Abstract
T-cell–based diagnostic tools identify pathogen exposure but lack differentiation between recent and historical exposures in acute infectious diseases. Here, T-cell receptor (TCR) RNA ...sequencing was performed on HLA-DR+/CD38+CD8+ T-cell subsets of hospitalized coronavirus disease 2019 (COVID-19) patients (n = 30) and healthy controls (n = 30; 10 of whom had previously been exposed to severe acute respiratory syndrome coronavirus 2 SARS-CoV-2). CDR3α and CDR3β TCR regions were clustered separately before epitope specificity annotation using a database of SARS-CoV-2–associated CDR3α and CDR3β sequences corresponding to >1000 SARS-CoV-2 epitopes. The depth of the SARS-CoV-2–associated CDR3α/β sequences differentiated COVID-19 patients from the healthy controls with a receiver operating characteristic area under the curve of 0.84 ± 0.10. Hence, annotating TCR sequences of activated CD8+ T cells can be used to diagnose an acute viral infection and discriminate it from historical exposure. In essence, this work presents a new paradigm for applying the T-cell repertoire to accomplish TCR-based diagnostics.
T-cell receptor (TCR) repertoire mining on selected activated T-cell subsets and subsequent epitope annotation successfully identifies SARS-CoV-2–infected individuals and distinguishes them from previously exposed individuals, putting forward a new paradigm of applying the T-cell repertoire to accomplish TCR-based diagnostics.
Abstract
The varicella-zoster virus (VZV) infects >95% of the population. VZV reactivation causes herpes zoster (HZ), known as shingles, primarily affecting the elderly and individuals who are ...immunocompromised. However, HZ can occur in otherwise healthy individuals. We analyzed the immune signature and risk profile in patients with HZ using a genome-wide association study across different UK Biobank HZ cohorts. Additionally, we conducted one of the largest HZ human leukocyte antigen association studies to date, coupled with transcriptomic analysis of pathways underlying HZ susceptibility. Our findings highlight the significance of the major histocompatibility complex locus for HZ development, identifying 5 protective and 4 risk human leukocyte antigen alleles. This demonstrates that HZ susceptibility is largely governed by variations in the major histocompatibility complex. Furthermore, functional analyses revealed the upregulation of type I interferon and adaptive immune responses. These findings provide fresh molecular insights into the pathophysiology and activation of innate and adaptive immune responses triggered by symptomatic VZV reactivation.
Thanks to the recommendation of a combined Measles/Mumps/Rubella (MMR) vaccine, like Priorix®, these childhood diseases are less common now. This is beneficial to limit the spread of these diseases ...and work towards their elimination. However, the measles, mumps and rubella antibody titers show a large variability in short- and long-term immunity. The recent outbreaks worldwide of measles and mumps and previous studies, which mostly focused on only one of the three virus responses, illustrate that there is a clear need for better understanding the immune responses after vaccination. Our healthy cohort was already primed with the MMR antigens in their childhood. In this study, the adult volunteers received one Priorix® vaccine dose at day 0. First, we defined 4 different groups of responders, based on their antibody titers’ evolution over 4 time points (Day 0, 21, 150 and 365). This showed a high variability within and between individuals. Second, we determined transcriptome profiles using 3′mRNA sequencing at day 0, 3 and 7. Using two analytical approaches, “one response group per time point” and “a time comparison per response group”, we correlated the short-term gene expression profiles to the different response groups. In general, the list of differentially expressed genes is limited, however, most of them are clearly immune-related and upregulated at day 3 and 7, compared to the baseline day 0. Depending on the specific response group there are overlapping signatures for two of the three viruses. Antibody titers and transcriptomics data showed that an additional Priorix vaccination does not facilitate an equal immune response against the 3 viruses or among different vaccine recipients.
Recent increases in the number of successful cancer treatments have stimulated interest in fertility preservation strategies in women of reproductive age and in prepubertal girls. However, research ...on the application of such programs under clinical conditions suffers from the scarce availability of human tissue for research purposes and from concurrent relevant ethical issues. To partly address this problem, this review focuses on the possibilities of ruminant in vitro models providing additional insights into several aspects of fertility preservation, ranging from preantral follicle collection to oocyte and follicle cryopreservation, to noninvasive quality assessment, and to follicle culture. After a brief introduction, we discuss currently available techniques involved in (human) fertility preservation, together with their inherent advantages and limitations. On the basis of literature, we describe specific points for improvement or urgent additional research, such as (1) the lack of noninvasive methods to assess viability and developmental capacity of preantral follicles (either isolated or “in situ”); (2) autotransplantation and cryopreservation of ovarian cortex and follicles; (3) ischemia, follicular burnout, and graft rejection as major causes of preantral follicle loss; and (4) the development of routine in vitro follicle culture methods. Within each section, an overview is given of similar available techniques in (ruminant) assisted reproduction, with suggestions as to where and how these research models might contribute to fill the identified gaps. After the identification of the remaining issues in the development of integrated fertility preservation strategies, available ruminant in vitro models are introduced, described, and matched to these challenges to define common grounds for reproductive research. Ruminant in vitro models are increasingly considered as being very relevant for human preimplantation reproductive research. Because ruminant in vitro models are not hampered by restrictive ethical constraints, they will undoubtedly boost research progress in fertility preservation. At the end of the review, future common research goals are proposed through which human and animal scientists can meet and hasten the development of integrated fertility preservation strategies.
The varicella-zoster virus (VZV) infects over 95% of the population. VZV reactivation causes herpes zoster (HZ), known as shingles, primarily affecting the elderly and immunocompromised individuals. ...However, HZ can also occur in otherwise healthy individuals. We analyzed the immune signature and risk profile in HZ patients using a genome-wide association study across different UK Biobank HZ cohorts. Additionally, we conducted one of the largest HZ HLA association studies to date, coupled with transcriptomic analysis of pathways underlying HZ susceptibility. Our findings highlight the significance of the MHC locus for HZ development, identifying five protective and four risk HLA alleles. This demonstrates that HZ susceptibility is largely governed by variations in the MHC. Furthermore, functional analyses revealed the upregulation of type I interferon and adaptive immune responses. These findings provide fresh molecular insights into the pathophysiology and the activation of innate and adaptive immune responses triggered by symptomatic VZV reactivation.
Around 30% of individuals will develop herpes zoster (HZ), caused by the varicella zoster virus (VZV), during their life. While several risk factors for HZ, such as immunosuppressive therapy, are ...well known, the genetic and molecular components that determine the risk of otherwise healthy individuals to develop HZ are still poorly understood. We created a computational model for the Human Leukocyte Antigen (HLA-A, -B, and -C) presentation capacity of peptides derived from the VZV Immediate Early 62 (IE62) protein. This model could then be applied to a HZ cohort with known HLA molecules. We found that HLA-A molecules with poor VZV IE62 presentation capabilities were more common in a cohort of 50 individuals with a history of HZ compared to a nationwide control group, which equated to a HZ risk increase of 60%. This tendency was most pronounced for cases of HZ at a young age, where other risk factors are less prevalent. These findings provide new molecular insights into the development of HZ and reveal a genetic predisposition in those individuals most at risk to develop HZ.
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