ABSTRACT
OBJECTIVE: Ivermectin is safe and widely used for treating helminth infections. It also kills arthropods feeding on treated subjects, including malaria vectors. Thus, ivermectin mass drug administration as an additional tool for malaria control is being evaluated by WHO. As in vitro data, animal experiments and epidemiological observations suggest that ivermectin has a direct effect on the liver stages of the malaria parasite, this study was designed to assess the prophylactic effect of ivermectin on Plasmodium falciparum controlled human malaria infection. METHODS: A total of 4 volunteers were randomised to placebo, and 8 volunteers were randomised to receive ivermectin 0.4 mg/kg, orally, once 2 h before being experimentally infected intravenously with 3200 P. falciparum sporozoites. The primary endpoint was time to parasitaemia detected by positive thick blood smear; RT-qPCR was performed in parallel. RESULTS: All but one volunteer became thick blood smear positive between day 11 and day 12 after infection, and there was no significant effect of ivermectin on parasitaemia. CONCLUSION: Ivermectin - at the dose used - has no clinically relevant activity against the pre-erythrocytic stages of P. falciparum.
OBJECTIF: L'ivermectine est sûr et largement utilisé pour traiter les helminthiases. Il tue également les arthropodes se nourrissant sur les sujets traités, y compris les vecteurs du paludisme. Ainsi, l'administration en masse d'ivermectine en tant qu'outil supplémentaire de lutte contre le paludisme est actuellement évaluée par l'OMS. Comme les données in vitro, les expériences sur animaux et les observations épidémiologiques suggèrent que l'ivermectine a un effet direct sur les stades hépatiques du parasite du paludisme, cette étude a été conçue pour évaluer l'effet prophylactique de l'ivermectine sur l'infection paludéenne humaine par Plasmodium falciparum contrôlée. MÉTHODES: Quatre volontaires ont été randomisés pour un placebo et 8 volontaires ont été randomisés pour recevoir de l'ivermectine à 0,4 mg/kg en une fois par voie orale, 2 heures avant d'être expérimentalement infectés par voie intraveineuse avec 3.200 sporozoïtes de P. falciparum. Le critère d'évaluation principal était le temps à la parasitémie détectée par un frottis sanguin épais positif. Une RT-qPCR a été réalisée en parallèle. RÉSULTATS: Tous les volontaires sauf un sont devenus positifs pour les frottis sanguins épais entre le jour 11 et le jour 12 après l'infection et il n'y avait aucun effet significatif de l'ivermectine sur la parasitémie. CONCLUSION: L'ivermectine - à la dose utilisée - n'a aucune activité cliniquement pertinente contre les stades pré-érythrocytaires de P. falciparum.
Subject(s)
Antimalarials/therapeutic use , Ivermectin/therapeutic use , Malaria, Falciparum/drug therapy , Plasmodium falciparum/drug effects , Adult , Antimalarials/pharmacology , Female , Humans , Ivermectin/pharmacology , Malaria, Falciparum/parasitology , Male , Mass Drug Administration , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: Malaria transmission in most of Latin America can be considered as controlled. In such a scenario, parameters of baseline immunity to malaria antigens are of specific interest with respect to future malaria eradication efforts. METHODS: A cross-sectional study was carried out in two indigenous population groups in Amazonas/Venezuela. Data from the regional malaria documentation system were extracted and participants from the ethnic groups of the Guahibo (n = 180) and Piaroa (n = 295) were investigated for the presence of Plasmodium parasites and naturally acquired antibodies to Plasmodium falciparum antigens in serum. The GMZ2 vaccine candidate proteins MSP3 and GLURP were chosen as serological markers. RESULTS: The incidence of P. falciparum in both communities was found to be less than 2%, and none of the participants harboured P. falciparum at the time of the cross-sectional. Nearly a quarter of the participants (111/475; 23,4%) had positive antibody titres to at least one of the antigens. 53/475 participants (11.2%) were positive for MSP3, and 93/475 participants (19.6%) were positive for GLURP. High positive responses were detected in 36/475 participants (7.6%) and 61/475 participants (12.8%) for MSP3 and GLURP, respectively. Guahibo participants had significantly higher antibody titres than Piaroa participants. CONCLUSIONS: Considering the low incidence of P. falciparum, submicroscopical infections may explain the comparatively high anti-P. falciparum antibody concentrations.
