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Research

Colin's research falls into 3 main areas: Plasmodium falciparum gametocyte biology, malaria drug resistance and molecular diagnostics for malaria infections. The following projects are currently active in the lab:

1) Drug resistant genotypes associated with reduced susceptibility of African P. falciparum

The Sutherland lab works with collaborators throughout Africa running trials and studies evaluating ACT efficacy, and the effectiveness of seasonal malaria chemoprevention (SMC). Our earlier work in western Kenya identified mutations in the P. falciparum genes, pfubp1 and pfap2mu that are associated with reduced susceptibility to ACT in vivo. Our data clearly show that determinants of susceptibility in Africa differ from those described from the Mekong region. Gene-editing studies by Ryan Henrici successfully established the role of polymorphisms in the pfap2mu and pfubp1 loci in modulating parasite response to antimalarial drugs in vitro. Variants at either of these loci reduce P. falciparum artemisinin susceptibility in vitro. Four years of MRC project funding to support this work was secured in 2020.

The deletion of genes encoding histidine-rich antigens is a fascinating adaptation by P. falciparum populations, particularly in east Africa, to the widespread use of HRPII-based diagnostic tests. By appearing "invisible" to the test, the parasite reduce the likelihood that drugs will be administered. We therefore see this as an adaptation by the parasite to drug pressure. The laboratory of our collaborator Khalid Beshir is leading innovative work to identify and map these deletions in natural parasite populations.

2) New molecular tools for surveillance of parasitic infections

The UK Health Security Agency (formerly PHE) is supporting the development of new assays for parasite genotyping in the Malaria Reference Laboratory (MRL) at LSHTM, with Dr Debbie Nolder, and Lindsay Stewart. New real-time qPCR assays for Plasmodium falciparum, P. vivax and P. ovale spp. have been developed and have entered routine diagnostic use. Currently we are bench-testing new specieis specific PCR detection assays for P. malariae, a ubiquitous but little studied human malaria parasite. This is complementary to exciting parasite genome studies with Prof Susana Campino and her team in the LSHTM Dept of Infection Biology. The MRL has also worked with support from hVivo to provide robust qPCR monitoring of P. falciparum growth and subsequent drug clearance for volunteers participating in controlled human malaria infections (CHMI).

3) Population biology of P. ovale curtisi and P. ovale wallikeri

Dr Mary Oguike led foundation work on these two distinct forms of malaria parasite, first described in 2010 as part of Colin's work in the UK Malaria Reference Laboratory, up to 2018. Mary successfully generated Ilumina paired-end genome seq data direct from blood samples from patients with ovale malaria. With Dr Mojca Kristan and Dr Julius Hafalla we have developed a mosquito transmission pipeline, and in have successfully infected cultured human hepatocytes with sporozoites from P. ovale spp. Together with Susana Campino and her team at LSHTM genomic analyses of these are two sibling species are continuing, using material from UK travellers provided by the MRL. New reference genomes for both species have now been submitted for publication.

4) In vitro drug responses of parasites isolated from UK malaria patients

As Clinical Scientist in the UKHSA Malaria Reference Laboratory, Colin has direct access to parasite isolates from malaria patients who have returned to or visited the UK from malaria-endemic countries. Dr Don van Schalkwyk and Lindsay Stewart have successfully adapted more than 40 P. falciparum cultures from across Africa to long-term in vitro growth since 2012. In MRC-funded work led by Don and Sade Pratt, we are now investigating impact of certain gene variants on in vitro artemisinin and partner drug susceptibility of African P. falciparum isolates. In particular, we have shown that travellers' malaria cases of Ugandan origin show in vitro evidence of reduced susceptibility to bnoth artemisinin and lumefantrine.

For parasites from travellers returning from right across Africa we have now gathered evidence and parasite genoptype information for more than 32 cases of ACT treatment failure in patients with P. falciparum infections. Where long-term ex vivo parasite culture was possible, we are assessing the in vitro susceptibility of these treatment failure isolates, and also obtaining whole genome sequence in each case.

5) In vitro drug susceptibility of P. knowlesi, P. malariae and P. ovale spp.

The Medicines for Malaria Venture (MMV) supporting work by Don van Schalkwyk, together with the lab of LSHTM colleague Dr Robert Moon, in which we have successfully established robust in vitro susceptibility assays for the zoonotic parasite P. knowlesi. We have used this to screen investigational lead compounds for activity against other non-falciparum malaria, and have identified important differences in drug susceptibility among the six human parasite species, supported by ground-breaking inter-species orthologue replacement experiments in P. knowlesi.

6) EDCTP-funded studies of ACT therapy for children with malaria in West Africa

The WANECAM II consortium, coordinated by Prof Abdoulaye Djimde in Bamako, builds on the previous work of WANECAM. We have EDCTP funding to provide molecular analyses of clinical trials of the new drug co-formulation KAF156 (ganaplacide) plus lumefantrine, being trialled in several west African countries. Julian Muwanguzi-Karugaba is our lead on this work, and has generated a full dataset by qPCR of parasite density dynamics in the first trial (KALUMI).