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Macrophage migration inhibitory factor is a valid drug target at the intersection of herpes simplex virus 1 replication and Alzheimer’s disease-relevant cellular pathology

Andreas Müller-Schiffmann, Felix Torres, Anatolly Kitaygorodskyy, Anand Ramani, Argyro Alatza, Sarah Tschirner, Ingrid Prikulis, Shaofeng Yu, Debendranath Dey, Verian Bader, Annemieke Rozemuller, Selina Wray, Jay Gopalakrishnan, Roland Riek, Vishwanath R. Lingappa, View ORCID ProfileCarsten Korth
doi: https://doi.org/10.1101/2021.09.11.459903
Andreas Müller-Schiffmann
1Department Neuropathology, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
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Felix Torres
2Department Physical Chemistry, Federal Research Institute, Zurich, Switzerland
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Anatolly Kitaygorodskyy
3Prosetta Biosciences, San Francisco, USA
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Anand Ramani
4Department Human Genetics, Heinrich Heine University, 40225 Düsseldorf, Germany
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Argyro Alatza
5Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London WC1N 1PJ, United Kingdom
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Sarah Tschirner
1Department Neuropathology, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
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Ingrid Prikulis
1Department Neuropathology, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
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Shaofeng Yu
3Prosetta Biosciences, San Francisco, USA
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Debendranath Dey
3Prosetta Biosciences, San Francisco, USA
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Verian Bader
1Department Neuropathology, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
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Annemieke Rozemuller
6Department Pathology, VUMC Amsterdam, 1081HV Amsterdam, The Netherlands
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Selina Wray
5Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London WC1N 1PJ, United Kingdom
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Jay Gopalakrishnan
4Department Human Genetics, Heinrich Heine University, 40225 Düsseldorf, Germany
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Roland Riek
2Department Physical Chemistry, Federal Research Institute, Zurich, Switzerland
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Vishwanath R. Lingappa
3Prosetta Biosciences, San Francisco, USA
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Carsten Korth
1Department Neuropathology, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
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  • ORCID record for Carsten Korth
  • For correspondence: ckorth@hhu.de
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Abstract

Herpes virus infections are endemic and ubiquitous. While only rarely leading to overt encephalitis, subchronic or latent infections have been associated to a variety of conditions, including Alzheimer’s disease (AD). The cellular consequences of herpes virus infection are determined by the host proteins recruited during virus replication and assembly. Identifying such virus-recruited host proteins therefore allows the interrogation fundamental cellular events leading to associated “sporadic” diseases.

A host protein-targeted small molecule drug highly active against herpes simplex virus 1 (HSV-1) infection in human brain organoids and cell lines was identified to interact with macrophage migration inhibitory factor (MIF) where it acted by intercalating between MIF units within a trimer, as determined by nuclear magnetic resonance (NMR). MIF knockout cells showed a decreased viral antigen/titer ratio corroborating its role in virus assembly.

From post-mortem brain homogenates of patients with Braak 6-staged AD the small molecule lead compound specifically eluted a MIF subpopulation that correlated with the oxidized conformer of MIF (oxMIF). HSV-1 led to an increase in tau phosphorylation at distinct residues, and the lead compound decreased tau phosphorylation in recombinant cell lines expressing mutant tau and in neuron-differentiated iPSCs also in the absence of HSV-1 infection.

We conclude that MIF is a cellular host factor involved in HSV-1 replication and a drug target with antiviral efficacy. At the same time, MIF also plays a role in tau phosphorylation and is enriched in an oxidized conformation in brains of AD patients. MIF thus presents as a molecular link connecting HSV-1 infection and cellular pathology characteristic of neurodegenerative diseases involving aberrant tau phosphorylation.

Competing Interest Statement

Co-authors Anatolly Kitaygorodskyy, Shaofeng Yu, Debendranath Dey, and Vishwanath Lingappa are or were full-time employees of Prosetta Biosciences. The performed work was in part supported by a grant from Prosetta Biosciences to senior author Carsten Korth.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted September 12, 2021.
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Macrophage migration inhibitory factor is a valid drug target at the intersection of herpes simplex virus 1 replication and Alzheimer’s disease-relevant cellular pathology
Andreas Müller-Schiffmann, Felix Torres, Anatolly Kitaygorodskyy, Anand Ramani, Argyro Alatza, Sarah Tschirner, Ingrid Prikulis, Shaofeng Yu, Debendranath Dey, Verian Bader, Annemieke Rozemuller, Selina Wray, Jay Gopalakrishnan, Roland Riek, Vishwanath R. Lingappa, Carsten Korth
bioRxiv 2021.09.11.459903; doi: https://doi.org/10.1101/2021.09.11.459903
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Macrophage migration inhibitory factor is a valid drug target at the intersection of herpes simplex virus 1 replication and Alzheimer’s disease-relevant cellular pathology
Andreas Müller-Schiffmann, Felix Torres, Anatolly Kitaygorodskyy, Anand Ramani, Argyro Alatza, Sarah Tschirner, Ingrid Prikulis, Shaofeng Yu, Debendranath Dey, Verian Bader, Annemieke Rozemuller, Selina Wray, Jay Gopalakrishnan, Roland Riek, Vishwanath R. Lingappa, Carsten Korth
bioRxiv 2021.09.11.459903; doi: https://doi.org/10.1101/2021.09.11.459903

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