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

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 Alzheimers 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.