Duraisingh Lab
Our laboratory investigates various facets of the biology of host-parasite interactions during malaria blood-stage infections. We use several experimental approaches to identify critical molecules and pathways with the goal of informing vaccine and drug development.
Harvard T. H. Chan School of Public Health
651 Huntington Avenue
FXB Building, Room 205
Boston, Massachusetts 02115
Malaria and the Red
Blood Cell
Elucidating Malaria Biology to Inform Therapeutics
Malaria remains a formidable global health problem with over 250 million cases each year and half a million deaths, and is a major contributor to childhood and maternal morbidity and mortality. Our laboratory studies the biology of host-parasite interactions during malaria blood-stage infections. We are defining parasite and red blood cell determinants used for invasion, intracellular growth, pathogenesis and transmission of these debilitating human pathogens. While we have a historical focus on P. falciparum, significant efforts are being made in the study of P. vivax, P. knowlesi, and Babesia spp.
To explore biological questions in both the lab and the field, we develop and use a variety of experimental approaches. We rely on reverse and forward genetics, combined with cell biology, chemical biology and computational approaches, focused on both parasites and their host red blood cells. The identification of critical molecules and pathways can inform vaccine and drug development.
Research Themes
Ligand-Receptor Interactions
Invasion pathways of Plasmodium spp. Parasites into host red-blood cells involve specific ligand-receptor interactions, many of which are unidentified. A direct focus on identifying host determinants of infection represents a novel approach for elucidating critical host-pathogen interactions.
Determinants of Host Cell Tropism
We are interested in identifying the molecular basis of the tropism of Plasmodium spp. parasites for different primate species, to explore the potential for cross-species transmission to humans, and define the molecular changes that facilitated the emergence of the extant human malaria parasites.
Worldwide Impact, Studies, and Collaboration
An important facet of our research is the ability to understand the significance of our laboratory findings with clinical isolates through collaborations with researchers in malaria endemic regions. We collaborate with institutions in India, Panama, Senegal, and other countries for our field studies.
Our Research Projects
Plasmodium invasion biology: ligand-receptor interactions and signal transduction
A major focus of our laboratory has been the elucidation of the mechanism by which Plasmodium parasites invade host red blood cells (RBCs), within which they proliferate or become transmissible sexual forms. Invasion occurs via a complex mechanism, with many features unique to apicomplexan parasites, beginning with attachment to the host RBCs, followed by the formation of a tight junction, active entry into the RBC and resolution of the parasitophorous vacuole (PV). Entry involves multiple and specific ligand-receptor interactions, which are known as invasion pathways. The merozoite surface is directly exposed to host immunity making invasion ligands potential candidates for vaccine development.
We are working to identify specific ligand-receptor interactions in different Plasmodium spp. to inform vaccine development and to understand the biological implications of the use of alternative ligand-receptor pairs, known as invasion pathways.
Red blood cell determinants of malaria infection: invasion, trafficking, growth and sexual development
We have developed in vitro genetic approaches for the identification of critical red blood cell genes involved in malaria infection, providing new tools to study the host determinants of interactions with malaria pathogens. Using a culture system to differentiate erythroid progenitors and targeted lentivirus-based methods for nuclear DNA targeting, we undertake forward genetic screens to identify red blood cell determinants of multiple aspects of malaria infection, including invasion, growth, protein trafficking and sexual development.
Malaria has imposed a major selective pressure on human evolution, with adaptations evident in genetic changes. The most well-known changes in human proteins found in malaria endemic populations result in red blood cell disorders.
Epigenetic regulation of virulence gene expression and sexual development in malaria parasites
Our laboratory has a long-standing interest in the regulation of variant expression of virulence gene families in P. falciparum. The mechanistic basis for how a parasite persists in human infections, evades the immune system, and switches from asexual proliferation to sexual development for transmission has been determined to involve epigenetic regulation of transcriptional pathways. Our current studies aim to establish a comprehensive functional understanding of the role of P. falciparum proteins involved in epigenetic regulation with a particular focus on histone deacetylases. These studies involve a combination of parasite genetics, transcriptomics, proteomics and single-cell approaches.
Zoonotic Infections of Plasmodium spp. and Babesia spp.
We are interested in identifying the molecular basis of the tropism of Plasmodium spp. parasites for different primate species in order to explore the potential for cross-species transmission to humans, and define the molecular changes that facilitated the emergence of the extant human malaria parasites.
We have established the zoonotic primate malaria parasite, P. knowlesi, as an in vitro model to study red blood cell invasion via detailed imagine and forward genetics approaches.
We have initiated studies of the biology of Babesia spp., that are evolutionarily closely related to Plasmodium spp.. Several Babesia spp. can be robustly cultured in vitro and we have established genetic methods for their functional analysis using genetics and chemical genetics.
Biology and determinants of in vitro proliferation of Plasmodium vivax
Unlike P. falciparum, P. vivax infections can persist in the liver, making this understudied parasite a great public health concern. Due to a lack of in vitro culture systems for P. vivax, there are extensive knowledge gaps in its mechanisms of infection.
P. vivax is limited to the invasion of reticulocytes. We are focused on identifying the ligand-receptor interactions which result in reticulocyte tropism, and to characterize those with potential for vaccine development. We are using cryopreserved isolates in Boston and India to facilitate the long-term goal of establishing in vitro P. vivax culture.
Publication Highlights
Recently Published Transposon Dataset
The data has been generated by the Duraisingh Lab and our collaborators and deposited in an online repository, so it can be used by the entire malaria community.
