Ivanovic Lab                   B randeis University, Biochemistry Department

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OVERVIEW OF RESEARCH INTERESTS


Viral outbreaks and pandemics arise when animal viruses adapt so that they can recognize human cells as their host. The ability to recognize and invade host cells is programmed in viral particle structure, yet we know very little about how particle structure contributes to the early steps of infection. Much of what we know about viral cell entry derives from studies of viral molecular players taken outside the authentic context on virus particles (e.g. displayed on cells or synthetic vesicles). While studies of viral proteins in isolation can teach us a great deal about the mechanics of cell entry, and can help identify conserved drug targets, research in the Ivanovic lab has revealed that the size and organization of virus particle structure determines the efficiency of cell entry, including sensitivity of virus particles to neutralization by the immune-system antibodies or synthetic inhibitors. In this way, the authentic particle structure plays a direct role in permitting adaptation likely to include zoonoses leading to new outbreaks or pandemics. 


Most of the research in the Ivanovic lab has focused on influenza and reovirus. More recently, we are starting new collaborations and branching into other viral systems, such as Ebola virus, measles, and RSV.


Phenotypic heterogeneity in particle size is a viral mechanism of persistence


Li et al., bioRxiv 2019


A model for the influenza virus phenotypic switch. Viral progeny is pleomorphic independent of the initiating-virus morphology. Random mutations arise during replication. (A) At low HA pressure, infections by spherical particles dominate. (B) Filamentous particles permit cell entry and replication when spherical particles are inhibited, and can lead to adaptive mutations. (C) Preventing macropinocytosis in combination with HA inactivation by inhibitors might avert resistance. The same strategy might apply to prolonging vaccine effectiveness or preventing zoonotic adaptations that can lead to pandemics. Circles, spherical particles; Ellipses, filaments; Blue, WT; Black/Orange/Green/Red, HA mutants; Red, an adaptive HA mutant; CME, clathrin-mediated endocytosis.

ONGOING PROJECTS

  • Mechanism of viral membrane fusion

  • Viral adaptation strategies - pandemic adaptation, persistence in the human host, resistance to antivirals

  • Cell biology of viral cell entry

  • Nonenveloped virus membrane penetration, particle assembly and disassembly