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  • 1. Jin, Jing
    et al.
    Galaz-Montoya, Jesus G.
    Sherman, Michael B.
    Sun, Stella Y.
    Goldsmith, Cynthia S.
    O'Toole, Eileen T.
    Ackerman, Larry
    Carlson, Lars-Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Weaver, Scott C.
    Chiu, Wah
    Simmons, Graham
    Neutralizing Antibodies Inhibit Chikungunya Virus Budding at the Plasma Membrane2018In: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 24, no 3, p. 417-+Article in journal (Refereed)
    Abstract [en]

    Neutralizing antibodies (NAbs) are traditionally thought to inhibit virus infection by preventing virion entry into target cells. In addition, antibodies can engage Fc receptors (FcRs) on immune cells to activate antiviral responses. We describe a mechanism by which NAbs inhibit chikungunya virus (CHIKV), the most common alphavirus infecting humans, by preventing virus budding from infected human cells and activating IgG-specific Fc gamma receptors. NAbs bind to CHIKV glycoproteins on the infected cell surface and induce glycoprotein coalescence, preventing budding of nascent virions and leaving structurally heterogeneous nucleocapsids arrested in the cytosol. Furthermore, NAbs induce clustering of CHIKV replication spherules at sites of budding blockage. Functionally, these densely packed glycoprotein-NAb complexes on infected cells activate Fc gamma receptors, inducing a strong, antibody-dependent, cell-mediated cytotoxicity response from immune effector cells. Our findings describe a triply functional antiviral pathway for NAbs that might be broadly applicable across virus-host systems, suggesting avenues for therapeutic innovation through antibody design.

  • 2. Jin, Jing
    et al.
    Sherman, Michael B.
    Chafets, Daniel
    Dinglasan, Nuntana
    Lu, Kai
    Lee, Tzong-Hae
    Carlson, Lars-Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Muench, Marcus O.
    Simmons, Graham
    An attenuated replication-competent chikungunya virus with a fluorescently tagged envelope2018In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 12, no 7, article id e0006693Article in journal (Refereed)
    Abstract [en]

    Background: Chikungunya virus (CHIKV) is the most common alphavirus infecting humans worldwide, causing acute and chronically debilitating arthralgia at a great economic expense.

    Methodology/Principal findings: To facilitate our study of CHIKV, we generated a mCherry tagged replication-competent chimeric virus, CHIKV 37997-mCherry. Single particle cryoEM demonstrated icosahedral organization of the chimeric virus and the display of mCherry proteins on virus surface. CHIKV 37997-mCherry is attenuated in both IFN alpha R knockout and wild-type mice. Strong antiCHIKV and anti-mCherry antibody responses were induced in CHIKV 37997-mCherry infected mice.

    Conclusions/Significance: Our work suggests that chimeric alphaviruses displaying foreign antigen can serve as vaccines against both aphaviruses and other pathogens and diseases.

  • 3. Schoneberg, Johannes
    et al.
    Pavlin, Mark Remec
    Yan, Shannon
    Righini, Maurizio
    Lee, Il-Hyung
    Carlson, Lars-Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Bahrami, Amir Houshang
    Goldman, Daniel H.
    Ren, Xuefeng
    Hummer, Gerhard
    Bustamante, Carlos
    Hurley, James H.
    ATP-dependent force generation and membrane scission by ESCRT-III and Vps42018In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 362, no 6421, p. 1423-+Article in journal (Refereed)
    Abstract [en]

    The endosomal sorting complexes required for transport (ESCRTs) catalyze reverse topology scission from the inner face of membrane necks in HIV budding, multivesicular endosome biogenesis, cytokinesis, and other pathways. We encapsulated ESCRT-III subunits Snf7, Vps24. and Vps2 and the AAA+ ATPase (adenosine triphosphatase) Vps4 in giant vesicles from which membrane nanotubes reflecting the correct topology of scission could be pulled. Upon ATP release by photo-uncaging, this system generated forces within the nanotubes that led to membrane scission in a manner dependent upon Vps4 catalytic activity and Vps4 coupling to the ESCRT-III proteins. Imaging of scission revealed Snf7 and Vps4 puncta within nanotubes whose presence followed ATP release, correlated with force generation and nanotube constriction, and preceded scission. These observations directly verify long-standing predictions that ATP-hydrolyzing assemblies of ESCRT-Ill and Vps4 sever membranes.

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