Biology subjects

Oestereich, L.

Publications and source records attributed to Oestereich, L..

4 recordsLinked to original sources

bioRxiv2026

Small aberrant viral genomes induce the innate immune response to arenaviruses

Arenaviruses are a family of negative-sense RNA viruses mainly found in rodents in which they cause chronic asymptomatic infections. Some arenaviruses, however, can occasionally infect humans and cause pathogenic viral haemorrhagic fevers. These viral haemorrhagic fevers are associated with a massively dysregulated immune response characterized by excessive release of pro-inflammatory cytokines resulting in hyperinflammatory immunopathology. Here, we systematically characterize the immune response of human cells to a wide panel of mammalian arenaviruses and identify a clear distinction between New World viruses, which uniformly induce a robust interferon response, and Old World viruses, which do not induce any significant host response. This innate immune response is primarily driven by RIG-I-mediated RNA sensing and might be aided by differences in viral interferon antagonist expression patterns. Furthermore, we identified differences in quantity and type of non-standard viral genomes produced in unpassaged Old World and New World virus infections. Finally, we demonstrate that small non-standard viral RNA expression by New World viruses are key drivers of the innate immune response and might help explain how the host response can shape viral disease phenotypes and inform triage of patients.

microbiology↗

bioRxiv2024

Molecular cloning and host range analysis of three cytomegaloviruses from Mastomys natalensis

Herpesvirus-based vectors are attractive for use as conventional or transmissible vaccines against emerging zoonoses in inaccessible animal populations. In both cases, cytomegaloviruses as members of the subfamily Betaherpesvirinae are particularly suitable for vaccine development as they are highly specific for their natural host species, infect a large proportion of their host population, and cause mild infections in healthy individuals. The Natal multimammate mouse (Mastomys natalensis) is the natural reservoir of Lassa virus, which causes deadly hemorrhagic fever in humans. M. natalensis was recently reported to harbor at least three different cytomegaloviruses (MnatCMV1, MnatCMV2 and MnatCMV3). Herein, we report the molecular cloning of three complete MnatCMV genomes in a yeast and bacterial artificial chromosome (YAC-BAC) hybrid vector. Purified viral genomes were cloned in yeast by single-step transformation-associated recombination (STAR cloning) and subsequently transferred to Escherichia coli for further genetic manipulation. Integrity of the complete cloned viral genomes was verified by sequencing, and replication fitness of viruses reconstituted from these clones was analyzed by replication kinetics in M. natalensis fibroblasts and kidney epithelial cells. We also found that neither parental nor cloned MnatCMVs replicated in mouse and rat fibroblasts, nor did they show sustained replication in baby hamster kidney cells, consistent with the expected narrow host range for these viruses. We further demonstrated that an exogenous sequence can be inserted by BAC-based mutagenesis between open reading frames M25 and m25.1 of MnatCMV2 without affecting replication fitness in vitro, identifying this site as potentially suitable for the insertion of vaccine target antigen genes. ImportanceCytomegaloviruses recently discovered in the Natal multimammate mouse (Mastomys natalensis) are widespread within the M. natalensis population. Since these rodents also serve as natural hosts of the human pathogen Lassa virus (LASV), we investigated the potential suitability of M. natalensis CMVs (MnatCMVs) as vaccine vectors. We describe the cloning of three different MnatCMV genomes as bacterial artificial chromosomes (BACs). Replicative capacity and species specificity of these BAC-derived MnatCMVs were analyzed in multiple cell types. We also identified a transgene insertion site within one of the MnatCMV genomes suitable for the incorporation of vaccine target antigens. Together, this study provides a foundation for the development of MnatCMVs as transmissible MnatCMV-based LASV vaccines to reduce LASV prevalence in hard-to-reach M. natalensis populations and thereby zoonotic transmission to humans.

microbiology↗

bioRxiv2024

Ebola virus infection of Flt3-dependent, conventional dendritic cells and antigen cross-presentation leads to high levels of T-cell activation

Severe Ebola virus disease (EVD) is characterized by excess, dysregulated T-cell activation and high levels of inflammation. Previous studies have described that in vitro EBOV infection of monocyte-derived DCs (moDCs) inhibits DC maturation resulting in suppression of T-cell activation. However, it is unknown how other DC subsets distinct from moDCs respond to EBOV infection. To better understand how DCs initiate T cell activation during EBOV infection, we assessed the response of FMS-like tyrosine kinase 3 (Flt3)-dependent, conventional mouse DCs (cDCs) to EBOV infection, and developed a DC-T-cell co-culture system utilizing a recombinant EBOV expressing the model antigen ovalbumin. Our findings suggested that, in contrast to moDCs, cDC2 and cDC1 were poorly infected with EBOV, although both infected and bystander cDCs displayed high levels of activation. DCs were able to activate CD8 T cells via cross-presentation of EBOV antigens obtained from cell debris of EBOV-infected cells. Of note, rather than interfering with cross-presentation, EBOV infection enhanced the cross-presentation capacity of DCs. Our findings indicate that EBOV infection of Flt3-dependent cDCs, results in activation rather than inhibition leading to high levels of CD8 T-cell activation. With that we propose a mechanistic explanation for the excess T-cell activation observed in severe human EVD.

immunology↗

bioRxiv2020

SARS-CoV-2 infects carotid arteries: implications for vascular disease and organ injury in COVID-19

Stroke and central nervous system dysfunction are cardinal symptoms in critically ill corona virus disease 19 (COVID-19) patients. In an autopsy series of 32 COVID-19 patients, we investigated whether carotid arteries were infected with SARS-CoV-2 by employing genomic, virologic, histochemical and transcriptomic analyses. We show that SARS-CoV-2 productively infects and modulates vascular responses in carotid arteries. This finding has far reaching implications for the understanding and clinical treatment of COVID-19.

microbiology↗