Alterations in the Expression of IFN Lambda, IFN Gamma and Toll-like Receptors in Severe COVID-19 Patients

Abstract

Contradictory results have been reported regarding interferon (IFN) lambda (λ1–3) and IFN gamma (γ) production in COVID-19 patients. To gain insight into the roles played by these IFNs in SARS-CoV-2 infection, IFNλ1–3 and IFNγ mRNA expression was evaluated in peripheral blood mononuclear cells (PBMCs) (n = 32) and in cells of paired bronchoalveolar lavages (BALs) (n = 12). Lower IFNλ1–3 values (p < 0.001 for IFNλ1 and 3 and p = 0.013 for IFNλ2) in the PBMCs of severely ill patients were found compared to healthy donors (n = 15). Reduced levels of IFNγ were also detected in patients’ PBMCs (p < 0.01) and BALs (p = 0.041) compared to healthy donors. The presence of secondary bacterial infections was associated with decreased IFNλ amounts in PBMCs (p = 0.001, p = 0.015 and p = 0.003, respectively) but increased concentrations of IFNλ3 (p = 0.022) in BALs. Patients with alterations in C-reactive protein, lactate dehydrogenase and D-dimer levels had decreased IFNλ1 and 3 (p = 0.003 and p < 0.001) and increased IFNγ (p = 0.08) in PBMCs. Analyzing Toll-like receptors (TLRs) involved in IFN production, we found that TLR3 was highly expressed (p = 0.033) in patients with bacterial superinfections, while TLR7 and 8 (p = 0.029 and p = 0.049) were reduced in BALs of deceased patients. Overall, severe COVID-19 might be characterized by dysregulation in IFNγ, IFNλ and TLR3, 7 and 8 production.

Association of Interferon Lambda 3 and 4 Gene SNPs and Their Expression with COVID-19 Disease Severity: A Cross-Sectional Study

“…36 It has also been demonstrated in another study that people with IFNL3 TT genotype (rs12979860) and IFNL4 ∆G/∆G genotypes (rs368234815) lead to a lower viral clearance. 17,33,37,38 We found the SNPs in the IFNL4 gene (rs368234815) to be statistically significantly different in the mild versus severe group, which was confirmed both in the univariate and multivariate analysis, where the unadjusted prevalence ratio (3.43) and adjusted prevalence ratio (3.33) were found to be in close agreement (Supplementary Tables 2A and B). This points to the possibility that people who have SNPs (rs368234815) in the IFNL4 gene may be more prone to getting severe COVID-19 disease in the Pakistani population, further creating the possibility that IFNL4 SNPs may serve as an indicator for severe infection.…”

“… 36 It has also been demonstrated in another study that people with IFNL3 TT genotype (rs12979860) and IFNL4 ∆G/∆G genotypes (rs368234815) lead to a lower viral clearance. 17 , 33 , 37 , 38 …”

Humoral Immunity of Unvaccinated COVID-19 Recovered vs. Naïve BNT162b2 Vaccinated Individuals: A Prospective Longitudinal Study

“…This together may suggest that repeated exposure, either by three vaccine doses or hybrid immunity of infection and a vaccine dose, is needed to achieve higher avidity and eventually sustained and robust immunity [ 25 , 32 , 33 ]. While we only studied the humoral response, the differences between vaccinated and recovered individuals could be due to a different cellular response, potentially due to the role of the initial innate immune response as shown during the early stage of infection [ 34 , 35 ], or the mucosal response induced in infected but not in vaccinated individuals.…”

Dr Jekyll and Mr Hyde: From Two Branches of Immune Response to Three Types of Interferon Response

“…Specifically, higher STAT6 expression in pneumocyte cytoplasm and the nucleus was indicated [182]. With regards to IFN signalling, some studies indicate that during infection of individuals (n=32), both TLR7/8 may potentially have been impaired unknown, ruling out type II IFN deficiency, with increases of relevant TLR gene transcripts (TLR3) during pulmonary infection [183]. It was noted that IFN-λR1/IL10RB2 is required by NK cells for type II IFN signalling [183].…”