Suppression of systemic T cell immunity to viral infection during liver injury is prevented by inhibition of interferon and IL-10 signaling

Patients with liver injury such as cirrhosis are at increased risk of intractable viral infections and are hyporesponsive to vaccination. Here, we report that liver injury leads to inhibition of systemic T cell immunity (LIST), which abrogated anti-viral immunity and caused persistent infection in preclinical liver injury models. Enhanced gut microbial-translocation but not dysbiosis induced tonic type-I-interferon (IFN) signaling in hepatic myeloid cells, which was responsible for their excessive production of IL-10 after viral infection. Antibiotic treatment reducing intestinal microbial burden or inhibition of IFN- and IL-10-signaling all restored anti-viral immunity without immune pathology. Importantly, inhibition of IL-10 restored virus-specific immune responses to vaccination in cirrhotic patients. Thus, LIST results from sequential events involving intestinal microbial translocation, hepatic myeloid cell-derived IFN-/IL-10 expression, and finally inhibitory IL-10 receptor-signaling in T cells, of which IL-10R-signaling may serve as target to reconstitute anti-viral T cell immunity in cirrhotic patients.

DiSCERN - Deep Single Cell Expression ReconstructioN for improved cell clustering and cell subtype and state detection

Single cell sequencing provides detailed insights into biological processes including cell differentiation and identity. While providing deep cell-specific information, the method suffers from technical constraints, most notably a limited number of expressed genes per cell, which leads to suboptimal clustering and cell type identification. Here we present DISCERN, a novel deep generative network that reconstructs missing single cell gene expression using a reference dataset. DISCERN outperforms competing algorithms in expression inference resulting in greatly improved cell clustering, cell type and activity detection, and insights into the cellular regulation of disease. We used DISCERN to detect two unseen COVID-19-associated T cell types, cytotoxic CD4+ and CD8+ Tc2 T helper cells, with a potential role in adverse disease outcome. We utilized T cell fraction information of patient blood to classify mild or severe COVID-19 with an AUROC of 81% that can serve as a biomarker of disease stage. DISCERN can be easily integrated into existing single cell sequencing workflows and readily adapted to enhance various other biomedical data types.

Three separate spike antigen exposures by COVID-19 vaccination or SARS-CoV-2 infection elicit strong humoral immune responses in healthcare workers

As part of our ongoing prospective seroprevalence study, we assessed the SARS-CoV-2 infection and COVID-19 vaccination-induced immunity of 697 hospital workers at the University Medical Center Hamburg-Eppendorf between January 17 and 31, 2022. The overall prevalence of anti-NC-SARS-CoV-2 antibodies indicating prior infection was 9.8% (n=68) and thus lower than the seroprevalence in the general population in Hamburg. At the current study visit, 99.3% (n=692) had received at least one vaccine dose and 93.1% (n=649) had received at least three vaccine doses. All vaccinated individuals had detectable anti-S1-RBD-SARS-CoV-2 antibodies (median AU/ml [IQR]: 13891 [8505 - 23543]), indicating strong protection against severe COVID-19. In addition, we show that individuals who received three COVID-19 vaccine doses (median AU/ml [IQR]: 13856 [8635 - 22705]), and those who resolved a prior SARS-CoV-2 infection and received two COVID-19 vaccine doses (median AU/ml [IQR] 13409 [6934 - 25000]) exhibited the strongest humoral immune responses. The low prevalence of anti-NC-SARS-CoV-2 antibodies indicates persistent effectiveness of established infection control interventions in preventing nosocomial SARS-CoV-2 transmission with the delta and omicron viral variants as predominant strains. Our study further indicates that three exposures to the viral spike protein by either SARS-CoV-2 infection or COVID-19 vaccination are necessary to elicit particularly strong humoral immune responses, which supports current vaccination recommendations.

High effectiveness of multimodal infection control interventions in preventing SARS-CoV-2 infections in healthcare professionals: a prospective longitudinal seroconversion study

ObjectiveTo assess the effectiveness of multimodal infection control interventions in the prevention of SARS-CoV-2 infections in healthcare professionals DesignSequential follow-up study SettingLargest tertiary care centre in northern Germany Participants1253 employees of the University Medical Center Hamburg-Eppendorf were sequentially assessed for the presence of SARS-CoV-2 IgG antibodies at the beginning of the covid-19 epidemic (20 March - 9 April), one month (20 April - 8 May), and another two months later (22 June - 24 July). Of those, 1026 were healthcare workers (HCWs) of whom 292 were directly involved in the care of covid-19 patients. During the study period, infection control interventions were deployed, those included i) strict barrier nursing of all known covid-19 patients including FFP2 (N95) masks, goggles, gloves, hoods and protective gowns, ii) visitor restrictions with access control at all hospital entries, iii) mandatory wearing of disposable face masks in all clinical settings, and iv) universal RT-PCR admission screening of patients. Main Outcome MeasuresSARS-CoV-2 IgG seroconversion rate ResultsAt the initial screening, ten participants displayed significant IgG antibody ratios. Another ten individuals showed seroconversion at the second time point one month later, only two further participants seroconverted during the subsequent two months. The overall SARS-CoV-2 seroprevalence in the study cohort at the last follow-up was 1.8%, the seroconversion rate dropped from 0.81% to 0.08% per month despite a longer observation period. Amongst HCWs seropositivity was increased in those directly involved in the care of patients with SARS-CoV-2 infections (3.8%, n=11) compared to other HCWs (1.4%, n=10, P=0.025). However, after the adoption of all multimodal infection control interventions seroconversions were observed in only two more HCWs, neither of whom were involved in inpatient care. ConclusionMultimodal infection control and prevention interventions are highly effective in mitigating SARS-CoV-2 infections of healthcare professionals.