Helminth Antigens Modulate Virus-Induced Activation of CD154 (CD40L) Expression on T Cells in Onchocerca volvulus-Infected Individuals

Background: The interaction between helminth and viral infections has important implications for understanding viral disease outcomes and vaccine efficacy in helminth-endemic regions. We previously demonstrated that helminth seropositivity is associated with reduced Th1/Th17 cytokine levels and reduced COVID-19 severity; however, the underlying immunological mechanisms remain unclear. This study further investigated these mechanisms by assessing how helminth antigens influence SARS-CoV-2-induced T-cell responses in individuals infected with filarial parasites in vitro. Methods: Peripheral blood mononuclear cells (PBMCs) from 43 participants, including Onchocerca volvulus-infected individuals, filarial lymphedema patients, and non-endemic controls, were stimulated in vitro with SARS-CoV-2 peptides and Ascaris lumbricoides antigens. Results: Fluorescence-activated cell sorting analysis showed a significant reduction in SARS-CoV-2-induced CD154 expression on CD4+ T cells but an increase on CD8+ T cells in O. volvulus-infected participants (p < 0.0001). A. lumbricoides antigens alone did not induce significant T-cell activation in O. volvulus-infected individuals. However, SARS-CoV-2 peptides strongly activated CD4+CD154+ T cells response (p = 0.0074), but co-stimulation with A. lumbricoides antigens markedly reduced CD3+ and CD4+CD154+ T-cell expression frequencies (p = 0.0329 and p = 0.0452). A. lumbricoides-specific IgG correlated inversely with SARS-CoV-2-induced CD4+CD154+ expression (r = −0.6025, p = 0.0049), whereas SARS-CoV-2-specific IgG was positively associated with CD4+CD154+ and CD8+CD154+ T-cell responses (β = 0.532, p = 0.016 and β = 0.509, p = 0.022). Conclusion: These findings demonstrate that helminth antigens modulate functional SARS-CoV-2-induced T-cell responses, offering a potential mechanism through which helminth co-infections shape antiviral immunity, vaccine efficacy, and clinical disease outcomes.