Summary - Host-directed therapy (HDT) is gaining traction as a strategy to combat infectious diseases. It provides (i) untapped targets to limit cross-resistance to existing antimicrobials, and (ii) reduced susceptibility to the emergence of de novo resistance, as the selection of pathogen genotypes encoding drug-insensitive mutated targets cannot occur. Host cell signaling protein kinases have proven druggability in the context of cancer, and we propose that host cell kinases required for the replication of pathogens (including malaria parasites) are attractive targets for HDT.
We have recently implemented an antibody microarray-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 pathways by infections. We first provided proof of principle, using a Hepatitis 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 receptor as a mediator of the block of viral superinfection in mosquitoes infected by Wolbachia (2), and to show that a small molecule inhibitor of the insulin receptor impairs Zika virus replication in live mosquitoes, further establishing the power of the approach. We have now completed a system-wide study of host erythrocyte response to infection with the malaria parasite Plasmodium falciparum and identified several human kinases that are activated by infection; furthermore, inhibitors against some of these kinases display high potency against parasite proliferation in vitro (3).
We were unable to raise resistant parasite lines against some of these inhibitors, validating that notion that targeting the 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 for this compound. Unexpectedly, some of the Trametinib-resistant lines are dependent on the presence of the inhibitor for optimal growth, suggesting that the inhibitor interferes with a host cell defense mechanism against the parasite.
Several of the host kinases required for Plasmodium proliferation in erythrocytes are 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 broad-spectrum anti-infective based on inhibitors of selected kinases.
1. Haqshenas G, Wu J, Simpson KJ, Daly RJ, Netter HJ, Baumert TF, Doerig C. (2017) Signalome-wide assessment of host cell response to hepatitis C virus. Nature Communications 8:15158. doi: 10.1038/ncomms15158
2. Haqshenas G, Terradas G, Paradkar PN, Duchemin JB, McGraw EA, Doerig, C. (2019) A Role for the Insulin Receptor in the Suppression of Dengue Virus and Zika Virus in Wolbachia-Infected Mosquito Cells. Cell Reports 26(3):529-535.e3.
3. Adderley et al., under review
4. Haqshenas &Doerig (2019) Targeting of host cell receptor tyrosine kinases by intracellular pathogens. Science Signaling 12:599
Biography - Christian Doerig obtained his PhD in molecular virology at the University of Lausanne, Switzerland. He then pioneered the study of phosphosignalling in the human malaria parasite Plasmodium falciparum, and is a recognised leader in this field. He initiated and coordinated several large EU-funded international consortia in malaria research which involved partners in Europe, India and Africa. His current research includes the host cell signaling response to various intracellular pathogens, with the purpose of developing Host-Directed Therapy against infectious diseases.
He is "Directeur de Recherches" (on secondment) at the French government biomedical research agency Inserm, Honorary Professor of the University of Glasgow, Scotland and Adjunct Professor at Monash University, Melbourne. He established the first international Inserm units in the UK at the Wellcome Trust Centre for Molecular Parasitology (Glasgow), and subsequently in Switzerland at Ecole Polytechnique Fédérale de Lausanne (EPFL).
In 2011, he joined Monash University as Head of the Department of Microbiology (2011-2015) and Professor of Microbiology (2011-2019). He holds a Swiss degree in science education, and after coming to Australia has contributed to teaching innovation initiatives, some of which, such as Duet Lectorials spanning complementary disciplines, have been communicated at international teaching conferences.
In 2019 he took on the position of Associate Dean for the Biomedical Sciences Cluster at RMIT University, where he pursues both his research on the kinomics of infection and his efforts in silo-breaking teaching approaches.