Abstract
The origin of SARS-CoV-2 variants of concern remains unclear. Here, we test whether intra-host virus evolution during persistent infections could be a contributing factor by characterizing ...the long-term SARS-CoV-2 infection dynamics in an immunosuppressed kidney transplant recipient. Applying RT-qPCR and next-generation sequencing (NGS) of sequential respiratory specimens, we identify several mutations in the viral genome late in infection. We demonstrate that a late viral isolate exhibiting genome mutations similar to those found in variants of concern first identified in UK, South Africa, and Brazil, can escape neutralization by COVID-19 antisera. Moreover, infection of susceptible mice with this patient’s escape variant elicits protective immunity against re-infection with either the parental virus and the escape variant, as well as high neutralization titers against the alpha and beta SARS-CoV-2 variants, B.1.1.7 and B.1.351, demonstrating a considerable immune control against such variants of concern. Upon lowering immunosuppressive treatment, the patient generated spike-specific neutralizing antibodies and resolved the infection. Our results suggest that immunocompromised patients could be a source for the emergence of potentially harmful SARS-CoV-2 variants.
Recent findings indicate that many immunopathologies are at their roots a consequence of impaired immune responses (“too little” immunity) and not the result of primarily exaggerated immune responses ...(“too much” immunity). We have summarized this conceptional view as “IMPATH paradox.” In this review, we will focus on impaired immune reactions in the context of CD8+ T‐cell‐mediated immunopathologies. In particular, we will exemplify this concept in two disease models: Virus‐triggered primary hemophagocytic lymphohistiocytosis, an inflammatory syndrome caused by genetically impaired cytolytic functions of T cells, and viral hepatitis, where T‐cell exhaustion is a major underlying mechanism for impaired effector functions. In both situations, T cells fail to eliminate the source of immune stimulation, which usually serves as an important negative feedback loop curtailing immune reactions. Persistent antigen presentation by APCs and/or infected cells results in continuous stimulation causing chronic inflammation and immunopathology mediated by residual T‐cell functions. Hence, immune stimulation or reconstitution rather than immune suppression may be strategies for therapeutic interventions.
In virus‐triggered primary hemophagocytic lymphohistiocytosis and chronic viral hepatitis, impaired immune reactions may cause the underlying immune‐mediated pathology. In particular, dysfunctional CD8+ T cells fail to eliminate the main sources of immune stimulation (infected APCs/hepatocytes), in turn, fueling persisting inflammation and, thus, chronic immunopathology.
Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide with a poor prognosis and limited therapeutic options. To aid the development of novel immunological interventions, we ...studied the breadth, frequency, and tumor‐infiltration of naturally occurring CD8+ T‐cell responses targeting several tumor‐associated antigens (TAA). We used overlapping peptides spanning the entire alpha‐fetoprotein (AFP), glypican‐3 (GPC‐3), melanoma‐associated gene‐A1 (MAGE‐A1) and New York‐esophageal squamous cell carcinoma‐1 (NY‐ESO‐1) proteins and major‐histocompatibility‐complex‐class‐I‐tetramers specific for epitopes of MAGE‐A1 and NY‐ESO‐1 to analyze TAA‐specific CD8+ T‐cell responses in a large cohort of HCC patients. After nonspecific expansion in vitro, we detected interferon‐γ (IFN‐γ)‐producing CD8+ T cells specific for all four TAA in the periphery as well as in liver and tumor tissue. These CD8+ T‐cell responses displayed clear immunodominance patterns within each TAA, but no consistent hierarchy was observed between different TAA. Importantly, the response breadth was highest in early‐stage HCC and associated with patient survival. After antigen‐specific expansion, TAA‐specific CD8+ T cells were detectable by tetramer staining but impaired in their ability to produce IFN‐γ. Furthermore, regulatory T cells (Treg) were increased in HCC lesions. Depletion of Treg from cultures improved TAA‐specific CD8+ T‐cell proliferation but did not restore IFN‐γ‐production. Conclusion: Naturally occurring TAA‐specific CD8+ T‐cell responses are present in patients with HCC and therefore constitute part of the normal T‐cell repertoire. Moreover, the presence of these responses correlates with patient survival. However, the observation of impaired IFN‐γ production suggests that the efficacy of such responses is functionally limited. These findings support the development of strategies that aim to enhance the total TAA‐specific CD8+ T‐cell response by therapeutic boosting and/or specificity diversification. However, further research will be required to help unlock the full potential of TAA‐specific CD8+ T‐cell responses. (Hepatology 2014;59:1415‐1426)
