Day 3 :
- Track 3: Potential Drug Targets Track 5: Mutation and Influenza Virus Track 11: Influenza: Alternate Treatment Methods
Hokkaido University, Japan
Professor, Hokkaido University, Japan
Time : 10:00-10:20
On October 2002, after spending 12 years in US at National Institute of Health in Bethesda (MD) and a faculty position at Harvard Medical School, I took a position as a full professor of the Institute for Genetic Medicine, Division of Cancer Biology at Hokkaido University (Sapporo, Japan). My research interest is to clarify how the balance between cell death and survival regulates in vivo homeostasis. The molecules which we are currently focusing on our effort is serine threonine kinase Akt (also known as protein kinase B, PKB), a central regulatory component of the PI3K signaling pathways, which plays a pivotal role in the regulation of cell survival and proliferation to maintain in vivo homeostasis.
The possibility of the pandemic spread of influenza viruses highlights the need for an effective cure for this life-threatening disease. Influenza A virus, belonging to a family of orthomyxoviruses is a negative-strand RNA virus which encodes 11 viral proteins. A number of intracellular signaling pathways in the host cells interact with influenza the viral proteins, which affect various stages of viral infection and replication. In this study, we investigated how inhibition of Akt kinase activity impacts on influenza virus infection by using “Akt-in”, a peptide Akt inhibitor. In PR8 influenza-infected A549 cells, Akt interacted with the NS1 (Non structural protein1), and hence increased phosphorylation of Akt kinase activity and NS1. Treatment of cells with either “TCL1-or TCL1b-based Akt-in” efficiently suppressed Akt kinase activity while decreasing the levels of phosphorylated NS1; this, in turn, inhibited viral replication in a dose- and time-dependent manner. The inhibitory effect on viral replication appears to not be due to inhibition of the production of inflammatory cytokines, including IL-6 and IL-8, in the host cells. Inhibition of Akt kinase activity in the host cells inhibited the efficiency of viral entry, which is associated with decreased levels of phosphorylated glycogen synthase kinase 3, a substrate of Akt. Further, Akt-in treatment of the host cells, which inhibited Akt kinase activity, modestly enhanced induction of autophagy. Taken together, inhibition of Akt kinase activity in host cells may have therapeutic advantages for influenza virus infection by inhibiting viral entry and replication.
Bipin Thomas is a global thought leader on consumer-centric healthcare transformation. He is recognized by American Hospital Association for redefining personalized care delivery by connecting all stakeholders in the emerging consumer-centric healthcare ecosystem. He has spearheaded the launch of Business Leadership Council for Global Virus Network as a critical platform for global corporations to safeguard their workforce and bottom line from pandemic virus threats. In a multifaceted career spanning over 25 years, he has deployed strategic initiatives across the care continuum including providers, payers, pharmacies, medical device manufacturers, pharmaceutical and life sciences, federal and state health agencies. As an industry practitioner, he is a recognized speaker in several digital health innovation conferences and path breaking forums
mHealth plays a critical role in the fight against flu. mHealth provides the platform and tools required to take care of patients through home healthcare technology instead of bringing them into the clinical setting where the flu could just continue to spread. Especially when there is a pandemic outbreak of flu, the management of flu is a perfect example of why we need to de-centralize healthcare in some situations. The care delivery needs to be extended beyond the four walls of the hospital or doctor’s office and find a place in the patient’s home, too. There is a heightened need to educate public on how to leverage mHealth to fight against flu. Must focus on changing the general behavior of the population to get used to monitoring health choices and care regimens for chronic disease management. Once we train the population to use these home health technology enabled services, we would be in a better position to apply those home health skills to potential emergency situations like the flu. Today’s smart phones with mHealth apps can display highly interactive maps to inform the public of potential health hazards. It can show where cases of any type of flu have been diagnosed — it could even send an alert message to users when they get close to an area where new outbreak of flu had been diagnosed. It helps people in those areas or traveling through those areas can take extra precautions. mHealth delivers timely and effective information for the enterprises directly from leading medical virologists on better ways to manage the flu. Enterprises are increasingly seeking more proactive measures to manage outbreak of flu because it directly impacts their worker productivity and bottom line. Global Virus Network (GVN) works with enterprises around the world to safeguard their workforce from pandemic threats, such as Ebola, Influenza, MERS, Chikungunya and other viral killers that tend to spread rapidly beyond national borders, inflicting serious economic and social impact to businesses and economies.
Institute of Biophysics, Chinese Academy of Sciences, China
Time : 11:20-11:40
Yingfang Liu obtained his PhD on Plant Science in Peking University, 1999. After that, he had his postdoctoral studies on structural biology in National Jewish Medical and Research Center, Cold Spring Harbor Laboratory and Duke University Medical Center. In 2005, he built up his own lab in Institute of Biophysics, Chinese Academy of Sciences. From then on, he has been working on some negative stranded RNA viruses and the host innate immune responses upon virus infection. Especially, they are trying to study viral proteins involved in viral genome replication and the host proteins that are induced by interferon upon viral infection. In recent years, his group made great achievement in studies of influenza polymerase.
Influenza A virus is an important pathogen accounting for epidemics and pandemics. The existing vaccines and drugs for influenza are unlikely to protect against some new strains emerging from animal reservoirs which possess the potential to cause high mortality. The influenza A RNA-dependent RNA polymerase (RdRP) complex catalyzes viral RNA replication and transcription activities which make it an attractive target for novel antiviral therapy development. The influenza RdRP consists of PB1, PB2 and PA. PB1 was suggested as the core of the RdRP complex, containing the polymerase active sites. PB2 has a cap-binding motif that snatches the 5’cap of host-cell pre-mRNAs. In our previous reports, we found that the N-terminal of PA carries the endonuclease activity. It cleaves the host pre-mRNAs resulting in primers with a 3΄-hydroxyl group for viral transcription. Both structural and functional results implicated that the C-terminal of PA (PA_C) takes part in a diverse range of functions including vRNA/cRNA promoter binding. However, the underlying mechanism of the RdRP complex is elusive due to lacking of whole structure information. Recently, we reconstructed a type A influenza RdRP sub-complex at 4.3 Å resolution using single particle cryo-EM method, compromising PA, PB1 and N-terminal of PB2. The sub-complex folds into a cage-like structure within which PA_C and PB1 creates a partially enclosed central cavity for RNA synthesis. This sub-complex exists as dimer in solution and can assemble into a tetrameric state, regulated by vRNA promoter. Our structural and biochemical results suggest an oligomeric transition model in replication process for influenza RdRP. These results also lead to further understanding of the mechanism of other negative-stranded viral RNA polymerases.