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COVID-19, caused by SARS-CoV-2, has emerged as a global pandemic. While immune responses of the adaptive immune system have been in the focus of research, the role of NK cells in COVID-19 remains less well understood. Here, we characterized NK cell-mediated SARS-CoV-2 antibody-dependent cellular cytotoxicity (ADCC) against SARS-CoV-2 spike-1 (S1) and nucleocapsid (NC) protein. Serum samples from SARS-CoV-2 resolvers induced significant CD107a-expression by NK cells in response to S1 and NC, while serum samples from SARS-CoV-2-negative individuals did not. Furthermore, serum samples from individuals that received the BNT162b2 vaccine induced strong CD107a expression by NK cells that increased with the second vaccination and was significantly higher than observed in infected individuals. As expected, vaccine-induced responses were only directed against S1 and not against NC protein. S1-specific CD107a responses by NK cells were significantly correlated to NK cell-mediated killing of S1-expressing cells. Interestingly, screening of serum samples collected prior to the COVID-19 pandemic identified two individuals with cross-reactive antibodies against SARS-CoV-2 S1, which also induced degranulation of NK cells. Taken together, these data demonstrate that antibodies induced by SARS-CoV-2 infection and anti-SARS-CoV-2 vaccines can trigger significant NK cell-mediated ADCC activity, and identify some cross-reactive ADCC-activity against SARS-CoV-2 by endemic coronavirus-specific antibodies.

The outcomes of many diseases differ between women and men, with women experiencing a higher incidence and more severe pathogenesis of autoimmune and some infectious diseases. It has been suggested that this is partially due to activation of plasmacytoid dendritic cells (pDCs), the main producers of interferon (IFN)-α, in response to toll-like receptor (TLR)7 stimulation. We investigated the induction of type I IFN (IFN-I) subtypes upon TLR7 stimulation on isolated pDCs. Our data revealed a sex-specific differential expression of IFN-Is, with pDCs from females showing a significantly higher mRNA expression of all 13 IFN-α subtypes. In addition, pDCs from females had higher levels of IFN-β mRNA after stimulation, indicating that sex differences in IFN-I production by pDCs were mediated by a signaling event upstream of the first loop of IFN-I mRNA transcription. Furthermore, the surface expression levels of the common IFN-α/β receptor subunit 2 were significantly higher on pDCs from females in comparison to males. These data indicate that higher IFN-α production is already established at the mRNA level and propose a contribution of higher IFN-α/β receptor 2 expression on pDCs to the immunological differences in IFN-I production observed between females and males.

The transcription factor X-box binding protein 1 (XBP1) represents a key component of the endoplasmatic reticulum (ER) stress response and is required for the production of several pro-inflammatory cytokines. XBP1 is furthermore essential for the development and survival of plasmacytoid dendritic cells (pDCs), and has recently been suggested to be involved in toll-like receptor (TLR) 2/4 signaling. Activation of TLR7 on pDCs results in an upregulation of pro-inflammatory cytokines, such as type I interferons (IFN-I), and has been implicated in several autoimmune and inflammatory diseases, but the role of XBP1 in this process remains unknown. Here, we show that signaling via TLR7 leads to an upregulation of XBP1 and IFNα-production. XBP1 mRNA expression levels positively correlated with the production of IFNα, while blocking of XBP1 mRNA splicing significantly reduced mRNA transcripts of IFNα. In conclusion, these data suggest a central role of XBP1 in TLR7-induced IFNα production and identify XBP1 as a potential novel therapeutic target in IFNα-driven autoimmune and inflammatory diseases.

Increased IFN-α production contributes to the pathogenesis of infectious and autoimmune diseases. Plasmacytoid dendritic cells (pDCs) from females produce more IFN-α upon TLR7 stimulation than pDCs from males, yet the mechanisms underlying this difference remain unclear. In this article, we show that basal levels of IFN regulatory factor (IRF) 5 in pDCs were significantly higher in females compared with males and positively correlated with the percentage of IFN-α–secreting pDCs. Delivery of recombinant IRF5 protein into human primary pDCs increased TLR7-mediated IFN-α secretion. In mice, genetic ablation of the estrogen receptor 1 (Esr1) gene in the hematopoietic compartment or DC lineage reduced Irf5 mRNA expression in pDCs and IFN-α production. IRF5 mRNA levels furthermore correlated with ESR1 mRNA levels in human pDCs, consistent with IRF5 regulation at the transcriptional level by ESR1. Taken together, these data demonstrate a critical mechanism by which sex differences in basal pDC IRF5 expression lead to higher IFN-α production upon TLR7 stimulation in females and provide novel targets for the modulation of immune responses and inflammation.

Background: A postprocedural increase of the serum troponin I concentration (TnI) reflects myocardial injury and occurs frequently during transcatheter aortic valve implantation (TAVI). Periprocedural coronary microembolization is a potential cause of such injury. We therefore evaluated each step of the transfemoral TAVI procedure for coronary embolization using intracoronary Doppler (ICD) in the left anterior descending (LAD) artery. Methods: 15 high-risk patients with severe, symptomatic aortic valve stenosis (age 79 ± 45 yrs; EuroScore 17 ± 4%) who underwent transfemoral TAVI using the balloon-expandable Edwards bioprosthesis were included. ICD examinations were recorded and evaluated off-line for high-intensity transient signals (HITS). Perioperative concentrations of TnI were serially measured within the first 72 h after TAVI, and a cardiac MRI with late gadolinium-enhancement (LGE) was performed within 7 days. Results: HITS were detected in all patients (figure 1), mostly during the initial crossing of the native valve and positioning of the prosthesis with subsequent implantation. TnI peaked at 24 h after TAVI (3.17 ng/ml), and LGE was observed in only one single case. There was no correlation between amount of HITS and TnI area under the curve in the first 72 h after TAVI. Conclusions: Procedural HITS were detected by ICD in all patients undergoing transfemoral TAVI. The highest amount of HITS was observed during initial valve passage and positioning of the prosthesis with subsequent implantation. However, no association was found between the number of HITS and myocardial injury, as reflected by increased serum TnI concentrations or LGE on cardiac MRI.

The outcomes of many diseases differ between women and men, with women having a higher incidence and more severe pathogenesis of autoimmune and some infectious diseases, including influenza and HIV-1. In HIV-1 infection, clinical studies have shown faster disease progression and stronger immune activation in females compared to males for the same level of viral replication, as well as better control of initial viremia in women during primary infection (Meier, 2009; Sterling, 2001; Farzadegan, 1998). It has been suggested that this is partially due to TLR-mediated activation of pDC, the main producers of IFN- α , in response to HIV-1 ssRNA. We investigated the induction of type I interferons upon TLR7/8 stimulation on sorted pDC. PBMCs were stimulated for 2 h with a synthetic TLR7/8 ligand. pDC cells were isolated by flow-based sorting and subsequently mRNA was isolated. qRT-PCR revealed a sex-specific differential expression of type I Interferons, with pDC from females showing a higher expression level of corresponding interferons compared to males, including all IFN α -subtypes (p = 0.003), as well as type III Interferons (IFN λ 1 p = 0.03). Of note, pDCs from females also showed higher IFN β expression (p = 0.059), which is part of the initial wave of gene transcription that triggers a positive feedback loop, leading to the induction of additional IFN α -encoding genes. These data demonstrate that sex-specific differences described in response to HIV-1 are associated with enhanced expression of several Interferons, with IFN β being potentially responsible for the initiation of differential type I Interferon production between males and females.