Emerging data indicate that SARS-CoV-2-specific CD8
T cells targeting different viral proteins are detectable in up to 70% of convalescent individuals
. However, very little information is currently ...available about the abundance, phenotype, functional capacity and fate of pre-existing and induced SARS-CoV-2-specific CD8
T cell responses during the natural course of SARS-CoV-2 infection. Here, we define a set of optimal and dominant SARS-CoV-2-specific CD8
T cell epitopes. We also perform a high-resolution ex vivo analysis of pre-existing and induced SARS-CoV-2-specific CD8
T cells, applying peptide-loaded major histocompatibility complex class I (pMHCI) tetramer technology. We observe rapid induction, prolonged contraction and emergence of heterogeneous and functionally competent cross-reactive and induced memory CD8
T cell responses in cross-sectionally analyzed individuals with mild disease following SARS-CoV-2 infection and three individuals longitudinally assessed for their T cells pre- and post-SARS-CoV-2 infection. SARS-CoV-2-specific memory CD8
T cells exhibited functional characteristics comparable to influenza-specific CD8
T cells and were detectable in SARS-CoV-2 convalescent individuals who were seronegative for anti-SARS-CoV-2 antibodies targeting spike (S) and nucleoprotein (N). These results define cross-reactive and induced SARS-CoV-2-specific CD8
T cell responses as potentially important determinants of immune protection in mild SARS-CoV-2 infection.
More than twenty years ago, non-HBV-specific CD8+ T cells were found to contribute to liver immunopathology in chronic HBV infection, while HBV-specific CD8+ T cells were noted to contribute to viral ...control. The role of HBV-specific CD8+ T cells in viral control and the mechanisms of their failure in persistent infection have been intensively studied during the last two decades, but the exact nature of nonspecific bystander CD8+ T cells that contribute to immunopathology has remained elusive. In this issue of the JCI, Nkongolo et al. report on their application of two methodological advances, liver sampling by fine-needle aspiration (FNA) and single-cell RNA sequencing (scRNA-Seq), to define a liver-resident CD8+ T cell population that was not virus specific but associated with liver damage, thus representing hepatotoxic bystander CD8+ T cells.
Effectiveness of seasonal influenza vaccination varies between individuals and might be affected by vaccination history among other factors. Here we show, by monitoring frequencies of CD4 T cells ...specific to the conserved hemagglutinin epitope HA
and titres of IgG against the corresponding recombinant hemagglutinin protein, that antigen-specific CD4 T cell and antibody responses are closely linked to pre-existing immunity and vaccine history. Upon immunization, a strong early reaction is observed in all vaccine naïve participants and also in vaccine experienced individuals who have not received the respective seasonal vaccine in the previous year. This response is characterized by HA
specific CD4 T cells with a follicular helper T cell phenotype and by ascending titers of hemagglutinin-specific antibodies from baseline to day 28 following vaccination. This trend was observed in only a proportion of those participants who received the seasonal vaccine the year preceding the study. Regardless of history, levels of pre-existing antibodies and CD127 expression on CD4 T cells at baseline were the strongest predictors of robust early response. Thus, both pre-existing immunity and vaccine history contribute to the response to seasonal influenza vaccines.
In chronic hepatitis C virus (HCV) infection, exhausted HCV-specific CD8
T cells comprise memory-like and terminally exhausted subsets. However, little is known about the molecular profile and fate ...of these two subsets after the elimination of chronic antigen stimulation by direct-acting antiviral (DAA) therapy. Here, we report a progenitor-progeny relationship between memory-like and terminally exhausted HCV-specific CD8
T cells via an intermediate subset. Single-cell transcriptomics implicated that memory-like cells are maintained and terminally exhausted cells are lost after DAA-mediated cure, resulting in a memory polarization of the overall HCV-specific CD8
T cell response. However, an exhausted core signature of memory-like CD8
T cells was still detectable, including, to a smaller extent, in HCV-specific CD8
T cells targeting variant epitopes. These results identify a molecular signature of T cell exhaustion that is maintained as a chronic scar in HCV-specific CD8
T cells even after the cessation of chronic antigen stimulation.
