Parasite and host factors that drive heterogeneity in human malaria

Malaria affects over half of the world’s population and causes half a million deaths annually, especially in Sub-Saharan Africa. Four species of the apicomplexan Plasmodium parasite (P. falciparum, P. ovale, P. malariae and P. vivax) are responsible for malaria in Africa. Both parasite and host factors contribute to heterogeneity in the risk of developing malaria, clinical manifestation of the disease as well as the number of treatments required to clear parasites. The epidemiology of the different species, and the role of exposure to mixed-species Plasmodium co-infections in generating heterogeneity remains poorly studied. Being an obligate intracellular parasite the blood-stage life cycle of the Plasmodium parasite takes place in the erythrocytes of the human host. The surfaces of these erythrocytes are the medically important ABO blood group antigens that have been reported to influence the susceptibility or otherwise of an individual developing severe malaria. In this thesis I have considered the contributions of the species of Plasmodium parasites and the ABO blood group of the host in driving heterogeneity in human malaria. The aims of this thesis were to determine: (i) the seroepidemiology of the different Plasmodium species in two mesoendemic African populations (Zimbabwe and Sudan); (ii) to determine if heterogeneity in clinical presentations of malaria (history of fever, body temperature and parasitaemia) and response to drug treatment is related to exposure to single vs. mixed-Plasmodium species infection; (iii) the spatial and temporal dynamics of malaria prevalence and Plasmodium species distribution in a mesoendemic village in eastern Sudan; (iv) gene expression changes in 3D7 P. falciparum parasites as they infect erythrocytes of different ABO blood group donors. For aims (i to iii) I developed an enzyme-linked immunosorbent assay using antigens derived from Plasmodium merozoite surface protein 1, also known as MSP-119, to detect IgG antibodies to all four malaria parasite species in Zimbabwean and Sudanese populations. In the Zimbabwean study, plasma samples from 100 individuals each (aged 5-18 years) from three villages (Burma Valley, Mutoko and Chiredzi) were screened for exposure to Plasmodium parasites. In Daraweesh, Sudan, plasma samples from 333 individuals (aged 1-74 years) who had experienced a first malaria episode between 1990 and 2000 were recruited into the study. For study aim (iv) I cultured a single clone of 3D7 P. falciparum parasite using erythrocytes of individuals of different ABO blood group types, harvested parasite RNA and sequenced it to determine gene expression changes in the different hosts. I showed that human IgG antibodies to MSP-119 antigens of the four Plasmodium species are species-specific and do not cross-react. In both study populations almost all antibody responses involved P. falciparum, and single-species responses were almost exclusively directed against P. falciparum antigens. Mixed-species responses accounted for more than a third of responses, and were associated with chloroquine treatment failure, with significantly high proportion of individuals with mixed-species infections requiring repeated treatment with chloroquine/sulfadoxine-pyrimethamine for parasite clearance. This finding highlights the need for a sensitive method for detecting mixed-species malaria infections to enable the assessment of the true prevalence and magnitude of the disease burden caused by the non-falciparum species in endemic populations. Drug treatment failures associated with mixed species infections have significant impact on malaria morbidity and mortality. Treatment failure or partial parasite clearance has the potential to allow dormant liver stages of P. vivax and P. ovale to become a source of parasite reservoir for onward transmission. Furthermore, untreated low-grade chronic infections caused by P. malariae have been reported to cause systemic diseases many years after the primary infection. Spatial analysis of malaria epidemiology showed that malaria parasite transmission in Daraweesh was focal, and that infections are not randomly distributed in the village. Two space-time clusters of significantly increased malaria risk were identified (1993- 1999, and 1998-1999) with marked variations between households, but little or no variation in the species of Plasmodium over time. Similarly, multiple significant clusters were identified for the parasite species; three for P. falciparum, two for P. vivax and P. malariae, and one for P. ovale. These clusters had overlapping time frames, with some of the species significantly infecting the same households. This suggests that even in a small geographic area malaria transmission shows heterogeneity, and that such data can provide useful information to guide malaria control efforts. Finally, I demonstrated that 3D7 P. falciparum parasite growth was similar in the erythrocytes of different blood group donors, and provide preliminary data to show that the non-coding RNA gene, PF3D7_1370800, is differentially expressed in blood group A donors relative to blood groups B and O donors. Further research is needed to better understand the role of this gene in malaria pathology. All together, these findings will aid malaria researchers and other stakeholders in making informed choices about tools for diagnosing Plasmodium species, and control programmes targeting eradication of malaria caused by all Plasmodium species, as is the case of incorporating these findings into current malaria research in Sudan

Implementation of the integrated management of childhood illness with parasitological diagnosis of malaria in rural Ghana: health worker perceptions.

