Malaria

Despite encouraging declines in disease over the past decade, malaria remains a leading cause of morbidity and mortality worldwide. The Malaria Modelling Group’s research takes a biological approach to constructing models to understand the transmission dynamics of malaria better both within the human and vector hosts and between hosts. From a public health perspective, they are using these models to consider how interventions can be optimally combined to reduce transmission and ultimately to lead to local elimination. For more information, visit their website.

Malaria has been the strongest of all known evolutionary forces on the human genome in recent history. The intense pressure of malaria-specific mortality has led to the selection of a vast number of resistance genes of which the best documented are those that affect the red blood cell – the primary target of the parasite life-cycle in humans. Classic examples include the sickle cell trait, the thalassaemias and the red blood group antigen systems. The main focus of Professor Tom Williams' work over the last 20 years has been to identify the genes involved, describe the ways in which they affect the risk of human malaria, and to try to understand their mechanisms of action. He collaborates extensively in this work with networks that include MalariaGEN and INDEPTH.

Most relevant publications: 

• Mackinnon, MJ, Ndila, C, Uyoga, S, Macharia, A, Snow, RW, Band, G, Rautanen, A, Rockett, KA, Kwiatkowski, DP, Williams, TN, in collaboration with the MalariaGEN Consortium (2016). Environmental correlation analysis for genes associated with protection against malaria. Molecular Biology and Evolution, doi: 10.1093/molbev/msw004, online first Jan 8^th, 2016. PMID: 26744416.
• Uyoga, S, Ndila, CM, Macharia, AW, Nyutu, G, Shah, S, Peshu, N, Clarke, GM, Kwiatkowski, DP, Rockett, KA, Williams, TN & the MalariaGEN Consortium (2015).Glucose-6-phosphate dehydrogenase deficiency and the risk of malaria and other diseases in children on the coast of Kenya: a case-control and a cohort study. The Lancet Haematology published online September 23, 2015 http://dx.doi.org/10.1016/ S2352-3026(15)00152-0, PMID: 26686045; PMCID: PMC4703047.
• Malaria Genomic Epidemiology Network (2015). A novel locus of resistance to severe malaria in a region of ancient balancing selection. Nature, published online October 1^st doi:10.1038/nature15390. PMID: 26416757; PMC4629224.
• Opi, DH, Ochola, LB, Tendwa, T, Siddondo, BR, Ocholla, H, Fanjo, H, Ghumra, A, Fergusson, DJ, Rowe, JA, Williams, TN (2014). Mechanistic studies of the negative epistatic malaria-protective interaction between sickle cell trait and a⁺thalassemia. eBioMedicine 1, 29-36. PMID: 25893206; PMC4397954.
• Shah, SS, Macharia, A, Uyoga, S, Craik, R, Hubbart, C, Wellems, TE, Rockett, KA, Kwiatkowski, DP, Williams, TN (2014). Modelling the relationship between genotype and bio chemotype at the G6PD locus in Kenya. BMC Medical Genetics 15:93 doi:10.1186/s12881-014-0093-6. PMC4236593.

The Imperial Centre of Excellence in Malaria is an interdisciplinary network of researchers at Imperial College London,  united in the common aim of malaria eradication. The Centre has a unique capacity to combine Insight, Innovation and Impact to achieve this aim: new scientific insights from studying malaria at every scale from molecules to populations; new technological innovations to develop the diagnostic tools and treatments we need to achieve our goal; and expertise in translation science, modelling and assessment to evaluate potential and actual impact.  The Centre brings together scientists working across the Imperial College Faculties of Natural Sciences, Engineering, Medicine and the Business School, together with a global network of research, industry and field partners including many in disease-endemic countries.

Read more about the Centre here.

Blagborough lab

If we are to contemplate control or elimination of malaria we must attack Plasmodium directly on two fronts; we must reduce the impact of disease upon the infected individual, and at the population level we must lessen the number of new infections. To reduce new infections, potentially the most efficient point to attack the parasite is during its transmission through the mosquito vector, a process that in the field, commonly results in infection of fewer than five parasites per mosquito. It is now unquestionable that transmission of Plasmodium to the mosquito is reduced by transmission-blocking drugs (e.g. mefloquine, primaquine, ACTs and atovaquone); and by transmission-blocking vaccines, targeting parasite stages that establish infection within the mosquito (e.g. gametocytes, gametes, zygotes and ookinetes).

Dr Andrew Blagborough's research team's activities involve performing internationally recognised research on the sexual stages of the Plasmodium parasite, with emphasis on gamete/ookinete cell biology and the assessment and blockade of transmission in the lab and field. Our primary interests focus on three individual but complementary and overlapping streams:

1. The identification and characterisation of novel anti-malarial transmission-blocking vaccine (TBV) targets;
2. Effective delivery of these vaccines to induce maximal efficacy;
3. The development of biological models to examine transmission-blocking intervention (TBI) efficacy with enhanced field relevance.

Most relevant publications:

• Blagborough AM, Sinden RE. Plasmodium berghei HAP2 induces strong malaria transmission-blocking immunity in vivo and in vitro. Vaccine. 2009 Aug 20;27(38):5187-94.
• Blagborough AM, Yoshida S, Sattabongkot J, Tsuboi T, Sinden RE. Intranasal and intramuscular immunisation with Baculovirus Dual Expression System-based Pvs25 vaccine substantially blocks Plasmodium vivax transmission. Vaccine. 2010 Aug 23;28(37):6014-20.
• Blagborough AM, Churcher TS, Upton LM, Ghani AC, Gething PW, Sinden RE. Transmission-blocking interventions eliminate malaria from laboratory populations. Nat Commun. 2013;4:1812.
• Baragana et al., A Novel multiple-stage antimalarial that inhibits protein synthesis. Nature. 2015. 522, 315–320
• K. Sala; H. Nishiura; LM Upton; S. Zakutansky; M. Delves; M. Iyori; M. Mizutani; R.E. Sinden; S Yoshida; A M Blagborough. The Plasmodium berghei sexual stage antigen PSOP12 induces anti-malarial transmission blocking immunity both in vivo and in vitro. Vaccine. 2015 Jan 9;33(3):437-45.

