@article {M{\"u}ller-Schiffmann2021.09.11.459903, author = {Andreas M{\"u}ller-Schiffmann and Felix Torres and Anatolly Kitaygorodskyy and Anand Ramani and Argyro Alatza and Sarah Tschirner and Ingrid Prikulis and Shaofeng Yu and Debendranath Dey and Verian Bader and Annemieke Rozemuller and Selina Wray and Jay Gopalakrishnan and Roland Riek and Vishwanath R. Lingappa and Carsten Korth}, title = {Macrophage migration inhibitory factor is a valid drug target at the intersection of herpes simplex virus 1 replication and Alzheimer{\textquoteright}s disease-relevant cellular pathology}, elocation-id = {2021.09.11.459903}, year = {2021}, doi = {10.1101/2021.09.11.459903}, publisher = {Cold Spring Harbor Laboratory}, 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{\textquoteright}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 {\textquotedblleft}sporadic{\textquotedblright} 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 StatementCo-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.}, URL = {https://www.biorxiv.org/content/early/2021/09/12/2021.09.11.459903}, eprint = {https://www.biorxiv.org/content/early/2021/09/12/2021.09.11.459903.full.pdf}, journal = {bioRxiv} }