TY - JOUR
T1 - An IFNγ-dependent immune–endocrine circuit lowers blood glucose to potentiate the innate antiviral immune response
AU - Šestan, Marko
AU - Mikašinović, Sanja
AU - Benić, Ante
AU - Wueest, Stephan
AU - Dimitropoulos, Christoforos
AU - Mladenić, Karlo
AU - Krapić, Mia
AU - Hiršl, Lea
AU - Glantzspiegel, Yossef
AU - Rasteiro, Ana
AU - Aliseychik, Maria
AU - Cekinović Grbeša, Đurđica
AU - Turk Wensveen, Tamara
AU - Babić, Marina
AU - Gat-Viks, Irit
AU - Veiga-Fernandes, Henrique
AU - Konrad, Daniel
AU - Wensveen, Felix M.
AU - Polić, Bojan
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.
PY - 2024/6
Y1 - 2024/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85194548636&partnerID=8YFLogxK
U2 - 10.1038/s41590-024-01848-3
DO - 10.1038/s41590-024-01848-3
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C2 - 38811816
AN - SCOPUS:85194548636
SN - 1529-2908
VL - 25
SP - 981
EP - 993
JO - Nature Immunology
JF - Nature Immunology
IS - 6
ER -