Subject(s)
Antibodies, Protozoan/blood , Antigens, Protozoan/immunology , Malaria, Falciparum/epidemiology , Protozoan Proteins/immunology , Adolescent , Adult , Child , Child, Preschool , Cross-Sectional Studies , Ethnicity , Female , Humans , Incidence , Infant , Malaria Vaccines/immunology , Malaria, Falciparum/immunology , Malaria, Falciparum/parasitology , Male , Plasmodium falciparum/isolation & purification , Pregnancy , Seroepidemiologic Studies , Venezuela/epidemiology , Young AdultABSTRACT
BACKGROUND: Loiasis is a highly prevalent helminth infection found in distinct regions of sub-Saharan Africa. The disease has been considered to be of minor clinical significance, but this belief is being increasingly challenged by recent evidence. We aimed to prospectively quantify the overall burden of disease caused by loiasis in an endemic region of Gabon, using disability-adjusted life years (DALYs). METHODS: We did a cross-sectional survey during 2017 and 2018 in rural Gabon. Volunteers underwent diagnostic tests for loiasis and were given a standardised questionnaire on symptoms. Participants reporting eye worm migration or harbouring Loa loa microfilariae were defined as loiasis positive. Morbidity-based DALYs associated with loiasis were estimated for the rural population of Gabon. FINDINGS: Between Sept 1, 2017 and May 31, 2018, 1235 participants residing in 38 villages in the Gabonese departments of Tsamba-Magotsi and Ogooué et des Lacs were screened. 626 (50·8%) of 1232 eligible participants had loiasis. 520 (42·2%) of 1232 participants reported eye worm migration. 478 (93·9%) of 509 individuals with eye worm migration also reported associated pain, and 397 (78·6%) of 505 reported vision disturbances. After correcting for age and sex, loiasis was significantly associated with a variety of symptoms, including transient painful oedema (adjusted odds ratio 1·76 [95% CI 1·37-2·26]) and arthralgia (1·30 [1·01-1·69]). Application of attributable fractions of correlating symptoms resulted in 412·9 (95% CI 273·9-567·7) morbidity-based DALYs per 100â000 people in rural Gabon. INTERPRETATION: Loiasis, with the pathognomonic sign of eye worm migration, appears to not be benign, but severely impeding to affected individuals. Furthermore, loiasis is associated with substantial morbidity, comparable to that of other neglected tropical parasitic diseases. These findings call for reconsideration of L loa as a relevant pathogen in affected populations, with a need for more concerted research and control of these infections. FUNDING: Federal Ministry of Science, Research and Economy of Austria, and the European Union.
Subject(s)
Cost of Illness , Loa/isolation & purification , Loiasis/epidemiology , Adolescent , Adult , Aged , Aged, 80 and over , Animals , Child , Child, Preschool , Cross-Sectional Studies , Endemic Diseases , Female , Gabon/epidemiology , Humans , Infant , Loiasis/parasitology , Male , Middle Aged , Morbidity , Prevalence , Prospective Studies , Quality-Adjusted Life Years , Surveys and Questionnaires , Young AdultABSTRACT
BACKGROUND: While the federal state of Amazonas bears the highest risk for malaria in Venezuela (2007: 68.4 cases/1000 inhabitants), little comprehensive information about the malaria situation is available from this area. The purpose of this rapid malaria appraisal (RMA) was to provide baseline data about malaria and malaria control in Amazonas. METHODS: The RMA methodology corresponds to a rapid health impact assessment (HIA) as described in the 1999 Gothenburg consensus. In conjunction with the actors of the malaria surveillance system, all useful data and information, which were accessible within a limited time-frame of five visits to Amazonas, were collected, analysed and interpreted. RESULTS: Mortality from malaria is low (< 1 in 105) and slide positivity rates have stayed at the same level for the last two decades (15% +/- 6% (SD)). Active case detection accounts for ca. 40% of slides taken. The coverage of the censured population with malaria notification points (NPs) has been achieved in recent years. The main parasite is Plasmodium vivax (84% of cases). The proportion of Plasmodium falciparum is on the decline, possibly driven by the introduction of cost-free artemisinin-based combination therapy (ACT) (1988: 33.4%; 2007: 15.4%). Monitoring and documentation is complete, systematic and consistent, but poorly digitalized. Malaria transmission displayed a visible lag behind rainfall in the capital municipality of Atures, but not in the other municipalities. In comparison to reference microscopy, quality of field microscopy and rapid diagnostic tests (RDTs) is suboptimal (kappa < 0.75). Hot spots of malaria risk were seen in some indigenous ethnic groups. Conflicting strategies in respect of training of community health workers (CHW) and the introduction of new diagnostic tools (RDTs) were observed. CONCLUSION: Malaria control is possible, even in tropical rain forest areas, if the health system is working adequately. Interventions have to be carefully designed and the features of the particular local Latin American context considered.
