properties. Post-translational glycosylation has been shown to play a key role in the modulation of antibodies' effector functions. Here, we investigated the link between total IgG-N-glycosylation patterns and the physiopathology of human lymphatic filariasis using UPLC-FLD/ESI-MS comparison of N-glycan profiles of total IgG purified from endemic normals (EN), MF+, and CP patients. We detected a total of 19 glycans released from all IgG samples. Strikingly, agalactosylated glycan residues were more prominent in EN, whereas sialylation and bisecting GlcNac correlated with asymptomatic infections. While IgG from all three clinical groups expressed high levels of fucosylated residues, significantly lower expressions of afucosylated IgG were seen in MF+ individuals compared to EN and CP. Our data reveal distinct N-linked IgG glycan profiles in EN, MF+, and CP and suggest that IgG galactosylation and sialylation are associated with chronic pathology, whereas agalactosylation correlates with putative immunity. The results also indicate a role for sialylation, fucosylation, and bisecting GlcNac in immune tolerance to the parasite. These findings highlight the link between N-glycosylation and the physiopathology of lymphatic filariasis and open new research avenues for next-generation therapeutic formulations against infectious diseases.
An ever-increasing demand for novel antimicrobials to treat life-threatening infections caused by the global spread of multidrug-resistant bacterial pathogens stands in stark contrast to the current ...level of investment in their development, particularly in the fields of natural-product-derived and synthetic small molecules. New agents displaying innovative chemistry and modes of action are desperately needed worldwide to tackle the public health menace posed by antimicrobial resistance. Here, our consortium presents a strategic blueprint to substantially improve our ability to discover and develop new antibiotics. We propose both short-term and long-term solutions to overcome the most urgent limitations in the various sectors of research and funding, aiming to bridge the gap between academic, industrial and political stakeholders, and to unite interdisciplinary expertise in order to efficiently fuel the translational pipeline for the benefit of future generations.
GeneXpert is an effective and rapid molecular system used for tuberculosis (TB) diagnosis. It is expected to improve the detection rate and treatment outcomes needed to meet the sustainable ...development goals (SDG) and End TB strategy targets set for 2030. This study aimed to evaluate the impact of GeneXpert on diagnosis and anti-TB treatment outcomes in the post-millennium development goals (MDGs) in the capital city of Ethiopia. Hence, the global priority indicator based on the End TB Strategy for TB treatment success rate was met early in 2018 in Addis Ababa, Ethiopia, which was anticipated to be met by 2025. A retrospective health facilities-based study was conducted in Addis Ababa, Ethiopia. Records of all TB cases diagnosed and treated in selected health facilities from January 1.sup.st, 2015 to December 31.sup.st, 2018 were reviewed and included in the study. Data analysis of descriptive and inferential statistics was conducted using SPSS version 20. The reviewed records have shown that a total of 45,158 presumptive pulmonary TB (PTB) cases had accessed TB diagnosis services. Of which, 28.9% (13072/45158) were tested by AFB microscopy and 71.1% (32086/45158) were tested by GeneXpert. During the study period, the coverage of Xpert MTB/RIF testing increased to 94.9% in 2018 compared to 1.6% in 2015. The number of presumptive PTB cases tested with the GeneXpert system showed a significant increase compared to smear microscopy. The odds of positivity were detected in males compared to females. The odds of detecting TB cases were much higher among study participants aged 15-44 years compared to younger than 15 years. Treatment success rate showed a relative improvement each year between 2015 and 2018 with a mean of 92.6%. Reduced odds of treatment successes were observed in age categories older than 35 years, and in TB/HIV co-infected patients. Increased odds of treatment successes were reported in the years between 2016 and 2018 compared to 2015. Scaling up the Xpert MTB/RIF assay as a point-of-care test for presumptive TB cases in resource-limited settings would have a significant impact to meet the SDG and End TB strategy both in TB detection and treatment success rates.
Filariae are parasitic roundworms, which can cause debilitating diseases such as lymphatic filariasis and onchocerciasis. Lymphatic filariasis, also known as elephantiasis, and onchocerciasis, ...commonly referred to as river blindness, can lead to stigmatizing pathologies and present a socio-economic burden for affected people and their endemic countries. Filariae typically induce a type 2 immune response, which is characterized by cytokines, i.e., IL-4, IL-5 and IL-13 as well as type 2 immune cells including alternatively activated macrophages, innate lymphoid cells and Th2 cells. However, the hallmark characteristic of filarial infections is a profound eosinophilia. Eosinophils are innate immune cells and pivotal in controlling helminth infections in general and filarial infections in particular. By modulating the function of other leukocytes, eosinophils support and drive type 2 immune responses. Moreover, as primary effector cells, eosinophils can directly attack filariae through the release of granules containing toxic cationic proteins with or without extracellular DNA traps. At the same time, eosinophils can be a driving force for filarial pathology as observed during tropical pulmonary eosinophilia in lymphatic filariasis, in dermatitis in onchocerciasis patients as well as adverse events after treatment of onchocerciasis patients with diethylcarbamazine. This review summarizes the latest findings of the importance of eosinophil effector functions including the role of eosinophil-derived proteins in controlling filarial infections and their impact on filarial pathology analyzing both human and experimental animal studies.
