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Antibody control and immunopathogenesis of viral infection

Şahin, Mehmet. Antibody control and immunopathogenesis of viral infection. 2018, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_13094

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Abstract

Across the animal kingdom, multivalency discriminates antibodies from all other immunoglobulin superfamily members. The evolutionary forces conserving multivalency above any other structural hallmark of antibodies remain, however, ill-defined. Here we have used antibody engineering techniques to investigate mechanisms of protection of neutralizing and non-neutralizing antibodies (nAbs, nnAbs) in a viral infection model in mice.
Antibody bivalency enabled the tethering of virions to the infected cell surface, thereby inhibiting the release of infectious virions in cell culture and suppressing viral loads in vivo independently of Fc. Conversely, virion release inhibition and in vivo control of infection by monovalent antibody formats were strictly Fc-dependent. Comparable amounts of nAb and nnAb were required for in vivo protection and correlated with similar virion release-inhibiting activity.
These observations provide a mechanistic understanding of the evolutionary conservation of antibody bivalency and may help establishing better correlates on nnAb protection for vaccine development.
Arenaviruses such as Lassa virus cause hemorrhagic fever. Terminal shock is associated with a systemic cytokine storm but remains mechanistically ill-defined.
In a mouse model of arenavirus hemorrhagic fever (AHF) disease manifested in pleural effusions, edematous skin swelling and serum albumin loss. It culminated in hypovolemic shock despite a compensatory increase in cardiac ejection fraction. A characteristic cytokine storm included numerous pro-inflammatory cytokines and NO metabolites. Intriguingly, edema formation and terminal shock were abrogated in mice lacking inducible nitric oxide synthase (iNOS), while the cytokine storm persisted. iNOS was upregulated in the liver in a T cell- and IFN-gamma dependent fashion. Accordingly, blockade of IFN-gamma or depletion of T cells repressed hepatic iNOS and prevented disease despite unchecked high-level viremia.
We identify the IFN-gamma– iNOS axis as an essential and druggable molecular pathway to AHF-induced shock, demonstrating that a virus-induced cytokine storm can be mechanistically dissected to devise novel therapeutic approaches.
Advisors:Bumann, Dirk and Pinschewer, Daniel David and Pircher, Hanspeter
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Infection Biology > Molecular Microbiology (Bumann)
UniBasel Contributors:Bumann, Dirk
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:13094
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:1 Online-Ressource (177 Seiten)
Language:English
Identification Number:
Last Modified:14 Jun 2019 04:30
Deposited On:13 Jun 2019 09:23

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