Biology subjects

Oxenius, A.

Publications and source records attributed to Oxenius, A..

24 records · Page 2Linked to original sources

bioRxiv2020

CD8 T cells induce destruction of bone marrow stromal niches and hematopoietic stem cell dysfunction in chronic viral infections

Chronic viral infections are associated with hematopoietic suppression and bone marrow (BM) failure, which have been linked to hematopoietic stem cell (HSC) exhaustion. However, how persistent viral infectious challenge and ensuing inflammatory responses target BM tissues and perturb hematopoietic homeostasis remains poorly understood. Here, we combine extensive functional analyses with advanced 3D microscopy to demonstrate that chronic infection with lymphocytic choriomeningitis virus clone 13 results in the long-term impairment of HSC function, concomitant with a persistent destruction of the HSC-supportive stromal networks of mesenchymal CXCL12-abundant reticular cells. During infections, long lasting injuries and aberrant transcriptional programs of the stromal infrastructure diminish the capacity of the BM microenvironment to adequately support HSC maintenance. Mechanistically, BM immunopathology is elicited by virus-specific, activated CD8 T cells, which accumulate in the BM via interferon-dependent mechanisms. Combined inhibition of type I and II IFN pathways completely preempts viral-mediated degeneration of CARc networks and protects HSCs from persistent dysfunction. Hence, viral infections and ensuing immune reactions chronically interfere with BM function by disrupting essential stromal-derived, hematopoietic-supporting cues.

immunology↗

bioRxiv2020

Single-cell immune repertoire and transcriptome sequencing reveals that clonally expanded and transcriptionally distinct lymphocytes populate the aged central nervous system in mice

Neuroinflammation plays a crucial role during ageing and various neurological conditions, including Alzheimers disease, multiple sclerosis and infection. Technical limitations, however, have prevented an integrative analysis of how lymphocyte immune receptor repertoires and their accompanying transcriptional states change with age in the central nervous system (CNS). Here, we leveraged single-cell sequencing to simultaneously profile B cell receptor (BCR) and T cell receptor (TCR) repertoires and accompanying gene expression profiles in young and old mouse brains. We observed the presence of clonally expanded B and T cells in the central nervous system (CNS) of aged mice. Furthermore, many of these B cells were of the IgM and IgD isotype and had low levels of somatic hypermutation. Integrating gene expression information additionally revealed distinct transcriptional profiles of these clonally expanded lymphocytes. Our findings implicate that clonally related T and B cells in the CNS of elderly mice may contribute to neuroinflammation accompanying homeostatic ageing.

immunology↗

bioRxiv2020

Mouse-specific but infection-unspecific IgM repertoire fingerprint following viral infection

Antibody repertoire sequencing provides a molecular fingerprint of current and past pathogens encountered by the immune system. Most repertoire studies in humans require measuring the B cell response in the blood, resulting in a large bias to the IgM isotype. The extent to which the circulating IgM antibody repertoire correlates to lymphoid tissue-resident B cells in the setting of viral infection remains largely uncharacterized. Therefore, we compared the IgM repertoires from both blood and bone marrow (BM) plasma cells (PCs) following acute or chronic lymphocytic choriomeningitis virus (LCMV) infection in mice. Despite previously reported serum alterations between acute and chronic infection, IgM repertoire signatures based on clonal diversity metrics, public clones, network and phylogenetic analysis were largely unable to distinguish infection cohorts. Our findings, however, revealed mouse-specific congruence between the blood and PC repertoires irrespective of infection status. Our study reveals that IgM repertoire analyses may be unsuitable for providing a fingerprint of current or previous immune challenges.

immunology↗

bioRxiv2020

Profiling virus-specific Tcf1+ T cell repertoires during acute and chronic viral infection

CD8 T cells play a crucial role in providing protection from viral infections. It has recently been established that a subset of CD8 T cells expressing Tcf1 are responsible for sustaining exhausted T cells during chronic lymphocytic choriomeningitis virus (LCMV) infection. Many of these studies, however, have been performed using T cell receptor (TCR) transgenic mice, in which CD8 T cells express a monoclonal TCR specific for the LCMV glycoprotein. To investigate whether the Tcf1+ and Tcf1-repertoires are naturally composed of similar or different clones in wild-type mice exposed to acute or chronic LCMV infection, we performed TCR repertoire sequencing of virus-specific CD8 T cells, including Tcf1+ and Tcf1-populations. Our analysis revealed that the Tcf1+ TCR repertoire is maintained at an equal or higher degree of clonal diversity despite harboring fewer cells. Additionally, within the same animal, there was extensive clonal overlap between the Tcf1+ and Tcf1-repertoires in both chronic and acute LCMV infection. We could further detect these virus-specific clones in longitudinal blood samples earlier in the infection. With respect to common repertoire parameters (clonal overlap, germline gene usage, and clonal expansion), we found minor differences between the virus-specific TCR repertoire of acute and chronic LCMV infection 40 days post infection. Overall, our results indicate that the Tcf1+ population emerging during chronic LCMV infection is not clonally distinct from the Tcf1-population, supporting the notion that the Tcf1+ pool is indeed a fuel for the more exhausted Tcf1-population within the heterogenous repertoire of LCMV-specific CD8 T cells.

immunology↗

bioRxiv2020

The influence of the phylogenetic inference pipeline on murine antibody repertoire sequencing data following viral infection

Understanding B cell evolution following vaccination or infection is crucial for instructing targeted immunotherapies when searching for potential therapeutic or virus-neutralizing antibodies. Antibody phylogenetics holds the potential to quantify both clonal selection and somatic hypermutation, two key players shaping B cell evolution. A wide range of bioinformatic pipelines and phylogenetic inference methods have been utilized on antibody repertoire sequencing datasets to delineate B cell evolution. Although the majority of B cell repertoire studies incorporate some aspect of antibody evolution, how the chosen computational methods affect the results is largely ignored. Therefore, we performed an extensive computational analysis on time-resolved antibody repertoire sequencing data to better characterize how commonly employed bioinformatic practices influence conclusions regarding antibody selection and evolution. Our findings reveal that different combinations of clonal lineage assignment strategies, phylogenetic inference methods, and biological sampling affect the inferred size, mutation rates, and topologies of B cell lineages in response to virus infection.

bioinformatics↗

bioRxiv2017

Mapping the drivers of within-host pathogen evolution using massive data sets

Differences among hosts, resulting from genetic variation in the immune system or heterogeneity in drug treatment, can impact within-host pathogen evolution. Identifying such interactions can potentially be achieved through genetic association studies. However, extensive and correlated genetic population structure in hosts and pathogens presents a substantial risk of confounding analyses. Moreover, the multiple testing burden of interaction scanning can potentially limit power. To address these problems, we have developed a Bayesian approach for detecting host influences on pathogen evolution that makes use of vast existing data sets of pathogen diversity to improve power and control for stratification. The approach models key processes, including recombination and selection, and identifies regions of the pathogen genome affected by host factors. Using simulations and empirical analysis of drug-induced selection on the HIV-1 genome we demonstrate the power of the method to recover known associations and show greatly improved precision-recall characteristics compared to other approaches. We build a high-resolution map of HLA-induced selection in the HIV-1 genome, identifying novel epitope-allele combinations.

genetics↗