Joshua Tan Hoong Yu
I am a Henry Wellcome Postdoctoral Fellow and have a project that is divided between the Newbold laboratory at the WIMM, the Institute for Research in Biomedicine in Bellinzona, and the National Institutes of Health in the United States. My main research interest lies in investigating the antibody response to different stages of the life cycle of the malaria-causing parasite Plasmodium falciparum. Specifically, I am interested in the sporozoite and infected erythrocyte stages. Sporozoites are injected by mosquitoes to initiate a malaria infection, while parasite division in the blood causes malaria symptoms. Antibodies against both stages have been associated with protection against malaria infection or symptoms, but little is known about the function and targets of these antibodies at the monoclonal level.
The main goal of my project is to identify and characterize monoclonal antibodies from individuals living in malaria-endemic areas who have been pre-selected for interesting antibody responses to P. falciparum. I have gained experience in this field during my DPhil (supervised by Peter Bull and Kevin Marsh), which aimed to investigate the antibody response of adults living in a malaria-endemic area in Kilifi, Kenya, to the surface of P. falciparum-infected erythrocytes. I spent a year in Kilifi and identified several Kenyan adults who made unusual cross-reactive antibody responses against P. falciparum-infected erythrocytes. To investigate this response at the monoclonal antibody level, I moved to the laboratory of Antonio Lanzavecchia at the Institute for Research in Biomedicine. There, we found that the broad reactivity of these antibodies was mediated by the insertion of a DNA fragment from a gene called LAIR1 (which is located on a different chromosome) into the antibody locus. We also identified the antigens targeted by these antibodies as RIFINs, which are a group of clonally variant proteins expressed on P. falciparum-infected erythrocytes. This represents a novel mechanism of antibody diversification that appears to occur at a relatively high frequency (5-10%) in individuals living in malaria-endemic areas.
I am also currently characterizing antibodies from protected volunteers in a malaria vaccine clinical trial that target the circumsporozoite protein (CSP), which is an immunodominant antigen that coats the sporozoite surface. Part of this protein is used in the most advanced malaria vaccine candidate so far, RTS,S, but we have found that a group of highly functional antibodies recognize a part of CSP that is not included in the vaccine. I am planning to continue investigating the function of these antibodies and their target epitope, as well as to follow up on the identification of more broadly reactive antibodies against P. falciparum-infected erythrocytes.
A public antibody lineage that potently inhibits malaria infection through dual binding to the circumsporozoite protein
Tan J. et al, (2018), Nature Medicine, 24, 401 - 407
Public antibodies to malaria antigens generated by two LAIR1 insertion modalities.
Pieper K. et al, (2017), Nature, 548, 597 - 601
A LAIR1 insertion generates broadly reactive antibodies against malaria variant antigens.
Tan J. et al, (2016), Nature, 529, 105 - 109