BACKGROUND: Timely and appropriate management of febrile illness among children under five years of age will contribute to achieving Millennium Development Goal-4. The revised World Health Organization-Global Malaria Programme's policy on test-based management of malaria must integrate effectively into the Integrated Management of Childhood Illness (IMCI). This study reports on perceptions of health workers on the health system factors influencing effective delivery of test-based diagnosis of malaria with IMCI. METHODS: A qualitative study was conducted among a range of health workers at different levels of the health system in the Brong Ahafo Region of Ghana. Interview transcripts were transferred into Nvivo 8 software for data management and analysis. A frame-work approach at two levels was used in the analysis, which included the processes required for implementation of test-based management of malaria and the health systems context. RESULTS: Forty-nine in-depth interviews were conducted. The National Health Insurance Scheme (NHIS) was perceived to have led to an increase in health facility attendance, thereby increasing the workload of health workers. Workload was reported as the main reason that health workers were not able to complete all of the examinations included in the IMCI algorithm. The NHIS financing guidelines were seen to be determining diagnosis and treatment practices by health-care givers. Concern was expressed about the erratic supply of malaria rapid diagnostic test kits (RDTs), the quality of RDTs related to potential false negative results when clinical symptoms were consistent with malaria. IMCI was seen as important but practically impossible to fully implement due to workload. CONCLUSIONS: Implementation of the WHO-revised IMCI guideline is confronted with a myriad of health systems challenges. The perceptions of front-line health workers on the accuracy and need for RDTs together with the capacity of health systems to support implementation plays a crucial role. The NHIS financing guidelines of diagnostics and treatments are influencing clinical decision-making in this setting. Further study is needed to understand the impact of the NHIS on the feasibility of integrating test-based management for malaria into the IMCI guidelines

Dynamics of paediatric urogenital schistosome infection, morbidity and treatment:a longitudinal study among preschool children in Zimbabwe

Background Recent research has shown that in schistosome-endemic areas preschool-aged children (PSAC), that is, <=5 years, are at risk of infection. However, there exists a knowledge gap on the dynamics of infection and morbidity in this age group. In this study, we determined the incidence and dynamics of the first urogenital schistosome infections, morbidity and treatment in PSAC.Methods Children (6 months to 5 years) were recruited and followed up for 12 months. Baseline demographics, anthropometric and parasitology data were collected from 1502 children. Urinary morbidity was assessed by haematuria and growth-related morbidity was assessed using standard WHO anthropometric indices. Children negative for Schistosoma haematobium infection were followed up quarterly to determine infection and morbidity incidence.Results At baseline, the prevalence of S haematobium infection and microhaematuria was 8.5% and 8.6%, respectively. Based on different anthropometric indices, 2.2%–8.2% of children were malnourished, 10.1% underweight and 18.0% stunted. The fraction of morbidity attributable to schistosome infection was 92% for microhaematuria, 38% for stunting and malnutrition at 9%–34%, depending on indices used. S haematobium-positive children were at greater odds of presenting with microhaematuria (adjusted OR (AOR)=25.6; 95% CI 14.5 to 45.1) and stunting (AOR=1.7; 95% CI 1.1 to 2.7). Annual incidence of S haematobium infection and microhaematuria was 17.4% and 20.4%, respectively. Microhaematuria occurred within 3 months of first infection and resolved in a significant number of children, 12 weeks post-praziquantel treatment, from 42.3% to 10.3%; P<0.001.Conclusion We demonstrated for the first time the incidence of schistosome infection in PSAC, along with microhaematuria, which appears within 3 months of first infection and resolves after praziquantel treatment. A proportion of stunting and malnutrition is attributable to S haematobium infection. The study adds scientific evidence to the calls for inclusion of PSAC in schistosome control programmes

The anthelmintic drug Praziquantel promotes human Tr1 differentiation

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Processing of pheromone information in related species of Heliothine moths

In heliothine moths, the male-specific olfactory system is activated by a few odor molecules, each of which is associated with an easily identifiable glomerulus in the primary olfactory center of the brain. This arrangement is linked to two well-defined behavioral responses, one ensuring attraction and mating behavior by carrying information about pheromones released by conspecific females and the other inhibition of attraction via signal information emitted from heterospecifics. The chance of comparing the characteristic properties of pheromone receptor proteins, male-specific sensory neurons and macroglomerular complex (MGC)-units in closely-related species is especially intriguing. Here, we review studies on the male-specific olfactory system of heliothine moths with particular emphasis on five closely related species, i.e., Heliothis virescens, Heliothis subflexa, Helicoverpa zea, Helicoverpa assulta and Helicoverpa armigera