Funktionelle Charakterisierung von Ago2, einem Erythrozyten-Wirtsprotein, das in den Plasmodium-Parasiten aufgenommen wird.
Zusammenfassung der Projektergebnisse
Plasmodium parasites are causing one of the most devastating infectious diseases, malaria. Being transmitted by mosquitoes and after an initial infection of liver cells, Plasmodium parasites invade red blood cells and multiply rapidly, causing the typical symptoms of malaria, anaemia and fever. While there are treatments available, parasites rapidly develop resistance, and it is thus important to continue to identify novel drug targets. Drugs targeting host proteins essential for parasite development offer the advantage that the parasite cannot mutate them to develop resistance. However, only little is known about host proteins required for malaria parasite development. Recent reports have suggested that the host protein Argonaute 2 (Ago2) is found inside the parasite. Ago2 is a key protein of the RNA interference pathway, which regulates the expression of genes in many animal cells, including humans. This pathway is however absent in Plasmodium cells, prompting the hypothesis that Plasmodium utilises host Ago2 for this purpose. During the DFG fellowship, I followed up those initial observations and investigated if host Ago2 is imported into Plasmodium cells and if it is a host factor utilised by the parasite. To this end, I used two independent experimental approaches to determine if host Ago2 is found inside of the parasite. In summary, both approaches demonstrated that Ago2 does not localise to the parasite. Previously reported findings are likely to be due to unspecific binding of the reagents to an unknown parasite protein. In addition, chemical inhibition of Ago2 did affect neither parasite development in the red blood cell, nor commitment to the sexual stages which are infectious to mosquitoes. These findings contradicted the initial hypothesis, leading to the conclusion that host Ago2 is not relevant for parasite development in the red blood cell. To communicate these negative data to the scientific community, we have published these findings in a peer-reviewed journal. While I have shown that Plasmodium does not rely on host Ago2, further studies are needed to identify other host factors that might be essential for parasite development.
Projektbezogene Publikationen (Auswahl)
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N. Wellcome Open Res 2020, 5:92o evidence for Ago2 translocation from the host erythrocyte into the Plasmodium parasite
Hentzschel F, Obrova K and Marti M
