Novel mechanisms restricting virus infection in the brain

A current dogma in immunology is that the first line of defense against virus infections is mediated by pattern recognition receptors (PRRs), which induce production of the antiviral interferon-a/b (IFN).

However, these responses can also induce pathological inflammation, thus arguing against their each time homeostasis is altered.

We recently proposed the existence of a novel layer of the immune system, which provides immediate antiviral defense independent of PRR/IFN signaling (Paludan et al, Nat Rev Immunol, 2021). To test this idea, we will first focus on the brain, which is particularly sensitive to inflammation.

Through a dual unbiased approach, including (i) whole-exome sequencing of patients with herpes simplex virus (HSV) encephalitis (HSE), and (ii) genome-wide CRISPR screen for susceptibility to HSV1 in neuron-like cells, we have identified TMEFF1 as a candidate novel factor restricting HSV1 replication.

In the proposed project, we will first establish whether TMEFF1 is responsible for anti-HSV1 defense in human primary neurons. Second, we will uncover the impact of TMEFF1 deficiency on antiviral defense in mice. Finally, we will identify the molecular mode of antiviral action of TMEFF1.

The required methodologies and reagents are in place for the project, including Tmeff1-/- mice and cells from TMEFF1-deficient HSE patients.

This work may lead to identification of a novel mode of antiviral defense, and contribute to establishment of a new concept in immunology.