Periodic Reporting for period 4 - MalPar.NET (Malaria Parasite Networking: Discovering Modes of Cell-Cell Communication)
Période du rapport: 2022-04-01 au 2023-09-30
Parasitic diseases continue to afflict millions of people globally. Hence, revealing new mechanisms that parasites utilize to advance their growth is essential for fighting the transmission of infectious diseases, particularly malaria, which almost half the world’s human population is at high risk of contracting.
Extracellular vesicles (EVs) provide a central mechanism of cell–cell communication. While EVs are found in most organisms, their pathogenesis-promoting roles in parasites are of particular interest given the potential for medical insight and consequential therapeutic intervention. Yet, a key features of EVs in human parasitic protozoa remain elusive: their roles and mechanisms of biogenesis.
In this ERC project, we study the roles of malaria-secreted EVs in two main host systems: I) Their direct and most essential host cells, the human Red Blood Cells (RBCs); and
II) Human immune cells as monocytes.
I) Studying the role of EVs in RBC hosts: we purified vesicles from malaria-infected (i) RBCs and introduced them to naïve RBCs. We then explored how these EVs rewire human RBCs to make them more amenable to parasite invasion.
II) Immune defense systems have evolved to protect the host from microbial invasion by detecting pathogen-derived material and responding through signaling cascades. At the same time, pathogens have developed an arsenal of strategies, including EVs, to evade and manipulate the immune response. We have provided evidence that
EVs released by the malaria parasite Plasmodium falciparum contain RNA and parasitic gDNA. We have further found that the parasites while growing inside RBCs use these EVs to engage host cytosolic innate immune cell receptors from a distance. Upon internalization by monocytes, the EVs' genetic cargo is released within the cell cytosol, leading to molecular alterations of the immune system, most probably as a decoy mechanism to confuse the immune response. We are currently studying the underlying molecular mechanism of this immune alteration.
Extracellular vesicles (EVs) provide a central mechanism of cell–cell communication. While EVs are found in most organisms, their pathogenesis-promoting roles in parasites are of particular interest given the potential for medical insight and consequential therapeutic intervention. Yet, a key features of EVs in human parasitic protozoa remain elusive: their roles and mechanisms of biogenesis.
In this ERC project, we study the roles of malaria-secreted EVs in two main host systems: I) Their direct and most essential host cells, the human Red Blood Cells (RBCs); and
II) Human immune cells as monocytes.
I) Studying the role of EVs in RBC hosts: we purified vesicles from malaria-infected (i) RBCs and introduced them to naïve RBCs. We then explored how these EVs rewire human RBCs to make them more amenable to parasite invasion.
II) Immune defense systems have evolved to protect the host from microbial invasion by detecting pathogen-derived material and responding through signaling cascades. At the same time, pathogens have developed an arsenal of strategies, including EVs, to evade and manipulate the immune response. We have provided evidence that
EVs released by the malaria parasite Plasmodium falciparum contain RNA and parasitic gDNA. We have further found that the parasites while growing inside RBCs use these EVs to engage host cytosolic innate immune cell receptors from a distance. Upon internalization by monocytes, the EVs' genetic cargo is released within the cell cytosol, leading to molecular alterations of the immune system, most probably as a decoy mechanism to confuse the immune response. We are currently studying the underlying molecular mechanism of this immune alteration.
The ERC project aimed to uncover the cell communication mechanisms employed by malaria parasites (Plasmodium falciparum) to govern their survival within human host cells.
In our current research, we 1) have focused on investigating the roles of parasite-derived extracellular vesicles (EVs) and 2) have delved into an unexplored mechanism for the release of small molecules as a mode of signaling. Our work has already yielded new discoveries on parasite-host interaction mechanisms and developed the necessary tools to study how parasitic-derived EVs impact human red blood cells and the human immune system.
In our current research, we 1) have focused on investigating the roles of parasite-derived extracellular vesicles (EVs) and 2) have delved into an unexplored mechanism for the release of small molecules as a mode of signaling. Our work has already yielded new discoveries on parasite-host interaction mechanisms and developed the necessary tools to study how parasitic-derived EVs impact human red blood cells and the human immune system.
By accomplishing this ERC project, we (i) provided a pioneering view of the facilitating role of the secreted EVs in parasite invasion into its essential host, the human RBCs (e.g. Dekel et al, Nature Com, 2021) (ii) identified genetic material that contribute to immunity crosstalk, we also discovered a new decision-sensing mechanism employed by the parasites and (e.g. Ofir-Birin el al, Nature Com. 2021) (iii) gained an in-depth understanding of the molecular events that activate parasite and host responses (e.g. Abo Karam et al, EMBO R, 2022). By that, we have provided an innovative perspective of the under-investigated area of parasite sensing and signaling pathways and decipher the multiple layers of parasite and host signaling networks.