Subject(s)
Diagnostic Tests, Routine/methods , Malaria , Plasmodium falciparum/isolation & purification , Plasmodium vivax/isolation & purification , Adolescent , Adult , Age Distribution , Aged , Animals , Antimalarials/therapeutic use , Child , Child, Preschool , Health Knowledge, Attitudes, Practice , Humans , Infant , Infant, Newborn , Malaria/diagnosis , Malaria/drug therapy , Malaria/epidemiology , Malaria/parasitology , Microscopy/methods , Middle Aged , Mosquito Control/methods , Prospective Studies , Reagent Kits, Diagnostic/parasitology , Reagent Kits, Diagnostic/standards , Retrospective Studies , Venezuela/epidemiology , Young AdultABSTRACT
Threonine-peptidases of the T1-family are multi-subunit complexes with broad substrate specificity. In eukaryotes, at least 14 genes encode subunits of the prototypic T1 threonine-peptidase, the proteasome. The proteasome determines the turnover of most proteins and thereby plays a fundamental role in diverse processes such as protein quality control, signal transduction, and cell cycle regulation. While eukaryotes and archaea possess a proteasome, bacteria generally express a second member of the T1-family, the proteasomal predecessor ClpQ/hslV that has a similar structure but is encoded by only one gene. The plasmodial genome is an exception because it encodes proteasomal subunits as well as a ClpQ/hslV-orthologe (Plasmodium falciparum-hslV; PfhslV). Structure, expression, and function of both types of peptidase-complex in P. falciparum are presently unknown. Our aim was to analyze both the coding sequences and derived proteins of both peptidase-complexes because highly specific and potent inhibitors can be designed against this class of enzymes. The proteasome was found expressed throughout the cell cycle, whereas PfhslV was detectable in schizonts and merozoites only. Treatment of P. falciparum with the threonine-peptidase inhibitor epoxomicin blocked two of three catalytically active proteasome subunits. This led to the accumulation of ubiquitinated proteins and, finally, to parasite death. In conclusion, we provide the first functional analysis of plasmodial threonine-peptidase-complexes and identify a lead compound for the development of a novel class of antimalarial drugs.
Subject(s)
Peptide Hydrolases/metabolism , Plasmodium falciparum/metabolism , Proteasome Endopeptidase Complex/metabolism , Protozoan Proteins/metabolism , Amino Acid Sequence , Animals , Catalytic Domain/drug effects , Genes, Protozoan , Molecular Sequence Data , Oligopeptides/pharmacology , Peptide Hydrolases/drug effects , Peptide Hydrolases/genetics , Plasmodium falciparum/growth & development , Proteasome Endopeptidase Complex/drug effects , Proteasome Endopeptidase Complex/genetics , Protozoan Proteins/drug effects , Protozoan Proteins/genetics , Sequence Alignment , ThreonineABSTRACT
BACKGROUND: The quartan malaria parasite Plasmodium malariae is the widest spread and best adapted human malaria parasite. The simian Plasmodium brasilianum causes quartan fever in New World monkeys and resembles P. malariae morphologically. Since the genetics of the two parasites are nearly identical, differing only in a range of mutations expected within a species, it has long been speculated that the two are the same. However, no naturally acquired infection with parasites termed as P. brasilianum has been found in humans until now. METHODS: We investigated malaria cases from remote Yanomami indigenous communities of the Venezuelan Amazon and analyzed the genes coding for the circumsporozoite protein (CSP) and the small subunit of ribosomes (18S) by species-specific PCR and capillary based-DNA sequencing. FINDINGS: Based on 18S rRNA gene sequencing, we identified 12 patients harboring malaria parasites which were 100% identical with P. brasilianum isolated from the monkey, Alouatta seniculus. Translated amino acid sequences of the CS protein gene showed identical immunodominant repeat units between quartan malaria parasites isolated from both humans and monkeys. INTERPRETATION: This study reports, for the first time, naturally acquired infections in humans with parasites termed as P. brasilianum. We conclude that quartan malaria parasites are easily exchanged between humans and monkeys in Latin America. We hypothesize a lack of host specificity in mammalian hosts and consider quartan malaria to be a true anthropozoonosis. Since the name P. brasilianum suggests a malaria species distinct from P. malariae, we propose that P. brasilianum should have a nomenclatorial revision in case further research confirms our findings. The expansive reservoir of mammalian hosts discriminates quartan malaria from other Plasmodium spp. and requires particular research efforts.
