BEGIN:VCALENDAR
VERSION:2.0
PRODID:-//Memento EPFL//
BEGIN:VEVENT
SUMMARY:The host cell signalome as a target for chemotherapy of infectious
  diseases
DTSTART:20200130T140000
DTEND:20200130T150000
DTSTAMP:20260503T221511Z
UID:ffd62a4555b73cae681af4e19b8fe597f63006c7bcdc86948221f226
CATEGORIES:Conferences - Seminars
DESCRIPTION:Christian DOERIG\, School of Health and Biomedical Sciences\, 
 RMIT University\, Australia\nHost-directed therapy (HDT) is gaining tracti
 on as a strategy to combat infectious diseases. It provides (i) untapped t
 argets to limit cross-resistance to existing antimicrobials\, and (ii) red
 uced susceptibility to the emergence of de novo resistance. Protein kinase
 s have proven druggability in the context of cancer chemotherapy\, and we 
 propose that host cell kinases required for the replication of pathogens a
 re attractive targets for HDT.\nWe have recently implemented an antibody m
 icroarray-based approach to systematically assess the host cell signalling
  response to intracellular pathogens\; most of the antibodies on the array
  are phospho-specific\, allowing to monitor the activation of signalling p
 athways by infections. We first provided proof of principle\, using a Hepa
 titis C virus/ hepatocyte model\, that this can lead to the identification
  of druggable host targets (protein kinases) and lead molecules to prevent
  infection (1). We also used this technology to identify the Insulin recep
 tor as a mediator of the block of viral superinfection in mosquitoes infec
 ted by Wolbachia (2)\, and to show that a small molecule inhibitor of the 
 insulin receptor impairs Zika virus replication in live mosquitoes. \nWe 
 have now completed a system-wide study of host erythrocyte response to inf
 ection with the malaria parasite Plasmodium falciparum and identified seve
 ral human kinases that are activated by infection\; furthermore\, inhibito
 rs against some of these kinases display high potency against parasite pro
 liferation in vitro (3). We were unable to raise resistant parasite lines 
 against some of these inhibitors\, validating that notion that targeting t
 he host limits the ability of the parasite to develop resistance. However\
 , resistance against Trametinib\, an inhibitor of the host cell kinase MEK
 \, appeared rapidly\, suggesting there is a parasite-encoded off-target fo
 r this compound.  Unexpectedly\, some of the Trametinib-resistant lines h
 ave become addicted to the inhibitor\, suggesting that the inhibitor inter
 feres with a host cell defense mechanism against the parasite.\nSeveral of
  the host kinases required for Plasmodium proliferation in erythrocytes ar
 e also implicated in the replication of other pathogens\; for example\, c-
 MET is implicated in infections with Plasmodium\, the bacterium Listeria\,
  as well as Influenza and Ebola viruses (4). This raises the prospect of b
 road-spectrum anti-infective based on inhibitors of selected kinases.\n\n1
 . Haqshenas G\, Wu J\, Simpson KJ\, Daly RJ\, Netter HJ\, Baumert TF\, Doe
 rig C. (2017) Signalome-wide assessment of host cell response to hepatitis
  C virus. Nature Communications 8:15158. doi: 10.1038/ncomms15158\n2. Haqs
 henas G\, Terradas G\, Paradkar PN\, Duchemin JB\, McGraw EA\, Doerig\, C.
  (2019)  A Role for the Insulin Receptor in the Suppression of Dengue Vir
 us and Zika Virus in Wolbachia-Infected Mosquito Cells.  Cell Reports 26(
 3):529-535.e3.\n3. Adderley et al.\, under review\n4. Haqshenas &Doerig (2
 019) Targeting of host cell receptor tyrosine kinases by intracellular pat
 hogens. Science Signaling 12:599
LOCATION:SV 1717 https://plan.epfl.ch/?room==SV%201717
STATUS:CONFIRMED
END:VEVENT
END:VCALENDAR