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Journal articleGeorgiadou A, Lee HJ, Walther M, et al., 2019,
Modelling pathogen load dynamics to elucidate mechanistic determinants of host-Plasmodium falciparum interactions
, Nature Microbiology, Vol: 4, Pages: 1592-1602, ISSN: 2058-5276During infection, increasing pathogen load stimulates both protective and harmful aspects of the host response. The dynamics of this interaction are hard to quantify in humans, but doing so could improve understanding of mechanisms of disease and protection. We sought to model the contributions of parasite multiplication rate and host response to observed parasite load in individual subjects with Plasmodium falciparum malaria, using only data obtained at the time of clinical presentation, and then to identify their mechanistic correlates. We predicted higher parasite multiplication rates and lower host responsiveness in severe malaria cases, with severe anemia being more insidious than cerebral malaria. We predicted that parasite growth-inhibition was associated with platelet consumption, lower expression of CXCL10 and type-1 interferon-associated genes, but increased cathepsin G and matrix metallopeptidase 9 expression. We found that cathepsin G and matrix metallopeptidase 9 directly inhibit parasite invasion into erythrocytes. Parasite multiplication rate was associated with host iron availability and higher complement factor H levels, lower expression of gametocyte-associated genes but higher expression of translation-associated genes in the parasite. Our findings demonstrate the potential of using explicit modelling of pathogen load dynamics to deepen understanding of host-pathogen interactions and identify mechanistic correlates of protection.
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Journal articlevan Beek AE, Sarr I, Correa S, et al., 2018,
Complement Factor H Levels Associate With Plasmodium falciparum Malaria Susceptibility and Severity.
, Open Forum Infect Dis, Vol: 5, ISSN: 2328-8957BACKGROUND: Plasmodium falciparum may evade complement-mediated host defense by hijacking complement Factor H (FH), a negative regulator of the alternative complement pathway. Plasma levels of FH vary between individuals and may therefore influence malaria susceptibility and severity. METHODS: We measured convalescent FH plasma levels in 149 Gambian children who had recovered from uncomplicated or severe P. falciparum malaria and in 173 healthy control children. We compared FH plasma levels between children with malaria and healthy controls, and between children with severe (n = 82) and uncomplicated malaria (n = 67). We determined associations between FH plasma levels and laboratory features of severity and used multivariate analyses to examine associations with FH when accounting for other determinants of severity. RESULTS: FH plasma levels differed significantly between controls, uncomplicated malaria cases, and severe malaria cases (mean [95% confidence interval], 257 [250 to 264], 288 [268 to 309], and 328 [313 to 344] µg/mL, respectively; analysis of variance P < .0001). FH plasma levels correlated with severity biomarkers, including lactate, parasitemia, and parasite density, but did not correlate with levels of PfHRP2, which represent the total body parasite load. Associations with severity and lactate remained significant when adjusting for age and parasite load. CONCLUSIONS: Natural variation in FH plasma levels is associated with malaria susceptibility and severity. A prospective study will be needed to strengthen evidence for causation, but our findings suggest that interfering with FH binding by P. falciparum might be useful for malaria prevention or treatment.
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Journal articleLee HJ, Georgiadou A, Walther M, et al., 2018,
Integrated pathogen load and dual transcriptome analysis of systemic host-pathogen interactions in severe malaria
, Science Translational Medicine, Vol: 10, Pages: 1-17, ISSN: 1946-6234The pathogenesis of infectious diseases depends on the interaction of host and pathogen. In Plasmodium falciparum malaria, host and parasite processes can be assessed by dual RNA-sequencing of blood from infected patients. Here we performed dual transcriptome analyses on samples from 46 malaria-infected Gambian children to reveal mechanisms driving the systemic pathophysiology of severe malaria. Integrating these transcriptomic data with estimates of parasite load and detailed clinical information allowed consideration of potentially confounding effects due to differing leukocyte proportions in blood, parasite developmental stage, and whole-body pathogen load. We report hundreds of human and parasite genes differentially expressed between severe and uncomplicated malaria, with distinct profiles associated with coma, hyperlactatemia, and thrombocytopenia. High expression of neutrophil granule-related genes was consistently associated with all severe malaria phenotypes. We observed severity-associated variation in the expression of parasite genes which determine cytoadhesion to vascular endothelium, rigidity of infected erythrocytes, and parasite growth rate. Up to 99% of human differential gene expression in severe malaria was driven by differences in parasite load, whereas parasite gene expression showed little association with parasite load. Co-expression analyses revealed interactions between human and P. falciparum, with prominent co-regulation of translation genes in severe malaria between host and parasite. Multivariate analyses suggested that increased expression of granulopoiesis and interferon-γ related genes, together with inadequate suppression of type-1 interferon signalling, best explained severity of infection. These findings provide a framework for understanding the contributions of host and parasite to the pathogenesis of severe malaria and identifying targets for adjunctive therapy.
