An IFNγ-dependent immune–endocrine circuit lowers blood glucose to potentiate the innate antiviral immune response

Marko Šestan, Sanja Mikašinović, Ante Benić, Stephan Wueest, Christoforos Dimitropoulos, Karlo Mladenić, Mia Krapić, Lea Hiršl, Yossef Glantzspiegel, Ana Rasteiro, Maria Aliseychik, Đurđica Cekinović Grbeša, Tamara Turk Wensveen, Marina Babić, Irit Gat-Viks, Henrique Veiga-Fernandes, Daniel Konrad, Felix M. Wensveen, Bojan Polić*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Viral infection makes us feel sick as the immune system alters systemic metabolism to better fight the pathogen. The extent of these changes is relative to the severity of disease. Whether blood glucose is subject to infection-induced modulation is mostly unknown. Here we show that strong, nonlethal infection restricts systemic glucose availability, which promotes the antiviral type I interferon (IFN-I) response. Following viral infection, we find that IFNγ produced by γδ T cells stimulates pancreatic β cells to increase glucose-induced insulin release. Subsequently, hyperinsulinemia lessens hepatic glucose output. Glucose restriction enhances IFN-I production by curtailing lactate-mediated inhibition of IRF3 and NF-κB signaling. Induced hyperglycemia constrained IFN-I production and increased mortality upon infection. Our findings identify glucose restriction as a physiological mechanism to bring the body into a heightened state of responsiveness to viral pathogens. This immune–endocrine circuit is disrupted in hyperglycemia, possibly explaining why patients with diabetes are more susceptible to viral infection.

Original languageEnglish
Pages (from-to)981-993
Number of pages13
JournalNature Immunology
Volume25
Issue number6
DOIs
StatePublished - Jun 2024

Funding

FundersFunder number
Sveučilište u Rijeci18-89-1224, 18-117-1256, 18-152-1301
Sveučilište u Rijeci
European Research Council647274
European Research Council
European Molecular Biology OrganizationEMBO ALTF 700-2019
European Molecular Biology Organization
Fundação para a Ciência e a TecnologiaPTDC/MED-IMU/6653/2020
Fundação para a Ciência e a Tecnologia
Hrvatska Zaklada za ZnanostIP-2016-06-9306, IP-2020-02-7928, IPCH-2020-10-8440, IP-CORONA-2020-04-2045, IP-2022-10-3414
Hrvatska Zaklada za Znanost
'la Caixa' FoundationHR20-00841
'la Caixa' Foundation
European Regional Development FundKK.01.1.1.01.0006
European Regional Development Fund
Chan Zuckerberg InitiativeINFL-0000000193
Chan Zuckerberg Initiative

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