Human toll-like receptor 8 (TLR8) activation induces a potent T helper-1 (Th1) cell response critical for defense against intracellular pathogens, including protozoa. The receptor harbors two ...distinct binding sites, uridine and di- and/or trinucleotides, but the RNases upstream of TLR8 remain poorly characterized. We identified two endolysosomal endoribonucleases, RNase T2 and RNase 2, that act synergistically to release uridine from oligoribonucleotides. RNase T2 cleaves preferentially before, and RNase 2 after, uridines. Live bacteria, P. falciparum-infected red blood cells, purified pathogen RNA, and synthetic oligoribonucleotides all required RNase 2 and T2 processing to activate TLR8. Uridine supplementation restored RNA recognition in RNASE2−/− or RNASET2−/− but not RNASE2−/−RNASET2−/− cells. Primary immune cells from RNase T2-hypomorphic patients lacked a response to bacterial RNA but responded robustly to small-molecule TLR8 ligands. Our data identify an essential function of RNase T2 and RNase 2 upstream of TLR8 and provide insight into TLR8 activation.
•Endolysosomal RNase 2 and RNase T2 cooperatively process RNA into TLR8 ligands•RNase 2 and RNase T2 synergistically release uridine from RNA ligands•RNase T2-hypomorphic patients have an impaired to TLR8 response to pathogen RNA•Sensing of live pathogens by TLR8 requires both RNase 2 and RNase T2
Toll-like receptor 8 (TLR8) is an endosomal RNA sensor that induces a robust T-helper 1 response downstream of pathogen recognition. Ostendorf and colleagues identify two RNases, RNase 2 and RNase T2, which synergistically process pathogen RNA into TLR8 ligands and are critically required for the sensing of live bacteria and plasmodia.
In an ongoing multinational trial, we obtained blood samples from 365 volunteers vaccinated with mRNA vaccines (Moderna, BioNTech), viral DNA-vectored vaccines (AstraZeneca, Sputnik-V, and Johnson ...and Johnson), or the attenuated virus vaccine from Sinopharm. After collecting reactogenicity data, the expression of S-Protein binding IgG and IgA was analyzed using an automated sandwich ELISA system. Serum neutralizing potentials were then investigated using an ACE-2-RBD neutralizing assay. Moderna’s vaccine induced the highest amounts of SARS-CoV-2 specific neutralizing antibodies compared to the other groups. In contrast, Sinopharm and Johnson and Johnson’s vaccinees presented the lowest SARS-CoV-2-specific antibody titers. Interestingly, moderate to high negative correlations between age and virus-specific IgG expression were observed in the Johnson and Johnson (ρ =-0.3936) and Sinopharm (ρ =-0.6977) groups according to Spearman’s rank correlation analysis. A negative correlation was seen between age and IgA expression in the Sputnik-V group (ρ =-0.3917). The analysis of virus neutralization potentials in age categories demonstrated that no significant neutralization potential was observed in older vaccinees (61and 80 years old) in the Sputnik-V Johnson and Johnson and Sinopharm vaccinees’ groups. In contrast, neutralization potentials in sera of Moderna, BioNTech, and AstraZeneca vaccinees were statistically comparable in all age categories. Furthermore, while the AstraZeneca vaccine alone induced moderate IgG and IgA expression, the combination with Moderna or BioNTech mRNA vaccines induced significantly higher antibody levels than a double dose of AstraZeneca and similar IgG expression and neutralization potential compared to Moderna or BioNTech vaccines used alone. These results suggest that mRNA vaccines are the most immunogenic after two doses. DNA vectored vaccines from AstraZeneca and Sputnik-V presented lower but significant antibody expression and virus neutralizing properties after two doses. The lowest antibody and neutralization potential were observed in the Sinopharm or Johnson and Johnson vaccinees. Especially elderly over 60 presented no significant increase in neutralizing antibodies after vaccination. The data also indicate that heterologous vaccination strategies combining the AstraZeneca DNA vectored vaccines and mRNA vaccines are more effective in the induction of neutralizing antibodies compared to their homologous counterparts.
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