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Journal articleGrimes JET, Tadesse G, Mekete K, et al., 2016,
School water, sanitation, and hygiene, soil-transmitted helminths, and schistosomes: national mapping in Ethiopia
, PLOS Neglected Tropical Diseases, Vol: 10:e0004515, ISSN: 1935-2735 -
Journal articleOpi DH, Uyoga S, Orori EN, et al., 2016,
Red blood cell complement receptor one level varies with Knops blood group, α+thalassaemia and age among Kenyan children
, Genes and Immunity, Vol: 17, Pages: 171-178, ISSN: 1476-5470Both the invasion of red blood cells (RBCs) by Plasmodium falciparum parasites and the sequestration of parasite-infected RBCs in the microvasculature are mediated in part by complement receptor one (CR1). RBC surface CR1 level can vary between individuals by more than 20-fold and may be associated with the risk of severe malaria. The factors that influence RBC CR1 level variation are poorly understood, particularly in African populations. We studied 3535 child residents of a malaria-endemic region of coastal Kenya and report, for the first time, that the CR1 Knops blood group alleles Sl2 and McCb, and homozygous HbSS are positively associated with RBC CR1 level. Sickle cell trait and ABO blood group did not influence RBC CR1 level. We also confirm the previous observation that α+thalassaemia is associated with reduced RBC CR1 level, possibly due to small RBC volume, and that age-related changes in RBC CR1 expression occur throughout childhood. RBC CR1 level in malaria-endemic African populations is a complex phenotype influenced by multiple factors that should be taken into account in the design and interpretation of future studies on CR1 and malaria susceptibility.
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Journal articleSeale AC, Davies MR, Anampiu K, et al., 2016,
Invasive group A Streptococcus amongst children in rural Kenya
, Emerging Infectious Diseases, Vol: 22, Pages: 224-232, ISSN: 1080-6059There are minimal data on the burden of Streptococcus pyogenes (group A Streptococcus; GAS) in sub-Saharan Africa and none on serotypes causing disease. We analyzed systematically collected clinical and microbiological surveillance data from 64,741 hospital admissions in Kilifi, Kenya (1998-2011), to describe incidence, clinical presentations and emm-types of invasive GAS (iGAS). There were 370 cases; commonly skin and soft tissue infections (258/369,70%), severe pneumonia (86/369,23%), and primary bacteremia (53/369,14%); overall case fatality risk was 45/369 (12%). Incidence of iGAS was, in neonates 0.6/1000 live-births; <1 year 101/100,000, and <5 years 35/100,000. Using genome sequencing, 88 different emm-types were observed, highlighting extensive circulating GAS heterogeneity. GAS is an important cause of serious bacterial disease in this setting, especially in neonates, with considerable genotypic diversity. There may be limited benefit from the most advanced GAS type-specific vaccines and efforts must be directed to protect against disease in high burden regions.
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Journal articleWilliams TN, 2016,
Sickle cell disease in Sub-Saharan Africa
, Hematology/Oncology Clinics of North America, Vol: 30, Pages: 343-358, ISSN: 1558-1977In Africa, at least 240,000 children are born each year with sickle cell disease. Historically, in the absence of newborn screening and appropriate treatment, most such children died undiagnosed in early childhood. However, with increasing awareness of the condition and economic and epidemiologic transition, increasing numbers are surviving. Greater investments in basic and applied research in the African context, and increased sensitization or African ministries of health regarding the importance of this condition, could make a substantial difference to the lives and livelihoods of millions of people living with sickle cell disease on the continent and their families.
