As part of the Malaria Centre’s monthly anniversary feature, this issue focusses on how research from members of the Centre have contributed to developing our understanding of malaria parasite biology and host biology. By presenting specific examples we show how the research contributes to, and underpins, our understanding of malaria control.

Parasite Biology

Malaria Centre research teams have focused on numerous exciting aspects of malaria parasite biology over the last 20 years. Many of the breakthroughs have been made possible by huge technical advances such as our ability to perform whole genome sequencing and reverse genetics.

Highlights include involvement in the discovery that the simian malaria parasite, P. knowlesi, is also a serious infection of humans. Rob Moon has adapted this species for laboratory growth in human red blood cells¹, which will greatly facilitate our efforts to understand this zoonotic infection (being able to transmit from animals to humans). Colin Sutherland’s team discovered that another human malaria parasite, P. ovale, actually comprises two separate species², which they discerningly named after two distinguished malaria researchers, Chris Curtis and David Walliker. David Conway’s group have capitalised on whole genome sequencing technology to extend their pioneering work on defining signatures of selection³ in P. falciparum genes to guide vaccinologists. Hans Dessens’ work on rodent malaria cell biology has revealed important information on the enigmatic ‘crystalloid body’, which is a key morphological feature⁴ of the motile ookinete that establishes infection in the mosquito vector. An international partnership involving the Baker/Clark/Campino groups identified a transcriptional regulator (AP2-G) that controls the switch to gametocyte formation⁵, which has paved the way for a mechanistic understanding of sexual differentiation.

Host Biology

In parallel to the advances made in malaria parasite biology, landmark studies spearheaded by members of the LSHTM Malaria Centre have also contributed to a better understanding of the host immune response to malaria infection, as well as mechanisms underlying the development of severe disease.

Experimental studies of malaria-salmonella co-infection by Aubrey Cunnington, for example, have revealed malaria-induced defects in neutrophil (a type of immune cell) function. This is the underlying cause of the well-documented association between malaria infection and subsequent invasive, non-typhoidal salmonella bacteremia⁶. This work has prompted ongoing investigations by Eleanor Riley’s group into the role of persistent, subclinical malaria infections in sub-Saharan Africa, where there is high-burden invasive bacterial disease⁷. Over the past 20 years, immunologists at LSHTM have provided pivotal information on the immune mechanisms influencing the development of severe malaria outcomes. This includes work by Kevin Couper, Brian de Souza and Julius Hafalla, which underscored the importance of timely regulation of the proinflammatory response (by TGF-beta-secreting myeloid cells and IL-10-secreting CD4+ T cells) to prevent immunopathology⁸. Most recently, neuroimaging of Indian cerebral malaria patients by Sam Wassmer’s group has showed for the first time that brain swelling during acute disease results from two distinct mechanisms: vasogenic oedema, which occurs when the blood-brain barrier is compromised, and vascular congestion due to sequestration of parasitised red blood cells⁹.

Collectively, these studies – and many others that cannot be listed due to space limitations – will make major contributions to reducing the incidence and severity of human malaria infections and providing a sound basis for efforts to eliminate malaria in many endemic areas.

References

1. Moon RW, Sharaf H, Hastings CH, Ho YS, Nair MB, Rchiad Z, Knuepfer E, Ramaprasad A, Mohring F, Amir A, Yusuf NA, Hall J, Almond N, Lau YL, Pain A, Blackman MJ, Holder AA. Normocyte-binding protein required for human erythrocyte invasion by the zoonotic malaria parasite Plasmodium knowlesi. Proc Natl Acad Sci U S A. 2016 Jun 28;113(26):7231-6.
2. Sutherland CJ, Tanomsing N, Nolder D, Oguike M, Jennison C, Pukrittayakamee S, Dolecek C, Hien TT, do Rosário VE, Arez AP, Pinto J, Michon P, Escalante AA, Nosten F, Burke M, Lee R, Blaze M, Otto TD, Barnwell JW, Pain A, Williams J, White NJ, Day NP, Snounou G, Lockhart PJ, Chiodini PL, Imwong M, Polley SD. Two nonrecombining sympatric forms of the human malaria parasite Plasmodium ovale occur globally. J Infect Dis. 2010 May 15;201(10):1544-50.
3. Amambua-Ngwa, A., Tetteh, K.K.A., Manske, M., Gomez-Escobar, N., Stewart, L.B., Deerhake, M.E., Cheeseman, I.H., Newbold, C.I., Holder, A.A., Knuepfer, E., Janha, O., Jallow, M., Campino, S., MacInnis, B., Kwiatkowski, D.P. & Conway, D.J. (2012) Population genomic scan for candidate signatures of balancing selection to guide antigen characterization in malaria parasites. PLOS Genetics, 8:e1002992.
4. Santos JM, Duarte N, Kehrer J, Ramesar J, Avramut MC, Koster AJ, Dessens JT, Frischknecht F, Chevalley-Maurel S, Janse CJ, Franke-Fayard B, Mair GR. Maternally supplied S-acyl-transferase is required for crystalloid organelle formation and transmission of the malaria parasite. Proc Natl Acad Sci U S A. 2016 Jun 28;113(26):7183-8.
5. Kafsack BF, Rovira-Graells N, Clark TG, Bancells C, Crowley VM, Campino SG, Williams AE, Drought LG, Kwiatkowski DP, Baker DA, Cortés A, Llinás M. A transcriptional switch underlies commitment to sexual development in malaria parasites. Nature. 2014 Mar 13;507(7491):248-52.
6. Cunnington AJ1, de Souza JB, Walther M, Riley EM. Malaria impairs resistance to Salmonella through heme- and heme oxygenase-dependent dysfunctional granulocyte mobilization. Nat Med. 2011 Dec 18;18(1):120-7.
7. Chen I, Clarke SE, Gosling R, Hamainza B, Killeen G, Magill A, O'Meara W, Price RN, Riley EM. "Asymptomatic" malaria: a chronic and debilitating infection that should be treated. PLoS Med. 2016 Jan 19;13(1):e1001942
8. Claser C, De Souza JB, Thorburn SG, Grau GE, Riley EM, Rénia L, Hafalla JCR. Host resistance to Plasmodium-induced acute immune pathology is regulated by interleukin-10 receptor signaling. Infect Immun. 2017 May 23;85(6).
9. Mohanty S, Benjamin LA, Majhi M, Panda P, Kampondeni S, Sahu PK, Mohanty A, Mahanta KC, Pattnaik R, Mohanty RR, Joshi S, Mohanty A, Turnbull IW, Dondorp AM, Taylor TE, Wassmer SC. Magnetic resonance imaging of cerebral malaria patients reveals distinct pathogenetic processes in different parts of the brain. mSphere. 2017 Jun 7;2(3)