An IFNγ-dependent immune-endocrine circuit lowers blood glucose to potentiate the innate antiviral immune response.
Journal
Nature immunology
ISSN: 1529-2916
Titre abrégé: Nat Immunol
Pays: United States
ID NLM: 100941354
Informations de publication
Date de publication:
29 May 2024
29 May 2024
Historique:
received:
01
02
2024
accepted:
18
04
2024
medline:
30
5
2024
pubmed:
30
5
2024
entrez:
29
5
2024
Statut:
aheadofprint
Résumé
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.
Identifiants
pubmed: 38811816
doi: 10.1038/s41590-024-01848-3
pii: 10.1038/s41590-024-01848-3
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : European Molecular Biology Organization (EMBO)
ID : ALTF 700-2019
Organisme : Hrvatska Zaklada za Znanost (Croatian Science Foundation)
ID : IP-2022-10-3414
Organisme : Hrvatska Zaklada za Znanost (Croatian Science Foundation)
ID : IPCH-2020-10-8440
Organisme : EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)
ID : 647274
Informations de copyright
© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.
Références
Hart, B. L. Biological basis of the behavior of sick animals. Neurosci. Biobehav Rev. 12, 123–137 (1988).
pubmed: 3050629
doi: 10.1016/S0149-7634(88)80004-6
Wensveen, F. M., Sestan, M., Turk Wensveen, T. & Polic, B. ‘Beauty and the beast’ in infection: how immune–endocrine interactions regulate systemic metabolism in the context of infection. Eur. J. Immunol. 49, 982–995 (2019).
pubmed: 31106860
doi: 10.1002/eji.201847895
Munger, J., Bajad, S. U., Coller, H. A., Shenk, T. & Rabinowitz, J. D. Dynamics of the cellular metabolome during human cytomegalovirus infection. PLoS Pathog. 2, e132 (2006).
pubmed: 17173481
pmcid: 1698944
doi: 10.1371/journal.ppat.0020132
Krapic, M., Kavazovic, I. & Wensveen, F. M. Immunological mechanisms of sickness behavior in viral infection. Viruses 13, 2245 (2021).
pubmed: 34835051
pmcid: 8624889
doi: 10.3390/v13112245
ElSayed, N. A. et al. 2. Classification and diagnosis of diabetes: standards of care in diabetes-2023. Diabetes Care 46, S19–S40 (2023).
pubmed: 36507649
doi: 10.2337/dc23-S002
Petersen, M. C. & Shulman, G. I. Mechanisms of insulin action and insulin resistance. Physiol. Rev. 98, 2133–2223 (2018).
pubmed: 30067154
pmcid: 6170977
doi: 10.1152/physrev.00063.2017
Šestan, M. et al. Virus-induced interferon-γ causes insulin resistance in skeletal muscle and derails glycemic control in obesity. Immunity 49, 164–177 (2018).
pubmed: 29958802
doi: 10.1016/j.immuni.2018.05.005
Kavazovic, I. et al. Hyperglycemia and not hyperinsulinemia mediates diabetes-induced memory CD8 T cell dysfunction. Diabetes 71, 706–721 (2022).
pubmed: 35044446
doi: 10.2337/db21-0209
Plummer, M. P. & Deane, A. M. Dysglycemia and glucose control during sepsis. Clin. Chest Med. 37, 309–319 (2016).
pubmed: 27229647
doi: 10.1016/j.ccm.2016.01.010
Devlin, B. A., Smith, C. J. & Bilbo, S. D. Sickness and the social brain: how the immune system regulates behavior across species. Brain Behav. Evol. 97, 197–210 (2021).
pubmed: 34915474
doi: 10.1159/000521476
Turk Wensveen, T., Gasparini, D., Rahelic, D. & Wensveen, F. M. Type 2 diabetes and viral infection; cause and effect of disease. Diabetes Res Clin. Pr. 172, 108637 (2021).
doi: 10.1016/j.diabres.2020.108637
Simonsen, J. R. et al. Bacterial infections in patients with type 1 diabetes: a 14-year follow-up study. BMJ Open Diabetes Res. Care 3, e000067 (2015).
pubmed: 25767718
pmcid: 4352693
doi: 10.1136/bmjdrc-2014-000067
Kornum, J. B. et al. Diabetes, glycemic control, and risk of hospitalization with pneumonia: a population-based case-control study. Diabetes Care 31, 1541–1545 (2008).
