Dekel E., Yaffe D., Rosenhek-Goldian I., Ben-Nissan G., Ofir-Birin Y., Morandi M. I., Ziv T., Sisquella X., Pimentel M. A., Nebl T., Kapp E., Ohana Daniel Y., Karam P. A., Alfandari D., Rotkopf R., Malihi S., Temin T. B., Mullick D., Revach O. Y., Rudik A., Gov N. S., Azuri I., Porat Z., Bergamaschi G., Sorkin R., Wuite G. J., Avinoam O., Carvalho T. G., Cohen S. R., Sharon M. & Regev-Rudzki N.
(2021)
Nature Communications.
12,
1,
1172.
Mature red blood cells (RBCs) lack internal organelles and canonical defense mechanisms, making them both a fascinating host cell, in general, and an intriguing choice for the deadly malaria parasite Plasmodium falciparum (Pf), in particular. Pf, while growing inside its natural host, the human RBC, secretes multipurpose extracellular vesicles (EVs), yet their influence on this essential host cell remains unknown. Here we demonstrate that Pf parasites, cultured in fresh human donor blood, secrete within such EVs assembled and functional 20S proteasome complexes (EV-20S). The EV-20S proteasomes modulate the mechanical properties of naïve human RBCs by remodeling their cytoskeletal network. Furthermore, we identify four degradation targets of the secreted 20S proteasome, the phosphorylated cytoskeletal proteins β-adducin, ankyrin-1, dematin and Epb4.1. Overall, our findings reveal a previously unknown 20S proteasome secretion mechanism employed by the human malaria parasite, which primes RBCs for parasite invasion by altering membrane stiffness, to facilitate malaria parasite growth.
Sisquella X., Ofir-Birin Y., Pimentel M. A., Cheng L., Abou Karam P., Sampaio N. G., Penington J. S., Connolly D., Giladi T., Scicluna B. J., Sharples R. A., Waltmann A., Avni D., Schwartz E., Schofield L., Porat Z., Hansen D. S., Papenfuss A. T., Eriksson E. M., Gerlic M., Hill A. F., Bowie A. G. & Regev-Rudzki N.
(2017)
Nat Commun.
8,
1,
1985.
STING is an innate immune cytosolic adaptor for DNA sensors that engage malaria parasite (Plasmodium falciparum) or other pathogen DNA. As P. falciparum infects red blood cells and not leukocytes, how parasite DNA reaches such host cytosolic DNA sensors in immune cells is unclear. Here we show that malaria parasites inside red blood cells can engage host cytosolic innate immune cell receptors from a distance by secreting extracellular vesicles (EV) containing parasitic small RNA and genomic DNA. Upon internalization of DNA harboring EVs by human monocytes, P. falciparum DNA is released within the host cell cytosol, leading to STING-dependent DNA sensing. STING subsequently activates the kinase TBK1, which phosphorylates the transcription factor IRF3, causing IRF3 to translocate to the nucleus and induce STING-dependent gene expression. This DNA-sensing pathway may be an important decoy mechanism to promote P. falciparum virulence and thereby may affect future strategies to treat malaria.
Regev-Rudzki N., Wilson D. W., Carvalho T. G., Sisquella X., Coleman B. M., Rug M., Bursac D., Angrisano F., Gee M., Hill A. F., Baum J. & Cowman A. F.
(2013)
Cell.
153,
5,
p. 1120-1133
Cell-cell communication is an important mechanism for information exchange promoting cell survival for the control of features such as population density and differentiation. We determined that Plasmodium falciparum-infected red blood cells directly communicate between parasites within a population using exosome-like vesicles that are capable of delivering genes. Importantly, communication via exosome-like vesicles promotes differentiation to sexual forms at a rate that suggests that signaling is involved. Furthermore, we have identified a P. falciparum protein, PfPTP2, that plays a key role in efficient communication. This study reveals a previously unidentified pathway of P. falciparum biology critical for survival in the host and transmission to mosquitoes. This identifies a pathway for the development of agents to block parasite transmission from the human host to the mosquito.
