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

  • Hart, B. L. Biological basis of the behavior of sick animals. Neurosci. Biobehav Rev. 12, 123–137 (1988).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • 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).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Krapic, M., Kavazovic, I. & Wensveen, F. M. Immunological mechanisms of sickness behavior in viral infection. Viruses 13, 2245 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • ElSayed, N. A. et al. 2. Classification and diagnosis of diabetes: standards of care in diabetes-2023. Diabetes Care 46, S19–S40 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Petersen, M. C. & Shulman, G. I. Mechanisms of insulin action and insulin resistance. Physiol. Rev. 98, 2133–2223 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 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).

    Article 
    PubMed 

    Google Scholar
     

  • Kavazovic, I. et al. Hyperglycemia and not hyperinsulinemia mediates diabetes-induced memory CD8 T cell dysfunction. Diabetes 71, 706–721 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Plummer, M. P. & Deane, A. M. Dysglycemia and glucose control during sepsis. Clin. Chest Med. 37, 309–319 (2016).

    Article 
    PubMed 

    Google Scholar
     

  • 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).

    Article 
    PubMed 

    Google Scholar
     

  • 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).

    Article 
    CAS 

    Google Scholar
     

  • 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).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 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).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hijano, D. R. et al. Clinical correlation of influenza and respiratory syncytial virus load measured by digital PCR. PLoS ONE 14, e0220908 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 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).

    Article 
    PubMed 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Goyal, P. & Rajala, M. S. Reprogramming of glucose metabolism in virus infected cells. Mol. Cell. Biochem. 478, 2409–2418 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • 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).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhang, W. et al. Lactate is a natural suppressor of RLR signaling by targeting MAVS. Cell 178, 176–189 e115 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Brown, G. R. et al. Gene: a gene-centered information resource at NCBI. Nucleic Acids Res. 43, D36–D42 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Pahl, H. L. Activators and target genes of Rel/NF-κB transcription factors. Oncogene 18, 6853–6866 (1999).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Steuerman, Y. et al. Dissection of influenza infection in vivo by single-cell RNA sequencing. Cell Syst. 6, 679–691 e674 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ivashkiv, L. B. IFNγ: signalling, epigenetics and roles in immunity, metabolism, disease and cancer immunotherapy. Nat. Rev. Immunol. 18, 545–558 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 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).

    Article 
    PubMed 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bekiaris, V. et al. Ly49H+ NK cells migrate to and protect splenic white pulp stroma from murine cytomegalovirus infection. J. Immunol. 180, 6768–6776 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Tracey, W. R. et al. Cardioprotective effects of ingliforib, a novel glycogen phosphorylase inhibitor. Am. J. Physiol. Heart Circ. Physiol. 286, H1177–H1184 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wensveen, F. M. et al. NK cells link obesity-induced adipose stress to inflammation and insulin resistance. Nat. Immunol. 16, 376–385 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Saisho, Y. Importance of beta cell function for the treatment of type 2 diabetes. J. Clin. Med 3, 923–943 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Teng, R. J., Wu, T. J. & Ho, M. M. Mumps infection complicated by transient hyperinsulinemic hypoglycemia. Pediatr. Infect. Dis. J. 16, 416–417 (1997).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • 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).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lewis, S. M., Williams, A. & Eisenbarth, S. C. Structure and function of the immune system in the spleen. Sci. Immunol. 4, eaau6085 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Stein, S. R. et al. SARS-CoV-2 infection and persistence in the human body and brain at autopsy. Nature 612, 758–763 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, A. et al. Opposing effects of fasting metabolism on tissue tolerance in bacterial and viral inflammation. Cell 166, 1512–1525 e1512 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Man, K. et al. A thermogenic fat-epithelium cell axis regulates intestinal disease tolerance. Proc. Natl Acad. Sci. USA 117, 32029–32037 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Guo, W. et al. Diabetes is a risk factor for the progression and prognosis of COVID-19. Diabetes Metab. Res Rev. 36, e3319 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Apicella, M. et al. COVID-19 in people with diabetes: understanding the reasons for worse outcomes. Lancet Diabetes Endocrinol. 8, 782–792 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Muller, U. et al. Functional role of type I and type II interferons in antiviral defense. Science 264, 1918–1921 (1994).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bubic, I. et al. Gain of virulence caused by loss of a gene in murine cytomegalovirus. J. Virol. 78, 7536–7544 (2004).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Conde, P. et al. DC-SIGN+ macrophages control the induction of transplantation tolerance. Immunity 42, 1143–1158 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lim, J. F., Berger, H. & Su, I. H. Isolation and activation of murine lymphocytes. J. Vis. Exp. 116, 54596 (2016).


    Google Scholar
     

  • Kohler, M. et al. One-step purification of functional human and rat pancreatic alpha cells. Integr. Biol. 4, 209–219 (2012).

    Article 

    Google Scholar
     

  • Cardoso, F. et al. Neuro-mesenchymal units control ILC2 and obesity via a brain–adipose circuit. Nature 597, 410–414 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

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