Unravelling mechanisms of stage conversion in malaria parasites
Malaria parasites have co-evolved with humans over thousands of years, mirroring their migration out of Africa. They persist to this day, despite continuous elimination efforts worldwide. It is proposed that this is because the parasites can adapt to changes within their host and between hosts, thus regulating investment into growth versus transmission. Studies in the major human malaria parasite, P. falciparum, show that such adaptation can be regulated epigenetically.
However, there is also increasing evidence for hardwired factors (i.e., genes) that determine differences in the investment into growth versus transmission between parasite strains. The work proposed here aims to identify these genetic determinants and thus define the parasite pathways that regulate the balance between growth and transmission in response to environmental cues.
Funding: Wellcome Trust (UK)
Collaborators: Thomas Otto (University of Glasgow, Glasgow, UK), Ashley Vaughan (Seattle Children’s, Seattle, USA), John Adams (University of South Florida, Tampa, USA)
Malaria: A cell atlas of host parasite interactions in the haematopoietic niche
Malaria is a major life-threatening infectious disease in humans, with over 400,000
fatalities per year. Whereas Plasmodium falciparum dominates in sub-Saharan Africa, Plasmodium vivax is responsible for most cases in many regions of Asia and South America. The past decade has seen a drastic reduction in malaria cases and deaths worldwide, however drug resistance in both parasite and vector species is spreading.
We have identified bone marrow and spleen as a major reservoir for parasite infection and the only site of transmission stage development in P. falciparum and P. vivax. Parasites accumulate and develop in particular in the reticulocyte-rich extravascular environments, i.e., the hematopoietic niche of these organs. This discovery establishes a new paradigm in parasite biology, similar to the identification of the liver cycle in 1948. Infection of this niche contributes to clinical manifestations such as anaemia, thrombocytopenia and splenomegaly, and it has major effects on the host immune response.
We demonstrate that the hematopoietic niche is the major parasite reservoir in reticulocyte-restricted species such as Plasmodium vivax and P. berghei. In fact, many known features are conserved across Plasmodium. I propose an ambitious research programme combining genetics, single cell transcriptomics, multi-parameter tissue imaging (CyTOF), and in vivo and ex vivo phenotyping to establish a functional and spatial map of the host parasite interplay in the hematopoietic niche. Performing experiments in samples directly sourced from human infection provides a direct path to translation, while parallel in vitro investigations enable mechanistic analysis.
Our study has implications for translation, including diagnostics and interventions to block transmission, reducing severe disease, and modifying the immune response.
Funding: Schweizerischer Nationalfonds
Collaborators: Christopher Moxon (Malawi-Liverpool Wellcome Clinical Research, Kamuzu University of Health Sciences, Blantyre, Malawi and University of Glasgow, UK), Thomas Otto (University of Glasgow, Glasgow, UK), Kevin Couper (University of Manchester, Manchester, UK)
Defining the role of the hematopoietic parasite reservoir in Plasmodium vivax infection and pathology
Plasmodium vivax is the most widely distributed malaria parasite and a major public health burden. Recent studies suggest that the majority of parasites is present outside of circulation, making it difficult to track and target them. We have demonstrated that bone marrow in particular represents an underappreciated reservoir which supports P. vivax growth and differentiation to transmission stages. Parallel studies have also reported major parasite accumulation in the spleen. Based on these findings we hypothesize that the haematopoietic niche of bone marrow and spleen represents the main parasite reservoir during infection and drives disease severity. In this ambitious research program, we will analyze infected bone marrow and spleen tissue from a series of cohorts of naturally exposed patients in endemic areas in Brazil. We will perform histological, molecular and phenotypic characterization of sequestered and circulating parasite and host cell populations to systematically investigate and quantify the role of bone marrow and spleen for parasite infection, transmission, diagnosis and pathology. This work will thus contribute much needed insights and critical tools for the ongoing global malaria elimination campaign.
Funding: Medical Research Council (UK) and FAPESP (Sao Paulo, Brazil)
Collaborators: Fabio Costa (University of Campinas, Campinas, Brazil), Marcus Lacerda (Tropical Medicine Foundation, Manaus, Brazil), Thomas Otto (University of Glasgow, Glasgow, UK), Kevin Couper (University of Manchester, Manchester, UK)
Utilizing gametocyte immunity to reduce malaria transmission
The continuing success of the current malaria elimination campaign requires novel tools to efficiently block human infection and subsequent transmission of the parasite to mosquitoes. Current transmission blocking strategies target the development of the parasite in the mosquito stage, requiring complicated mosquito feeding readouts to measure efficacy. We recently identified the bone marrow as the major site of transmission stage development during infection. Based on this finding we hypothesized that the underlying host parasite interactions could be exploited to block parasite transmission. Indeed, our preliminary studies demonstrates natural immune responses against parasite surface antigens and their functionality in terms of immune clearance. Here we utilize this new understanding to systematically define the immunity targeting malaria transmission with the ultimate goal of prioritizing a set of novel transmission blocking vaccine candidates.
Funding: Medical Research Council (UK)
Collaborators: Teun Bousema and Mathijs Jore (Radboud University, Nijmegen, the Netherlands), Chris Drakeley (LSHTM, London, UK), Josh Tan (NIH, Bethesda, USA), Lauren Cohee (University of Maryland, College Park, USA, Blantyre Malaria Project, College of Medicine, Blantyre, Malawi)