pubmed: 18487479
pmcid: 2494631
doi: 10.2337/dc08-0138
Hijano, D. R. et al. Clinical correlation of influenza and respiratory syncytial virus load measured by digital PCR. PLoS ONE 14, e0220908 (2019).
pubmed: 31479459
pmcid: 6720028
doi: 10.1371/journal.pone.0220908
Carrat, F. et al. Time lines of infection and disease in human influenza: a review of volunteer challenge studies. Am. J. Epidemiol. 167, 775–785 (2008).
pubmed: 18230677
doi: 10.1093/aje/kwm375
Smith, H. R. et al. Recognition of a virus-encoded ligand by a natural killer cell activation receptor. Proc. Natl Acad. Sci. USA 99, 8826–8831 (2002).
pubmed: 12060703
pmcid: 124383
doi: 10.1073/pnas.092258599
Goyal, P. & Rajala, M. S. Reprogramming of glucose metabolism in virus infected cells. Mol. Cell. Biochem. 478, 2409–2418 (2023).
pubmed: 36709223
doi: 10.1007/s11010-023-04669-4
Liang, S., Wu, Y. S., Li, D. Y., Tang, J. X. & Liu, H. F. Autophagy in viral infection and pathogenesis. Front. Cell Dev. Biol. 9, 766142 (2021).
pubmed: 34722550
pmcid: 8554085
doi: 10.3389/fcell.2021.766142
Zhang, W. et al. Lactate is a natural suppressor of RLR signaling by targeting MAVS. Cell 178, 176–189 e115 (2019).
pubmed: 31155231
pmcid: 6625351
doi: 10.1016/j.cell.2019.05.003
Brown, G. R. et al. Gene: a gene-centered information resource at NCBI. Nucleic Acids Res. 43, D36–D42 (2015).
pubmed: 25355515
doi: 10.1093/nar/gku1055
Pahl, H. L. Activators and target genes of Rel/NF-κB transcription factors. Oncogene 18, 6853–6866 (1999).
pubmed: 10602461
doi: 10.1038/sj.onc.1203239
Sohn, W. J. et al. Novel transcriptional regulation of the schlafen-2 gene in macrophages in response to TLR-triggered stimulation. Mol. Immunol. 44, 3273–3282 (2007).
pubmed: 17434208
doi: 10.1016/j.molimm.2007.03.001
Steuerman, Y. et al. Dissection of influenza infection in vivo by single-cell RNA sequencing. Cell Syst. 6, 679–691 e674 (2018).
pubmed: 29886109
pmcid: 7185763
doi: 10.1016/j.cels.2018.05.008
Ivashkiv, L. B. IFNγ: signalling, epigenetics and roles in immunity, metabolism, disease and cancer immunotherapy. Nat. Rev. Immunol. 18, 545–558 (2018).
pubmed: 29921905
pmcid: 6340644
doi: 10.1038/s41577-018-0029-z
Sun, G. et al. γδ T cells provide the early source of IFN-γ to aggravate lesions in spinal cord injury. J. Exp. Med. 215, 521–535 (2018).
pubmed: 29282251
pmcid: 5789408
doi: 10.1084/jem.20170686
Inoue, S. et al. Enhancement of dendritic cell activation via CD40 ligand-expressing gammadelta T cells is responsible for protective immunity to Plasmodium parasites. Proc. Natl Acad. Sci. USA 109, 12129–12134 (2012).
pubmed: 22778420
pmcid: 3409789
doi: 10.1073/pnas.1204480109
Marinovic, S. et al. NKG2D-mediated detection of metabolically stressed hepatocytes by innate-like T cells is essential for initiation of NASH and fibrosis. Sci. Immunol. 8, eadd1599 (2023).
pubmed: 37774007
pmcid: 7615627
doi: 10.1126/sciimmunol.add1599
Mladenic, K., Lenartic, M., Marinovic, S., Polic, B. & Wensveen, F. M. The ‘Domino effect’ in MASLD: the inflammatory cascade of steatohepatitis. Eur. J. Immunol. 54, e2149641 (2024).
pubmed: 38314819
doi: 10.1002/eji.202149641
Bergman, R. K., Munoz, J. J. & Portis, J. L. Vascular permeability changes in the central nervous system of rats with hyperacute experimental allergic encephalomyelitis induced with the aid of a substance from Bordetella pertussis. Infect. Immun. 21, 627–637 (1978).