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Journal articleMaitland K, 2015,
Transfusion and Treatment of severe anaemia in African children (TRACT): a study protocol for a randomized controlled trial
, Trials, Vol: 16, ISSN: 1745-6215BackgroundIn sub-Saharan Africa, where infectious diseases and nutritional deficiencies are common, severe anaemia is a common cause of paediatric hospital admission, yet the evidence to support current treatment recommendations is limited. To avert overuse of blood products, the World Health Organisation advocates a conservative transfusion policy and recommends iron, folate and anti-helminthics at discharge. Outcomes are unsatisfactory with high rates of in-hospital mortality (9–10 %), 6-month mortality and relapse (6 %). A definitive trial to establish best transfusion and treatment strategies to prevent both early and delayed mortality and relapse is warranted.Methods/DesignTRACT is a multicentre randomised controlled trial of 3954 children aged 2 months to 12 years admitted to hospital with severe anaemia (haemoglobin < 6 g/dl). Children will be enrolled over 2 years in 4 centres in Uganda and Malawi and followed for 6 months. The trial will simultaneously evaluate (in a factorial trial with a 3 x 2 x 2 design) 3 ways to reduce short-term and longer-term mortality and morbidity following admission to hospital with severe anaemia in African children.The trial will compare: (i) R1: liberal transfusion (30 ml/kg whole blood) versus conservative transfusion (20 ml/kg) versus no transfusion (control). The control is only for children with uncomplicated severe anaemia (haemoglobin 4–6 g/dl); (ii) R2: post-discharge multi-vitamin multi-mineral supplementation (including folate and iron) versus routine care (folate and iron) for 3 months; (iii) R3: post-discharge cotrimoxazole prophylaxis for 3 months versus no prophylaxis. All randomisations are open. Enrolment to the trial started September 2014 and is currently ongoing. Primary outcome is cumulative mortality to 4 weeks for the transfusion strategy comparisons, and to 6 months for the nutritional support/antibiotic prophylaxis comparisons. Secondary outcomes include mortality, morbidity
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Journal articleTempleton MR, 2015,
Pitfalls and progress: a perspective on achieving sustainable sanitation for all
, Environmental Science: Water Research and Technology, Vol: 1, Pages: 17-21, ISSN: 2053-1400Why is it that so many people in our world still lack access to a toilet? Many developing countries have met their Millennium Development Goal target for access to clean water but still lag far behind their goal for access to improved forms of sanitation, especially in the rural and unplanned peri-urban settlements that are inhabited by the poorest of the poor. A great deal of thinking, funding, and time has been invested recently in developing clever new toilets, but there is also a need to better understand and get the most out of the sanitation facilities to which many poor people already have access, such as basic pit latrines. There is an urgent need for longer lasting, sustainable sanitation solutions, but this should look beyond just new toilet designs and include providing sanitation services, enabling community leadership in sanitation programmes, and training the in-country sanitation specialists of the future. Achieving sustainable sanitation for all is not just an engineering challenge, nor is it only for economists and social scientists; multi-disciplinary efforts are critical to achieving successful outcomes. As sanitation needs expand and justification is sought for large-scale infrastructure projects, especially in booming urban areas, greater recognition is needed that investment in sanitation infrastructure is not only about improving health, but will also ultimately lead to significant economic returns.
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Journal articleFurlong C, Gibson WT, Templeton MR, et al., 2015,
The development of an onsite sanitation system based on vermifiltration: the 'Tiger Toilet'
, Journal of Water, Sanitation and Hygiene for Development, Vol: 5, Pages: 608-613, ISSN: 2043-9083This paper describes the development of a novel onsite sanitation system based on vermifiltration, the ‘Tiger Toilet’. Initial laboratory experiments demonstrated that feed distribution was not required, a worm density of 2 kg/m2 could be used, worms preferred wetter environments, and system configuration did not affect effluent quality. Installing the first prototype in the UK proved that the process functioned when scaled, i.e., chemical oxygen demand and thermotolerant coliform reduction were found to be comparable with the laboratory results. Ten prototypes were then tested by households in rural India; all were working well after six months. The vermifilters were processing the amount of faeces entering the system on a daily basis, so faeces was not accumulating. It was estimated that they would require emptying after approximately five years, based on the depth of the vermicompost generated. With further development, it is believed that the Tiger Toilet has the potential to become a superior form of onsite sanitation, when compared with traditional onsite sanitation technologies.
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