Biology subjects

Seehusen, F.

Publications and source records attributed to Seehusen, F..

4 recordsLinked to original sources

bioRxiv2025

SARS-CoV-2 infection of the brain: the K18-hACE2 mouse model to illustrate the role and response of the vasculature in neurotropic viral infection

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) primarily affects the respiratory tract and lungs; however, the associated disease, coronavirus disease 2019 (COVID-19), can involve the central nervous system (CNS) in both its acute and long-term (Long COVID) clinical manifestation. The pathomechanisms underlying neurological impairments in COVID-19 are not yet fully understood, hence experimental studies to clarify the direct effect of SARS-CoV-2 in the brain can provide further insight. In the present study we used the K18-hACE2 model, intranasally challenged with SARS-CoV-2 ancestral and Delta isolates at low or medium doses, to address the hypothesis that the inflammatory response raised in the brain of infected mice is secondary to neuronal infection. Our data confirmed that the virus reaches the brain even after low dose (102 PFU/mouse, Delta isolate) infection where it targets the neurons without overt neuropathic effect, sparing the blood vessels. In situ investigation of the resulting inflammatory response showed the recruitment of leukocytes via postcapillary venules, with their accumulation in the perivascular space and occasional migration into the neuroparenchyma, without targeting and/or damage to the vessel wall. These changes were reflected in the brain transcriptome and proteome which showed positive enrichment of pathways and up-regulation of genes involved in the inflammatory response including the recruitment (including adhesion and migration) and activity of leukocytes. Additionally, morphological and transcriptome/proteome changes suggest minimal associated blood-brain barrier dysfunction. The brain metabolome and lipidome showed minimal changes; these were consistent with oxidative stress and inflammatory and immune/antiviral responses. The results obtained from our model indicate that SARS-CoV-2 infection of the neurons can result in limited neuroinflammation. These data can help to understand more fully the reaction of the CNS in COVID-19 patients, and neurotropic virus infections in general.

pathology↗

bioRxiv2024

Monocyte-derived cells but not Microglia cause Oxidative Tissue Damage in Neuroinflammation

Multiple sclerosis (MS) is characterized by neuroinflammation, oxidative stress, iron toxicity and mitochondrial dysfunction. Reactive oxygen species (ROS) produced by mononuclear phagocytes (MPs) are widely held to drive tissue damage, yet the specific roles of central nervous system (CNS)- resident versus CNS-invading MPs remain unclear. Here, by combining single-cell profiling with conditional gene targeting, we systematically dissected and interfered with ROS production across CNS MPs in a preclinical model for neuroinflammation. We show that CNS-invading monocyte derived cells (MdCs) exhibit a higher oxidative stress gene signature and produce more ROS compared to CNS-resident microglia. While NADPH oxidase 2 (NOX2), a phagocytic source of ROS, proved redundant, our findings underscore the critical role of mitochondrial ROS (mtROS) in driving oxidative tissue damage. Quenching mtROS through mitocatalase overexpression in MdCs, but not microglia, significantly alleviated neuroinflammation in mice. Thus, our study resolves a longstanding controversy, identifying MdCs as the primary driver of ROS-mediated neuropathology.

immunology↗

bioRxiv2021

Viral neuroinvasion and neurotropism without neuronal damage in the hACE2 mouse model of COVID-19

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) not only affects the respiratory tract but also causes neurological symptoms such as loss of smell and taste, headache, fatigue or severe cerebrovascular complications. Using transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) we investigated the spatiotemporal distribution and pathomorphological features in the CNS following intranasal infection with SARS-CoV-2 variants, also after prior influenza A virus infection. Apart from Omicron, we found all variants to frequently spread to and within the CNS. Infection was restricted to neurons and appeared to spread from the olfactory bulb mainly in basally orientated regions in the brain and into the spinal cord, independent of ACE2 expression and without evidence of neuronal cell death, axonal damage or demyelination. However, microglial activation, microgliosis and a mild macrophage and T cell dominated inflammatory response was consistently observed, accompanied by apoptotic death of endothelial, microglial and immune cells, without their apparent infection. Microgliosis and immune cell apoptosis indicate a potential role of microglia for pathogenesis and viral effect in COVID-19 and possible impairment of neurological functions, especially in long COVID. These data may also be informative for the selection of therapeutic candidates, and broadly support investigation of agents with adequate penetration into relevant regions of the CNS.

pathology↗

bioRxiv2020

Activation of cryptic splicing in bovine WDR19 is associated with reduced semen quality and male fertility

Cattle are ideally suited to investigate the genetics of male reproduction, because semen quality and fertility are recorded for all ejaculates of artificial insemination bulls. We analysed 26,090 ejaculates of 794 Brown Swiss bulls to assess ejaculate volume, sperm concentration, sperm motility, sperm head and tail anomalies and insemination success. The heritability of the six semen traits was between 0 and 0.26. Genome-wide association testing on 607,511 SNPs revealed a QTL on bovine chromosome 6 that was associated with sperm motility (P = 2.5 x 10-27), head (P = 2.0 x 10-44) and tail anomalies (P = 7.2 x 10-49) and insemination success (P = 9.9 x 10-13). The QTL harbors a recessive allele that compromises semen quality and male fertility. We replicated the effect of the QTL on fertility (P = 7.1 x 10-32) in an independent cohort of 2481 Brown Swiss bulls. The analysis of whole-genome sequencing data revealed that a synonymous variant (BTA6:58373887C>T, rs474302732) in WDR19 encoding WD repeat-containing protein 19 was in linkage disequilibrium with the fertility-associated haplotype. WD repeat-containing protein 19 is a constituent of the intraflagellar transport complex that is essential for the physiological function of motile cilia and flagella. Bioinformatic and transcription analyses revealed that the BTA6:58373887 T-allele activates a cryptic exonic splice site that eliminates three evolutionarily conserved amino acids from WDR19. Western blot analysis demonstrated that the BTA6:58373887 T-allele decreases protein expression. We make the remarkable observation that, in spite of negative effects on semen quality and bull fertility, the BTA6:58373887 T-allele has a frequency of 24 % in the Brown Swiss population. Our findings are the first to uncover a variant that is associated with quantitative variation in semen quality and male fertility in cattle. Author summaryIn cattle farming, artificial insemination is the most commonly used method of breeding. To ensure high fertilization rates, ejaculate quality and insemination success are closely monitored in artificial insemination bulls. We analyse semen quality, insemination success and microarray-called genotypes at more than 600,000 genome-wide SNP markers in 794 bulls to identify a recessive allele that compromises semen quality. We take advantage of whole-genome sequencing to pinpoint a variant in the coding sequence of WDR19 encoding WD repeat-containing protein 19 that activates a novel exonic splice site. Our results indicate that cryptic splicing in WDR19 is associated with reduced male reproductive performance. This is the first report of a variant that contributes to quantitative variation in bovine semen quality.

genomics↗