Longitudinal analyses of the innate immune system including earliest time points are essential to understand the immunopathogenesis and clinical course of COVID-19. Here, we performed a detailed characterization of natural killer cells in 205 patients (403 samples, day 2-41 after symptom onset) from four independent cohorts using single-cell transcriptomics and proteomics together with functional studies. We found elevated IFN-α plasma levels in early severe COVD-19 alongside increased NK cell expression of ISGs and genes involved in IFN-α signaling, while upregulation of TNF-induced genes was observed in moderate disease. NK cells exert anti-SARS-CoV-2 activity but are functionally impaired in severe COVID-19. Further, NK cell dysfunction may be relevant for development of fibrotic lung disease in severe COVID-19, as NK cells exhibited impaired anti-fibrotic activity. Our study indicates preferential IFN-α and TNF responses in severe and moderate COVID-19, respectively, and associates prolonged IFN-α-induced NK cell response with poorer disease outcome.

Background De novo steatosis is the main criteria for non-alcoholic fatty liver disease (NAFLD), which is becoming a clinically relevant comorbidity in HIV-infected patients. This may be due to the HIV virus itself, as well as long-term toxicities deriving from antiretroviral therapy. Therefore, HIV infected patients require prevention and monitoring regarding NAFLD. Methods This study investigated the differential role of body mass index (BMI) and combination antiretroviral treatment (cART) drugs on NAFLD progression. This single center prospective longitudinal observational study enrolled HIV monoinfected individuals between August 2013 to December 2018 with yearly visits. Each visit included liver stiffness and steatosis [defined as controlled attenuation parameter (CAP)>237 dB/m] assessment by annually transient elastography using an M- or XL-probe of FibroScan, and calculation of the novel FibroScan-AST (FAST) score. Risk factors for denovo/progressed steatosis and tripling of FAST-score increase were investigated using Cox regression model with time-dependent covariates. Findings 319 monoinfected HIV positive patients with at least two visits were included into the study, of which 301 patients had at least two valid CAP measurements. 51·5%(155) patients did not have steatosis at first assessment, of which 45%(69) developed steatosis during follow-up. A BMI>23 kg/m 2 (OR: 4·238, 95% CI: 2·078–8·938; p < 0·0001), tenofovir-alafenamid (TAF) (OR: 5·073, 95% CI: 2·362–10·899); p < 0·0001) and integrase strand transfer inhibitors (INSTI) (OR: 2·354, 95% CI: 1·370–4·048; p = 0·002), as well as type 2 diabetes mellitus (OR: 7·605, 95% CI: 2·315–24·981; p < 0·0001) were independent predictors of de novo steatosis in multivariable analysis. Tenofovir disoproxilfumarate (TDF) was associated with a lower risk for weight gain and steatosis progression/onset using CAP value (HR: 0·28, 95% CI: 0·12–0·64; p = 0·003) and FAST scores (HR: 0·31, 95% CI: 0·101–0·945; p = 0·04). Interpretation Steatosis can develop despite non-obese BMI in patients with HIV monoinfection under cART, especially in male patients with BMI over 23 kg/m 2 . While TAF and INSTI increase the risk of progression of steatosis, TDF was found to be independently associated with a lower risk of a clinically significant weight gain and thereby, might slow down development and progression of steatosis. Funding There was no additional funding received for this project. All funders mentioned in the ‘declaration of interests’ section had no influence on study design, data collection and analysis, decision to publish, or preparation of the manuscript.

We found high SVR12 rates in monoinfected as well as coinfected individuals. No differences were detected between the two subgroups regardless of whether there was accompanying liver cirrhosis or a shortened treatment duration.

We compared the ability of SARS-CoV2 Spike-specific antibodies to induce natural killer (NK) cell-mediated antibody dependent cellular cytotoxicity (ADCC) in patients with natural infection and vaccinated persons. Analyzing plasma samples from 39 COVID-19 patients and 11 vaccinated individuals, significant induction of ADCC could be observed over a period of more than three months in both vaccinated and recovered individuals. Although plasma antibody concentrations were lower in recovered patients, we found antibodies elicited by natural infection induced a significantly stronger ADCC response compared to those induced by vaccination, which may affect protection conferred by vaccination.

Endotoxin inhibits HSP70 expression in PBMC ex vivo. In vivo, the suppression of HSP70 expression induced by endotoxin and high levels of proinflammatory cytokines may contribute to the cellular dysfunction of immunocompetent cells concerning antigen presentation, phagocytosis and antibody production associated with decreased resistance to infectious insults during severe sepsis.