Mouse models carrying patient-derived mutations in IRF3 and TBK1 enable mechanistic characterization of herpes simplex encephalitis.
Manja Idorn, Søren Holste, Line S Reinert, Stefanie Fruhwürth, Trine H Mogensen and Søren R Paludan.
E-mail: Manja.idorn@biomed.au.dk
Gene variants in key viral sensing pathways can predispose individuals to severe infectious diseases. Heterozygous variants in IRF3 R285Q and TBK1 G159A, respectively, have been described in patients presenting with Herpes Simplex-1 (HSV-1) Encephalitis (HSE). IRF3 and TBK1 are part of the signaling pathways for induction of interferons, which exert early innate antiviral defense. To investigate the mechanism underlying the disease, we generated two mouse models carrying patient specific amino-acid substitutions in murine IRF3R278Q or TBK1G159A . While homozygous IRF3R278Q mice exhibited no developmental abnormalities and breed at Mendelian ratios, homozygous TBK1G159A showed embryonic lethality, as previously reported for TBK1KO mice, thus suggesting that the TBK1G159A renders TBK1 non-functional. However, heterozygous TBK1G159A are viable. The mice were infected with HSV-1, and brain disease development was monitored. Both TBK1G159A (HET) IRF3R278Q (HET and HOM) mice showed accelerated disease phenotype, suggesting that the mice phenocopy the patients. In line with this, IRF3R278Q mice exhibited significantly higher viral load in the brainstem compared to WT mice, and responded to infection with impaired expression of IFNβ. Importantly, this was also observed in iPSC derived microglia generated from the HSE patient harbouring the IRF3 R285Q mutation. In contrast to the impaired IFN response, the IRF3R278Q mice responded with earlier and more potent expression of inflammatory cytokines; TNFα, IL-1β and IL-6. These data demonstrate that the models provide powerful tools to uncover the disease mechanisms of HSE now being characterized. The principle of using mice harboring disease-specific mutations may be broadly applicable to uncover clinically important mechanisms in viral infection pathogenesis.

Mouse models carrying patient-derived mutations in IRF3 and TBK1 enable mechanistic characterization of herpes simplex encephalitis

Exploring the intricacies of host-pathogen communication is vital in order to understand why
some microbes persist within a host, while others are effectively cleared. As such,
host-pathogen communication is an urgent area of research underpinning human health
and disease, especially given the emerging concerns of antibiotic resistance.
Understanding host-pathogen pathways requires intricate knowledge in the fields of both
microbiology and immunology.

Living in a world of specialists, where scientists sometimes invest their whole career
studying one organism, a specific pathway or a protein, multidisciplinary discussions of
host-pathogen interactions are highly needed. This international conference will provide
such a forum for scientific exchange at the highest level, between scientists from different
research areas related to host-pathogen interactions, with the aim to trigger fruitful
collaborations addressing the urgent questions in the field.

This meeting has an additional special focus of bringing researchers from Ireland, Denmark
and Israel together to learn about cutting edge biology and form new collaborations.
Thus, the conference will be a showcase for the exciting and original research emanating
from these three small but innovative countries.

Host-Pathogen Communication (HPC) 2021

Awards & close

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