Over the last 15 years, Professor Kath Maitland has been based full-time at the East Africa, where she leads a research group whose principal research portfolio includes severe malaria, bacterial sepsis and severe malnutrition in children and clinical trials in emergency care.

Her work has also contributed to the development of national and international guidelines. Her team conducted the largest trial of critically sick children ever undertaken in Africa (FEAST). This trial examined fluid resuscitation strategies in children with severe febrile illness. The trial demonstrated that fluid boluses increased mortality compared to no-bolus (control), with the most adverse outcome in children with the most severe forms of shock (NEJM 2011) and won the prestigious BMJ Research Paper of the Year award. 

Most relevant publications:

• Maitland K: Management of severe paediatric malaria in resource-limited settings. BMC Med 2015, 13:42, 4348099.
• Maitland K, George EC, Evans JA, Kiguli S, Olupot-Olupot P, Akech SO, Opoka RO, Engoru C, Nyeko R, Mtove G et al: Exploring mechanisms of excess mortality with early fluid resuscitation: insights from the FEAST trial. BMC Med 2013, 11:68, 3599745.
• Olupot-Olupot P, Engoru C, Thompson J, Nteziyaremye J, Chebet M, Ssenyondo T, Dambisya CM, Okuuny V, Wokulira R, Amorut D et al: Phase II trial of standard versus increased transfusion volume in Ugandan children with acute severe anaemia. BMC Med 2014, 12:67, 4101869.
• Maitland K, Kiguli S, Opoka RO, Engoru C, Olupot-Olupot P, Akech SO, Nyeko R, Mtove G, Reyburn H, Lang T et al: Mortality after fluid bolus in African children with severe infection. The New England journal of medicine 2011, 364:2483-2495.
• Dondorp AM, Fanello CI, Hendriksen IC, Gomes E, Seni A, Chhaganlal KD, Bojang K, Olaosebikan R, Anunobi N, Maitland K et al: Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet 2010, 376:1647-1657, 3033534. 

"A century of research has not produced a clear understanding of how malaria kills, or more importantly how to stop it killing – we are working to change this, right now."

The main focus of Dr Aubrey Cunnington's research is understanding how malaria causes life-threatening disease, and in finding new ways to save the lives of children with severe malaria. His research integrates data from patients, from experimental models, and from mathematical models, to identify causative biological mechanisms. His team places particular emphasis on using transcriptomics to understand differences in parasite behaviour and host response during different manifestations of severe malaria. They work in close collaboration with The MRC Gambia Unit, and other malaria researchers at Imperial College, London School of Hygiene and Tropical Medicine, and Yale University.  Dr Cunnington's additional research interests include: finding new ways to prevent malaria; finding ways to prevent the susceptibility to bacterial infections which occurs as a consequence of malaria; and reducing susceptibility to infection in children with sickle cell disease. 

Most relevant publications:

• Evans C, Orf K, Horvath E, Levin M, De La Fuente J, Chakravorty S, Cunnington AJ. Impairment of neutrophil oxidative burst in children with sickle cell disease is associated with heme oxygenase-1. Haematologica. 2015 100:1508-16
• Orf K, Cunnington AJ. Infection-related hemolysis and susceptibility to Gram-negative bacterial co-infection. Frontiers in Microbiology. 2015 6:666. 
• Takem EN, Roca A, Cunnington A. The association between malaria and non-typhoid Salmonella bacteraemia in children in sub-Saharan Africa: a literature review. Malaria Journal. 2014 13:400
• Cunnington AJ, Walther M, Riley EM. Piecing together the puzzle of severe malaria. Science Translational Medicine. 2013 5(211):211ps18.
• Cunnington AJ, Riley EM, Walther M. Stuck in a rut? Reconsidering the role of parasite sequestration in severe malaria syndromes.Trends in Parasitology 2013 29(12):585-92.
• Cunnington AJ, Bretscher MT, Nogaro SI, Riley EM, Walther M. Comparison of parasite sequestration in uncomplicated and severe childhood Plasmodium falciparum malaria. Journal of Infection. 2013 67(3):220-30.
• Cunnington AJ, Njie M, Correa S,Takem EN, Riley EM, Walther M. Prolonged Neutrophil Dysfunction Following Plasmodium falciparum Malaria is Related to Hemolysis and Heme Oxygenase-1 Induction. Journal of Immunology. 2012 189(11):5336-46.
• Cunnington AJ, de Souza J.B., Walther R.-M., Riley E.M. Malaria impairs resistance to Salmonella through heme and heme-oxygenase dependent dysfunctional granulocyte mobilisation. Nature Medicine. 2011 18(1):120-7.
•  Cunnington AJ, Riley EM. Suppression of vaccine responses by malaria: insignificant or overlooked? Expert Review of Vaccines. 2010 9(4):409-29.
• Cunnington AJ, Kendrick SFW, Wamola B, Lowe B, Newton CRJC. Carboxyhemoglobin levels in Kenyan children with Falciparum malaria. American Journal of Tropical Medicine and Hygiene 2004 71(1): 43-47.