Subject(s)
Malaria/parasitology , Parasites/physiology , Plasmodium/physiology , Animals , Haplorhini , Humans , Malaria/diagnosis , Phylogeny , Protozoan Proteins/metabolism , VenezuelaSubject(s)
Disease Eradication/statistics & numerical data , Health Care Reform/organization & administration , Immunization Programs/organization & administration , Smallpox Vaccine/therapeutic use , Smallpox/epidemiology , Smallpox/prevention & control , Disease Eradication/methods , Epidemiological Monitoring , Humans , International Cooperation , Public Health , World Health OrganizationABSTRACT
El propósito de este trabajo fue estudiar los factores asociados con el sistema de salud y con los pacientes, que determinan la adherencia al tratamiento antimalárico en el municipio Atures, estado Amazonas. Se utilizó el Método Comparativo Constante como técnica cualitativa para el análisis de los datos recogidos mediante la observación participante y las entrevistas semi-estructuradas. Los resultados mostraron que las deficiencias del Programa de Control de Malaria, como errores en el diagnóstico, registro y seguimiento de los casos maláricos y suministro del tratamiento son factores que afectan negativamente la adherencia al tratamiento antimalárico. Por otro lado, las actitudes positivas de los pacientes ante el Programa de Control de Malaria y sus conocimientos sobre la enfermedad son factores que determinan una adherencia positiva. Sin embargo, la muestra reducida de pacientes no permite que los resultados concernientes a estos actores sean conclusivos.
The aim of this study was to investigate the factors that determine adherence to antimalarial treatment associated with the Malaria Control Program and patients in the Atures municipality, Amazonas state. The Constant Comparative Method was used as a qualitative technique for analyzing data collected through participant observation and semi-structured interviews. The results showed that deficiencies in the Malaria Control Program, such as misdiagnosis, mistakes in record keeping and monitoring of malaria cases, and treatment supply are all factors that negatively affect adherence to antimalarial treatment. On the other hand, patients´ positive attitudes to the control programme and their knowledge about the disease positively affected adherence to treatment. The small sample of patients meant, however, that the results obtained remain inconclusive.
ABSTRACT
The Gram negative bacterium Helicobacter pylori is a human pathogen which infects the gastric mucosa and causes an inflammatory process leading to gastritis, ulceration and cancer. A systematic, proteome based approach was chosen to detect candidate antigens of H. pylori for diagnosis, therapy and vaccine development and to investigate potential associations between specific immune responses and manifestations of disease. Sera from patients with active H. pylori infection (n = 24), a control group with unrelated gastric disorders (n = 12) and from patients with gastric cancer (n = 6) were collected and analyzed for the reactivity against proteins of the strain HP 26695 separated by two-dimensional electrophoresis. Overall, 310 antigenic protein species were recognized by H. pylori positive sera representing about 17% of all spots separated. Out of the 32 antigens most frequently recognized by H. pylori positive sera, nine were newly identified and 23 were confirmed from other studies. Three newly identified antigens which belong to the 150 most abundant protein species of H. pylori, were specifically recognized by H. pylori positive sera: the predicted coding region HP0231, serine protease HtrA (HP1019) and Cag3 (HP0522). Other antigens were recognized differently by sera from gastritis and ulcer patients, which may identify them as candidate indicators for clinical manifestations. The data from these immunoproteomic analyses are added to our public database (http://www.mpiib-berlin.mpg.de/2D-PAGE). This platform enables one to compile many protein profiles and to integrate data from other studies, an approach which will greatly assist the search for more immunogenic proteins for diagnostic assays and vaccine design.
Subject(s)
Antigens, Bacterial/chemistry , Bacterial Proteins/chemistry , Helicobacter Infections/immunology , Helicobacter pylori/immunology , Proteome , Stomach Diseases/immunology , Antibodies, Bacterial/blood , Antibodies, Bacterial/immunology , Antigens, Bacterial/immunology , Bacterial Proteins/immunology , Electrophoresis, Gel, Two-Dimensional , Helicobacter Infections/microbiology , Helicobacter pylori/chemistry , Helicobacter pylori/genetics , Humans , Immunoblotting , Peptide Mapping , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Stomach Diseases/microbiologyABSTRACT
The merozoite surface protein 2 (MSP2) of Plasmodium falciparum is recognized by human antibodies elicited during natural infections, and may be a target of protective immunity. In this prospective study, serum IgG antibodies to MSP2 were determined in a cohort of 329 Gambian children immediately before the annual malaria transmission season, and the incidence of clinical malaria in the following 5 months was monitored. Three recombinant MSP2 antigens were used, representing each of the two major allelic serogroups and a conserved region. The prevalence of serum IgG to each antigen correlated positively with age and with the presence of parasitaemia at the time of sampling. These antibodies were associated with a reduced subsequent incidence of clinical malaria during the follow-up. This trend was seen for both IgG1 and IgG3, although the statistical significance was greater for IgG3, the most common subclass against MSP2. After adjusting for potentially confounding effects of age and pre-season parasitaemia, IgG3 reactivities against each of the major serogroups of MSP2 remained significantly associated with a lower prospective risk of clinical malaria. Individuals who had IgG3 reactivity to both of the MSP2 serogroup antigens had an even more significantly reduced risk. Importantly, this effect remained significant after adjusting for a simultaneous strong protective association of antibodies to another antigen (MSP1 block 2) which itself remained highly significant.