Comparative Flavivirus-host protein interaction mapping to reveal mechanisms of Dengue and Zika virus pathogenesis

Written by Dr Vinod Balasubramaniam, Jeffrey Cheah School of Medicine and Health Sciences

Mosquito-borne Flaviviruses, including dengue virus (DENV) and Zika virus (ZIKV), are a growing public health concern. Host cellular machinery plays a vital role in the survival of viruses. The outcome of infection is determined by complex host-virus interactions with a large number of altered transcriptional and translational rates, and functional kinetics of participating genes.

To date, the first-hand information on the molecular changes in the host induced by the virus to promote its replication and also the pathways triggered in the host that result in immunity and or clearance of the viral infection are still lacking.

Having insights into the host's responses to viruses would help define targets for therapeutic intervention. Systems level analysis of how Flaviviruses hijack cellular processes through virus-host protein-protein interactions (PPIs) provide information about their replication and pathogenic mechanisms. We used various techniques to compare Flavivirus-host interactions for two viruses (DENV and ZIKV) in two hosts (human and mosquito).

Conserved virus-host PPIs revealed various host factors important for Flavivirus life cycle which is vital information that can be used for future drug design or discovery of novel biologics that can be used against these viruses. Thus, comparative Flavivirus-host PPI mapping has provided biological insights, and when coupled with in vivo models, can be used to unravel pathogenic mechanisms.

Impact of work in Malaysia

Being a tropical country, Malaysia remains a “hotbed’ for various viruses, especially Flaviviruses which can cause a fully blown epidemic as demonstrated by worldwide spread of Zika virus. Establishment of research “niche” involving cross-talks between different “Omics” to better understand the fundamental strategy used by these viruses to replicate and overcome host defence mechanism.

The recent worldwide epidemic of Zika virus illustrates the importance of Flaviviruses as an emerging human pathogen. Some of the factors contributed to the spread of this virus which is transmitted by Aedes species mosquitoes include urbanisation and globalisation leading to higher international mobility. The severity of Zika virus fever leading to many new neurological phenomena in particular towards newborns and the ability of the virus to spread to new regions previously not known for Flavivirus infection has led to a strong interest in developing novel strategies for the prevention and treatment of Zika virus induced disease.

Some of the questions we hope to answer through our work:

  • How did this virus acquire the ability to induce severe neuropathogenesis in cases involving pregnant woman and their fetus? i.e. microcephaly?
  • How Zika virus “communicates” with host proteins to induce disease?
  • Cross-talk between the virus and various hosts i.e. human, mosquitoes have been fully mapped, revealing key proteins of the virus which is responsible for innate immunity antagonism, neuropathogenesis and replication in mosquitoes.

Where do we go from here?

Vector-borne Flavivirus infection has been constant threat to public health for decades. In particular, the recently caused epidemic by Zika virus should be a lesson to us on how lethal the virus could manifest especially in introducing neurological complications in humans. Through this study, we may discover potential anti-virals or drugs targeting that particular protein which is necessary for viral survival. For instance, mapping of the particular domain of Zika virus NS5 interacting with human STAT2 could reveal amino acids which are necessary for interaction.

This would allow us to generate recombinant Zika virus with NS5 mutant which won’t be able to bind and degrade STAT2 such recombinant viruses could still be grown in interferon deficient cell lines, such as Vero cells, and used as live-attenuated vaccines if proven safe and immunogenic. Apart from that, chemical modulation of SEC61 translocon, inhibits both Dengue and Zika replication. Further modifications on delivery systems of the drug can also be investigated.

Collaborators: This research is a collaborative effort between researchers from University of California San Francisco, Mount Sinai Hospital, New York, Jan and Dan Duncan Neurological Research Institute, Houston, Texas, Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas, University of Pennsylvania, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Chan-Zuckerberg Biohub, San Francisco and Fundación Instituto Leloir-CONICET, Buenos Aires, Argentina.