tetano
Editor, Senior Moderator
Front Immunol
. 2026 May 4:17:1787799.
doi: 10.3389/fimmu.2026.1787799. eCollection 2026.
De novo COVID-19-associated insulin resistance drives dysregulated neutrophil extracellular trap formation (NETosis) four months after infection
Sergio Sanhueza[SUP] #[/SUP][SUP] 1 [/SUP], Camilo Cabrera[SUP] #[/SUP][SUP] 1 [/SUP], Romina Quiroga[SUP] 1 [/SUP], Bárbara Antilef[SUP] 1 [/SUP], Camila Muñoz[SUP] 1 2 [/SUP], Agustín Vera[SUP] 1 [/SUP], Ricardo Cartes[SUP] 1 3 [/SUP], Liliana Lamperti[SUP] 1 [/SUP], Enrique Guzmán-Gutiérrez[SUP] 1 [/SUP], Claudio Aguayo[SUP] 1 [/SUP], Valeska Ormazábal[SUP] 1 [/SUP], Mauricio Alejandro Hernández[SUP] 4 [/SUP], Jaime Lastra[SUP] 5 [/SUP], Benilde Riffo[SUP] 6 [/SUP], Gustavo Cerda[SUP] 7 [/SUP], Luciano Ferrada[SUP] 7 [/SUP], David De Gonzalo-Calvo[SUP] 8 9 [/SUP], María C García-Hidalgo[SUP] 8 9 [/SUP], Mario Henríquez[SUP] 10 11 12 [/SUP], María Inés Barría[SUP] 13 [/SUP], Ricardo A Verdugo[SUP] 14 [/SUP], Alicia Colombo[SUP] 15 [/SUP], Gonzalo Labarca[SUP] 1 12 16 17 [/SUP], Estefanía Nova-Lamperti[SUP] 1 [/SUP]
Affiliations
Background: Glucose metabolism disorders (GMDs) are established risk factors for severe COVID-19, but increasing evidence indicates that they may also develop de novo after SARS-CoV-2 infection. Neutrophil extracellular trap formation (NETosis) plays a central role in immunothrombosis, and because neutrophils rely predominantly on glycolysis, they are particularly sensitive to systemic metabolic disturbances. However, the impact of post-COVID-19 GMDs on NETosis remains poorly understood. This study aimed to characterize the emergence of GMDs after COVID-19 and to determine their effect on neutrophil NETosis.
Methods: Sixty COVID-19 patients were stratified according to the presence or absence of GMDs before infection and at four months post-infection. Demographic, clinical, metabolic, and inflammatory parameters were assessed. Vital NETosis was quantified by flow cytometry. In addition, the capacity of patient plasma to induce NETosis was evaluated using live-cell imaging of healthy neutrophils as biosensors.
Results: Among patients without pre-existing GMDs, 24 of 36 developed insulin resistance (IR) four months after COVID-19. Neutrophils from these patients exhibited increased basal NETosis but showed impaired NETosis in response to TLR7/8 agonists, key sensors of viral single-stranded RNA, compared with control groups. In contrast, NETosis responses to IL-6 and TNF-α were preserved, excluding an intrinsic neutrophil defect. Plasma from IR patients significantly enhanced NETosis, and in vitro experiments demonstrated that insulin enhances NETosis independently of glucose concentrations.
Discussion: De novo IR following COVID-19 dysregulates NETosis primarily through an insulin-enhancing effect. Post-viral control of glucose metabolism disorders may be critical to limit pathological NETosis and its thrombo-inflammatory consequences.
Keywords: COVID-19; NETosis; insulin resistance; long-covid; neutrophil.
. 2026 May 4:17:1787799.
doi: 10.3389/fimmu.2026.1787799. eCollection 2026.
De novo COVID-19-associated insulin resistance drives dysregulated neutrophil extracellular trap formation (NETosis) four months after infection
Sergio Sanhueza[SUP] #[/SUP][SUP] 1 [/SUP], Camilo Cabrera[SUP] #[/SUP][SUP] 1 [/SUP], Romina Quiroga[SUP] 1 [/SUP], Bárbara Antilef[SUP] 1 [/SUP], Camila Muñoz[SUP] 1 2 [/SUP], Agustín Vera[SUP] 1 [/SUP], Ricardo Cartes[SUP] 1 3 [/SUP], Liliana Lamperti[SUP] 1 [/SUP], Enrique Guzmán-Gutiérrez[SUP] 1 [/SUP], Claudio Aguayo[SUP] 1 [/SUP], Valeska Ormazábal[SUP] 1 [/SUP], Mauricio Alejandro Hernández[SUP] 4 [/SUP], Jaime Lastra[SUP] 5 [/SUP], Benilde Riffo[SUP] 6 [/SUP], Gustavo Cerda[SUP] 7 [/SUP], Luciano Ferrada[SUP] 7 [/SUP], David De Gonzalo-Calvo[SUP] 8 9 [/SUP], María C García-Hidalgo[SUP] 8 9 [/SUP], Mario Henríquez[SUP] 10 11 12 [/SUP], María Inés Barría[SUP] 13 [/SUP], Ricardo A Verdugo[SUP] 14 [/SUP], Alicia Colombo[SUP] 15 [/SUP], Gonzalo Labarca[SUP] 1 12 16 17 [/SUP], Estefanía Nova-Lamperti[SUP] 1 [/SUP]
Affiliations
- PMID: 42158877
- PMCID: PMC13182236
- DOI: 10.3389/fimmu.2026.1787799
Background: Glucose metabolism disorders (GMDs) are established risk factors for severe COVID-19, but increasing evidence indicates that they may also develop de novo after SARS-CoV-2 infection. Neutrophil extracellular trap formation (NETosis) plays a central role in immunothrombosis, and because neutrophils rely predominantly on glycolysis, they are particularly sensitive to systemic metabolic disturbances. However, the impact of post-COVID-19 GMDs on NETosis remains poorly understood. This study aimed to characterize the emergence of GMDs after COVID-19 and to determine their effect on neutrophil NETosis.
Methods: Sixty COVID-19 patients were stratified according to the presence or absence of GMDs before infection and at four months post-infection. Demographic, clinical, metabolic, and inflammatory parameters were assessed. Vital NETosis was quantified by flow cytometry. In addition, the capacity of patient plasma to induce NETosis was evaluated using live-cell imaging of healthy neutrophils as biosensors.
Results: Among patients without pre-existing GMDs, 24 of 36 developed insulin resistance (IR) four months after COVID-19. Neutrophils from these patients exhibited increased basal NETosis but showed impaired NETosis in response to TLR7/8 agonists, key sensors of viral single-stranded RNA, compared with control groups. In contrast, NETosis responses to IL-6 and TNF-α were preserved, excluding an intrinsic neutrophil defect. Plasma from IR patients significantly enhanced NETosis, and in vitro experiments demonstrated that insulin enhances NETosis independently of glucose concentrations.
Discussion: De novo IR following COVID-19 dysregulates NETosis primarily through an insulin-enhancing effect. Post-viral control of glucose metabolism disorders may be critical to limit pathological NETosis and its thrombo-inflammatory consequences.
Keywords: COVID-19; NETosis; insulin resistance; long-covid; neutrophil.