SARS-CoV-2 in severe COVID-19 induces a TGF-β-dominated chronic immune response that does not target itself

Abstract

The pathogenesis of severe COVID-19 reflects an inefficient immune reaction to SARS-CoV-2. Here we analyze, at the single cell level, plasmablasts egressed into the blood to study the dynamics of adaptive immune response in COVID-19 patients requiring intensive care. Before seroconversion in response to SARS-CoV-2 spike protein, peripheral plasmablasts display a type 1 interferon-induced gene expression signature; however, following seroconversion, plasmablasts lose this signature, express instead gene signatures induced by IL-21 and TGF-β, and produce mostly IgG1 and IgA1. In the sustained immune reaction from COVID-19 patients, plasmablasts shift to the expression of IgA2, thereby reflecting an instruction by TGF-β. Despite their continued presence in the blood, plasmablasts are not found in the lungs of deceased COVID-19 patients, nor does patient IgA2 binds to the dominant antigens of SARS-CoV-2. Our results thus suggest that, in severe COVID-19, SARS-CoV-2 triggers a chronic immune reaction that is instructed by TGF-β, and is distracted from itself.

Endothelial dysfunction determines severe COVID-19 in combination with dysregulated lymphocyte responses and cytokine networks

“…Regarding the humoral immunity to SARS-CoV-2, several studies demonstrated an extraordinary B cell response with absence of germline centers in deceased COVID-19 patients, appearance of extra-follicular B cell activation together with neutralizing antibodies, an extensive class switching to IgG and IgA accompanied by limited somatic hypermutation, as well as TGF-β instructed SARS-CoV-2 unspecific B cell responses (24)(25)(26)(27). As others have previously shown (6), we observed a significant expansion of plasmablasts in severe COVID-19 patients accompanied by IgA and IgG SARS-CoV-2-specific antibodies.…”

Induction of cross-reactive antibody responses against the RBD domain of the spike protein of SARS-CoV-2 by commensal microbiota

“…Systemically distributed antibodies (mainly IgG, IgM, and IgA1) curtail virus propagation after productive infection of the host, while the presence of antigenspecific antibodies secreted at the mucosal surfaces (IgA2, IgA1, and IgM) may prevent initial infection of the host [7]. The absence of IgA2 antibodies specific for SARS-CoV-2 antigens in severely diseased COVID-19 patients has also been demonstrated [8], suggesting that mucosal anti-viral IgA antibodies may protect the host from a severe course of COVID-19. Several studies have reported the presence of RBD-binding antibodies in unexposed healthy individuals [9,10,11,12,13].…”

FGF10 and Lipofibroblasts in Lung Homeostasis and Disease: Insights Gained From the Adipocytes

“…Furthermore, activation of PPAR-γ signaling via rosiglitazone (a potent PPAR-γ agonist) treatment antagonized TGF-β-mediated myofibroblast differentiation likely by reinforcing the lipogenic phenotype ( El Agha et al, 2017b ). Interestingly, TGF-β upregulation has been found to be induced by SARS-Cov-2 infection ( Agrati et al, 2020 ; Chen, 2020 ; Ferreira-Gomes et al, 2021 ) and associated with several complications of severe COVID19, such as ARDS and pulmonary fibrosis. Thus, it is plausible that FGF10, likely via PPAR-γ activation, gets involved in an attempt to replenish LIFs lost to unrestrained MYF differentiation – driven by TGF-β upregulation and chronic epithelial injury ( Figure 2B ).…”