pubmed: 211087
pmcid: 422039
doi: 10.1128/iai.21.2.627-637.1978
Bekiaris, V. et al. Ly49H
pubmed: 18453597
doi: 10.4049/jimmunol.180.10.6768
Sestan, M. et al. Virus-induced interferon-gamma causes insulin resistance in skeletal muscle and derails glycemic control in obesity. Immunity 49, 164–177 e166 (2018).
pubmed: 29958802
doi: 10.1016/j.immuni.2018.05.005
Dror, E. et al. Postprandial macrophage-derived IL-1β stimulates insulin, and both synergistically promote glucose disposal and inflammation. Nat. Immunol. 18, 283–292 (2017).
pubmed: 28092375
doi: 10.1038/ni.3659
Zhang, J. N., Hiken, J., Davis, A. E. & Lawrence, J. C. Jr. Insulin stimulates dephosphorylation of phosphorylase in rat epitrochlearis muscles. J. Biol. Chem. 264, 17513–17523 (1989).
pubmed: 2507543
doi: 10.1016/S0021-9258(18)71523-8
Tracey, W. R. et al. Cardioprotective effects of ingliforib, a novel glycogen phosphorylase inhibitor. Am. J. Physiol. Heart Circ. Physiol. 286, H1177–H1184 (2004).
pubmed: 14615278
doi: 10.1152/ajpheart.00652.2003
Muller, L. M. et al. Increased risk of common infections in patients with type 1 and type 2 diabetes mellitus. Clin. Infect. Dis. 41, 281–288 (2005).
pubmed: 16007521
doi: 10.1086/431587
Wensveen, F. M. et al. NK cells link obesity-induced adipose stress to inflammation and insulin resistance. Nat. Immunol. 16, 376–385 (2015).
pubmed: 25729921
doi: 10.1038/ni.3120
Saisho, Y. Importance of beta cell function for the treatment of type 2 diabetes. J. Clin. Med 3, 923–943 (2014).
pubmed: 26237486
pmcid: 4449644
doi: 10.3390/jcm3030923
Teng, R. J., Wu, T. J. & Ho, M. M. Mumps infection complicated by transient hyperinsulinemic hypoglycemia. Pediatr. Infect. Dis. J. 16, 416–417 (1997).
pubmed: 9109149
doi: 10.1097/00006454-199704000-00018
Tucey, T. M. et al. Glucose homeostasis is important for immune cell viability during candida challenge and host survival of systemic fungal infection. Cell Metab. 27, 988–1006 e1007 (2018).
pubmed: 29719235
pmcid: 6709535
doi: 10.1016/j.cmet.2018.03.019
Wensveen, F. M., van Gisbergen, K. P. & Eldering, E. The fourth dimension in immunological space: how the struggle for nutrients selects high-affinity lymphocytes. Immunol. Rev. 249, 84–103 (2012).
pubmed: 22889217
doi: 10.1111/j.1600-065X.2012.01156.x
Dao, M., MacDonald, I. & Asaro, R. J. Erythrocyte flow through the interendothelial slits of the splenic venous sinus. Biomech. Model. Mechanobiol. 20, 2227–2245 (2021).
pubmed: 34535857
pmcid: 8609975
doi: 10.1007/s10237-021-01503-y
Lewis, S. M., Williams, A. & Eisenbarth, S. C. Structure and function of the immune system in the spleen. Sci. Immunol. 4, eaau6085 (2019).
pubmed: 30824527
pmcid: 6495537
doi: 10.1126/sciimmunol.aau6085
Stein, S. R. et al. SARS-CoV-2 infection and persistence in the human body and brain at autopsy. Nature 612, 758–763 (2022).
pubmed: 36517603
pmcid: 9749650
doi: 10.1038/s41586-022-05542-y
Wu, X. X. et al. The viral distribution and pathological characteristics of BALB/c mice infected with highly pathogenic Influenza H7N9 virus. Virol. J. 18, 237 (2021).
pubmed: 34844617
pmcid: 8628282
doi: 10.1186/s12985-021-01709-7
Hoft, D. F. et al. Live and inactivated influenza vaccines induce similar humoral responses, but only live vaccines induce diverse T-cell responses in young children. J. Infect. Dis. 204, 845–853 (2011).
pubmed: 21846636
pmcid: 3156924
doi: 10.1093/infdis/jir436
Sabbaghi, A. et al. Role of gammadelta T cells in controlling viral infections with a focus on influenza virus: implications for designing novel therapeutic approaches. Virol. J. 17, 174 (2020).
