Hepatitis Delta co-infection in humanized mice leads to pronounced induction of innate immune responses in comparison to HBV mono-infection

Background & Aims: The limited availability of hepatitis Delta virus (HDV) infection models has hindered studies of interactions between HDV and infected hepatocytes. The aim was to investigate the antiviral state of HDV infected human hepatocytes in the setting of co-infection with hepatitis B virus (HBV) compared to HBV mono-infection using human liver chimeric mice. Methods: Viral loads, human interferon stimulated genes (hISGs) and cytokines were determined in humanized uPA/SCID/beige (USB) mice by qRT-PCR, ELISA and immunofluorescence. Results: Upon HBV/HDV inoculation, all mice developed viremia, which was accompanied by a significant induction of hISGs (i.e. hISG15, hSTATs, hHLA-E) compared to uninfected mice, while HBV mono-infection led to weaker hISG elevations. In the setting of chronic infection enhancement of innate defense mechanisms was significantly more prominent in HBV/HDV infected mice. Also the induction of human-specific cytokines (hIP10, hTGF-beta, hIFN-beta and hIFN-lambda) was detected in HBV/HDV co-infected animals, while levels remained lower or below detection in uninfected and HBV mono-infected mice. Moreover, despite the average increase of hSTAT levels determined in HBV/HDV infected livers, we observed a weaker hSTAT accumulation in nuclei of hepatocytes displaying very high HDAg levels, suggesting that HDAg may in part limit hSTAT signaling. Conclusions: Establishment of HDV infection provoked a clear enhancement of the antiviral state of the human hepatocytes in chimeric mice. Elevated pre-treatment ISG and interferon levels may directly contribute to inflammation and liver damage, providing a rationale for the more severe course of HDV-associated liver disease. Such antiviral state induction might also contribute to the lower levels of HBV activity frequently found in co-infected hepatocytes. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved

Control of SARS-CoV-2 infection in rituximab-treated neuroimmunological patients

Background!#!Diagnostic classification of central vs. peripheral etiologies in acute vestibular disorders remains a challenge in the emergency setting. Novel machine-learning methods may help to support diagnostic decisions. In the current study, we tested the performance of standard and machine-learning approaches in the classification of consecutive patients with acute central or peripheral vestibular disorders.!##!Methods!#!40 Patients with vestibular stroke (19 with and 21 without acute vestibular syndrome (AVS), defined by the presence of spontaneous nystagmus) and 68 patients with peripheral AVS due to vestibular neuritis were recruited in the emergency department, in the context of the prospective EMVERT trial (EMergency VERTigo). All patients received a standardized neuro-otological examination including videooculography and posturography in the acute symptomatic stage and an MRI within 7 days after symptom onset. Diagnostic performance of state-of-the-art scores, such as HINTS (Head Impulse, gaze-evoked Nystagmus, Test of Skew) and ABCD!##!Results!#!Machine-learning methods (e.g., MultiGMC) outperform univariate scores, such as HINTS or ABCD!##!Conclusions!#!Established clinical scores (such as HINTS) provide a valuable baseline assessment for stroke detection in acute vestibular syndromes. In addition, machine-learning methods may have the potential to increase sensitivity and selectivity in the establishment of a correct diagnosis

KIR3DS1 directs NK cell-mediated protection against human adenovirus infections

Human adenoviruses (HAdVs) are a major cause for disease in children, in particular after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Currently, effective therapies for HAdV infections in immunocompromised hosts are lacking. To decipher immune recognition of HAdV infection and determine new targets for immune-mediated control, we used an HAdV infection 3D organoid system, based on primary human intestinal epithelial cells. HLA-F, the functional ligand for the activating NK cell receptor KIR3DS1, was strongly up-regulated and enabled enhanced killing of HAdV5-infected cells in organoids by KIR3DS1(+) NK cells. In contrast, HLA-A and HLA-B were significantly down-regulated in HAdV5-infected organoids in response to adenoviral E3/glycoprotein 19K, consistent with evasion from CD8(+) T cells. Immunogenetic analyses in a pediatric allo-HSCT cohort showed a reduced risk to develop severe HAdV disease and faster clearance of HAdV viremia in children receiving KIR3DS1(+)/HLA-Bw4(+) donor cells compared with children receiving non-KIR3DS1(+)/HLA-Bw4(+) cells. These findings identify the KIR3DS1/HLA-F axis as a new target for immunotherapeutic strategies against severe HAdV disease