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Publications

Journal Article Multicenter Study Epublish

PubMed: 40342417 DOI: 10.3389/fimmu.2025.1543626

Regulatory cytokines modulate early isotype-specific response associated with COVID-19 survival.

Front Immunol 16:1543626

Authors: Sebastián Castro-Trujillo, Juanita Castro-Meneses, María Clemencia Rojas, Marcela Castro-Amaya, Giovani Lastra, Carlos F Narváez

Affiliations

  • División de Inmunología, Programa de Medicina, Facultad de Ciencias de la Salud, Universidad Surcolombiana, Neiva, Huila, Colombia.
  • División de Inmunología, Programa de Medicina, Facultad de Ciencias de la Salud, Universidad Surcolombiana, Neiva, Huila, Colombia. Programa de Biología Aplicada, Facultad de Ciencias Exactas y Naturales, Universidad Surcolombiana, Neiva, Huila, Colombia.
  • Dirección Laboratorio de Salud Pública, Secretaría de Salud Departamental, Gobernación del Huila, Neiva, Huila, Colombia.
  • Departamento de Medicina Interna, E.S.E. Hospital Universitario de Neiva. Programa de Medicina, Universidad Surcolombiana, Neiva, Huila, Colombia.
  • Servicio de Neumología, E.S.E. Hospital Universitario de Neiva. Programa de Medicina, Universidad Surcolombiana, Neiva, Huila, Colombia.

Abstract

Identifying immune markers driving early and effective antibody response in patients with severe coronavirus disease 2019 (COVID-19) is critical due to the threat of future coronavirus pandemics, incomplete global vaccination, and suboptimal booster coverage. Patients with life-threatening severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are characterized by dysregulated thromboinflammation and cytokine storm that could influence the isotype virus-specific antibody response and the subsequent clinical outcome. We investigated the association between COVID-19-related mortality with the dynamics, magnitude, and relative avidity of nucleoprotein (N), spike (S), and receptor-binding domain (RBD)-specific IgM, IgA, and IgG in circulation. We also assessed the relationship between the virus-specific antibody responses and cytokine patterns, as well as systemic and pulmonary thromboinflammation markers. This multicenter study included COVID-19 patients hospitalized early in the pandemic, classified as survivors (n=62) and non-survivors (n=17). We developed indirect enzyme-linked immunosorbent assays (ELISAs) to evaluate each virus-specific isotype using well-characterized outpatient COVID-19 (n=180) and pre-pandemic cohorts (n=111). The pro-inflammatory interleukin (IL)-6 and tumor necrosis factor (TNF)-α, as well as the regulatory IL-10, transforming growth factor (TGF)-β1, and soluble tumor necrosis factor receptor I (sTNFRI) levels were evaluated. The ELISAs performed highly for all virus-specific isotypes, although modest for IgM-N. Non-survivors increased N-specific, but no S-specific, IgM and IgA responses throughout the disease course and, more notably, a delayed class switching to IgG-S and IgG-RBD compared to survivors. No differences were observed in the virus-specific IgG relative avidity. Survivors exhibited an antibody response proportional to the degree of systemic and pulmonary thromboinflammation, whereas non-survivors showed those dissociated because of their uncontrolled severe thromboinflammation. Only the survivors showed a dominant regulatory cytokine pattern in the early phase of infection (<10 days after symptoms onset), which strongly correlated with developing IgG-S and IgG-RBD protective antibodies. We developed easy-to-use immune assays that enable patient monitoring and identify at-risk populations in low- to middle-income regions. Non-survivors displayed an ineffective N-mediated antibody response, marked by an inability to control inflammation and a compromised time-dependent class switching toward S and RBD-specific IgG. The regulatory cytokine axis, including TGF-β1, maybe a critical immune correlate of effective antibody-mediated immunity in COVID-19.

MeSH

Cytokines, Coronavirus, Antibody Formation, Sars-Cov-2, Tumor Necrosis Factor-Alpha, Neoplasms, Covid-19, Immune System Diseases, Viruses, Immunoglobulin Class Switching, Necrosis, Pandemics, Infections