pubmed: 33183352
pmcid: 7659406
doi: 10.1186/s12985-020-01449-0
Wang, A. et al. Opposing effects of fasting metabolism on tissue tolerance in bacterial and viral inflammation. Cell 166, 1512–1525 e1512 (2016).
pubmed: 27610573
pmcid: 5555589
doi: 10.1016/j.cell.2016.07.026
Man, K. et al. A thermogenic fat-epithelium cell axis regulates intestinal disease tolerance. Proc. Natl Acad. Sci. USA 117, 32029–32037 (2020).
pubmed: 33257580
pmcid: 7749324
doi: 10.1073/pnas.2012003117
Guo, W. et al. Diabetes is a risk factor for the progression and prognosis of COVID-19. Diabetes Metab. Res Rev. 36, e3319 (2020).
pubmed: 32233013
pmcid: 7228407
doi: 10.1002/dmrr.3319
Apicella, M. et al. COVID-19 in people with diabetes: understanding the reasons for worse outcomes. Lancet Diabetes Endocrinol. 8, 782–792 (2020).
pubmed: 32687793
pmcid: 7367664
doi: 10.1016/S2213-8587(20)30238-2
Mombaerts, P. et al. Mutations in T-cell antigen receptor genes alpha and beta block thymocyte development at different stages. Nature 360, 225–231 (1992).
pubmed: 1359428
doi: 10.1038/360225a0
Muller, U. et al. Functional role of type I and type II interferons in antiviral defense. Science 264, 1918–1921 (1994).
pubmed: 8009221
doi: 10.1126/science.8009221
Postic, C. et al. Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic beta cell-specific gene knock-outs using Cre recombinase. J. Biol. Chem. 274, 305–315 (1999).
pubmed: 9867845
doi: 10.1074/jbc.274.1.305
Scheu, S., Dresing, P. & Locksley, R. M. Visualization of IFNβ production by plasmacytoid versus conventional dendritic cells under specific stimulation conditions in vivo. Proc. Natl Acad. Sci. USA 105, 20416–20421 (2008).
pubmed: 19088190
pmcid: 2629269
doi: 10.1073/pnas.0808537105
Wagner, F. M. et al. The viral chemokine MCK-2 of murine cytomegalovirus promotes infection as part of a gH/gL/MCK-2 complex. PLoS Pathog. 9, e1003493 (2013).
pubmed: 23935483
pmcid: 3723581
doi: 10.1371/journal.ppat.1003493
Bubic, I. et al. Gain of virulence caused by loss of a gene in murine cytomegalovirus. J. Virol. 78, 7536–7544 (2004).
pubmed: 15220428
pmcid: 434107
doi: 10.1128/JVI.78.14.7536-7544.2004
Wueest, S. et al. Deletion of Fas in adipocytes relieves adipose tissue inflammation and hepatic manifestations of obesity in mice. J. Clin. Investig. 120, 191–202 (2010).
pubmed: 19955656
doi: 10.1172/JCI38388
Burrack, K. S. et al. Interleukin-15 complex treatment protects mice from cerebral malaria by inducing interleukin-10-producing natural killer cells. Immunity 48, 760–772 e764 (2018).
pubmed: 29625893
pmcid: 5906161
doi: 10.1016/j.immuni.2018.03.012
Conde, P. et al. DC-SIGN
pubmed: 26070485
pmcid: 4690204
doi: 10.1016/j.immuni.2015.05.009
Copenhaver, A. M., Casson, C. N., Nguyen, H. T., Duda, M. M. & Shin, S. IL-1R signaling enables bystander cells to overcome bacterial blockade of host protein synthesis. Proc. Natl Acad. Sci. USA 112, 7557–7562 (2015).
pubmed: 26034289
pmcid: 4475993
doi: 10.1073/pnas.1501289112
Lim, J. F., Berger, H. & Su, I. H. Isolation and activation of murine lymphocytes. J. Vis. Exp. 116, 54596 (2016).
Kohler, M. et al. One-step purification of functional human and rat pancreatic alpha cells. Integr. Biol. 4, 209–219 (2012).
doi: 10.1039/c2ib00125j
Cardoso, F. et al. Neuro-mesenchymal units control ILC2 and obesity via a brain–adipose circuit. Nature 597, 410–414 (2021).
pubmed: 34408322
pmcid: 7614847
doi: 10.1038/s41586-021-03830-7