Hepatitis E virus and Bell’s palsy Fritz‐Weltin, Miriam; Niedermeier, Lisa; Frommherz, Estelle ...
European journal of neurology,
March 2022, 2022-03-00, 20220301, Volume:
29, Issue:
3
Journal Article
Peer reviewed
Open access
Background and purpose
Acute hepatitis E virus (HEV) infections have been associated with various neurological disorders, including individual cases with Bell's palsy. Nonetheless, systematic studies ...in the latter are lacking. Therefore, this retrospective study systematically screened a cohort of patients with Bell's palsy for an acute HEV infection.
Methods
Overall, 104 patients with Bell's palsy treated in our clinic between 2008 and 2018 were identified. Serum samples were analyzed for anti‐HEV immunoglobulin (Ig)M and IgG antibodies by enzyme‐linked immunosorbent assay. Additionally, serum samples were tested for HEV RNA by polymerase chain reaction in 92 of these 104 patients presenting within the first 7 days from symptom onset. A large group of 263 healthy individuals served as controls.
Results
None of the patients with Bell's palsy but two healthy controls (0.8%) had an acute HEV infection. Anti‐HEV IgG seroprevalence indicating previous infection was unexpectedly high in patients with Bell's palsy (34%) and revealed an age‐dependent increase.
Conclusions
In this first systematic study, no cases of Bell's palsy in association with an acute HEV infection were identified. However, based on previous case descriptions, rare associations cannot be excluded. Therefore, large prospective multicenter studies will be necessary for conclusions that are more definitive.
This retrospective monocentric study analyzed the association of an acute hepatitis E virus (HEV) infection in 104 patients presenting with Bell’s palsy. 263 healthy individuals served as controls. None of the patients with Bell’s palsy, but two healthy controls (0.8%) had an acute HEV infection. Anti‐HEV IgG seroprevalence indicating previous infection was high in both patients (36%) and controls (17%) with an age‐dependent increase. In this first systematic study, no association of Bell’s palsy and an acute HEV infection was found.
Zusammenfassung
Zur Therapie der chronischen Hepatitis-B-Virus-(HBV-)Infektion stehen aktuell pegyliertes Interferon-Alpha und Nucleosid‑/Nucleotidanaloga (Entecavir und Tenofovir) zur Verfügung. ...Diese Medikamente ermöglichen eine Virussuppression und eine Normalisierung des Leberenzyms Glutamat-Pyruvat-Transaminase (GPT) und verhindern ein Fortschreiten der Lebererkrankung. Zahlreiche noch in klinischer Entwicklung befindliche Therapiestrategien haben jedoch eine funktionelle Heilung zum Ziel. Dabei soll erreicht werden, dass das HBV-Hüllprotein HBsAg im Blutserum nicht mehr nachweisbar ist („ausgeheilte“ Hepatitis B). Der vorliegende Beitrag gibt eine Übersicht über aktuelle und mögliche zukünftige antivirale Therapien gegen die chronische HBV-Infektion. Als Grundlage diente eine Literaturrecherche unter besonderer Berücksichtigung der aktuellen Leitlinien sowie aktueller Kongressbeiträge.
Die aktuell verfügbaren antiviralen Therapien führen nur sehr selten zur Elimination von HBsAg (funktionelle Heilung). Auch ist bisher weitgehend unklar, bei welchen Patienten ein Absetzen der Langzeittherapie mit Entecavir bzw. Tenofovir sinnvoll ist. Neue Therapiestrategien in klinischer Entwicklung führen bei einem höheren Anteil der Patienten zur funktionellen Heilung. Wahrscheinlich ist aber eine Kombination mehrerer antiviraler Strategien erforderlich, um die funktionelle Heilung für die Mehrheit der Patienten zu erreichen. Eine solche Therapie kann voraussichtlich in den nächsten 5–10 Jahren vorliegen.
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