Biology subjects

Faber, S.

Publications and source records attributed to Faber, S..

5 recordsLinked to original sources

bioRxiv2025

Caspase-11 Mediated Hyperinflammation Impairs CD8⁺ T Cell Immunity and Viral Clearance in Severe SARS-CoV-2 Infection

Severe SARS-CoV-2 infection is characterized by lung hyperinflammation, impaired interferon responses, and defective T-cell activation, yet the molecular drivers of these immune dysregulations remain incompletely understood. Caspase-11 (CASP11), a key mediator of the non-canonical inflammasome, has been shown to mediate an innate hyperinflammatory response and cytokine release in a non-severe, non-lethal SARS-CoV-2 infection model. However, the role played by CASP11 in severe SARS-CoV-2 disease and how it impacts adaptive immunity is not identified. Here, we newly discover that CASP11 exacerbates severe SARS-CoV-2 pathogenesis by amplifying early innate immune responses while concurrently impairing antiviral CD8 T-cell immunity. Using global knockouts, reciprocal bone marrow chimeras, and phagocyte-monocyte system (PMS) cell-specific CASP11 deletion models, we show that CASP11 deletion in monocyte-derived cells reduces lung inflammation, enhances type I and II interferon signaling, and promotes robust virus-specific effector CD8 T-cell response. This was associated with enhanced viral clearance and improved survival, even under lethal infection conditions. Importantly, CASP11 KO mice also exhibited faster resolution of post-viral inflammation, suggesting a role in long-term immune remodeling. These findings position CASP11 as a promising immunomodulatory target for acute and delayed manifestations of severe SARS-CoV-2.

microbiology↗

bioRxiv2025

AI-based decoding of long covid cognitive impairments in mice using automated behavioral system and comparative transcriptomic analysis

Long COVID (LC) following SARS-CoV-2 infection affects millions of individuals world-wide and manifests with a variety of symptoms including cognitive dysfunction also known as "brain fog". This is characterized by difficulties in executive functions, planning, decision-making, working memory, impairments in complex attention, loss of ability to learn new skills and perform sophisticated brain tasks. No effective treatment options currently exist for LC-related cognitive dysfunction. Here, we use the IntelliCage, which is an automated tracking system of cognitive functions, following SARS-CoV-2 infection in mice, measuring the ability of each mouse within a group to perform tasks that mimic complex human behaviors, such as planning, decision-making, cognitive flexibility, and working memory. Artificial intelligence and machine learning analyses of the tracking data classified LC mice into distinct behavioral categories from non-infected control mice, permitting precise identification and quantification of complex cognitive dysfunction in a controlled, replicable manner. Importantly, we find that brains from LC mice with cognitive dysfunction exhibit transcriptomic alterations similar to those observed in humans suffering from LC-related cognitive impairments, including altered expression of genes involved in learning, executive functions, synaptic functions, neurotransmitters and memory. Together, our findings establish a validated murine model and an automated unbiased approach to study LC-related cognitive dysfunction for the first time, and providing a valuable tool for screening potential treatments and therapeutic interventions.

neuroscience↗

bioRxiv2024

Network connectivity differences in music listening among older adults following a music-based intervention

Music-based interventions are a common feature in long-term care with clinical reports highlighting musics ability to engage individuals with complex diagnoses. While these findings are promising, normative findings from healthy controls are needed to disambiguate treatment effects unique to pathology and those seen in healthy aging. The present study examines brain network dynamics during music listening in a sample of healthy older adults before and after a music-based intervention. We found intervention effects from hidden Markov model-estimated fMRI network data. Following the intervention, participants demonstrated greater occupancy (the amount of time a network was occupied) in a temporal-mesolimbic network. We conclude that network dynamics in healthy older adults are sensitive to music-based interventions. We discuss these findings implications for future studies with individuals with neurodegeneration.

neuroscience↗

bioRxiv2024

Identification of distinct genotypes in circulating RSV A strains based on variants on the virus replication-associated genes

Respiratory syncytial virus is a common cause of respiratory infection that often leads to hospitalization of infected younger children and older adults. RSV is classified into two strains, A and B, each with several subgroups or genotypes. One issue with the definition of these subgroups is the lack of a unified method of identification or genotyping. We propose that genotyping strategies based on the genes coding for replication-associated proteins could provide critical information on the replication capacity of the distinct subgroup, while clearly distinguishing genotypes. Here, we analyzed the virus replication-associated genes N, P, M2, and L from de novo assembled RSV A sequences obtained from 31 newly sequenced samples from hospitalized patients in Philadelphia and 78 additional publicly available sequences from different geographic locations within the US. In-depth analysis and annotation of the protein variants in L and the other replication-associated proteins N, P, M2-1, and M2-2 identified the polymerase protein L as a robust target for genotyping RSV subgroups. Importantly, our analysis revealed non-synonymous variations in L that were consistently accompanied by conserved changes in its co-factor P or the M2-2 protein, suggesting associations and interactions between specific domains of these proteins. These results highlight L as an alternative to other RSV genotyping targets and demonstrate the value of in-depth analyses and annotations of RSV sequences as it can serve as a foundation for subsequent in vitro and clinical studies on the efficiency of the polymerase and fitness of different virus isolates. IMPORTANCEGiven the historical heterogeneity of Respiratory Syncytial Virus (RSV) and the disease it causes, there is a need to understand the circulating RSV strains each season. This requires an informative and consensus method of genotype definition. Here, we carried out a variant analysis that shows a pattern of specific variations among the replication-associated genes of RSV A across different seasons. Interestingly, these variation patterns point to previously defined interactions of domains within these genes, suggesting co-variation in the replication-associated genes. Our results also suggest a genotyping strategy that can prove to be particularly important in understanding the genotype-phenotype correlation in the era of RSV vaccination, where selective pressure on the virus to evolve is anticipated. More importantly, the categorization of RSV strains based on these patterns may prove to be of prognostic value.

microbiology↗

bioRxiv2023

Probing the sub-cellular mechanisms of LCA5-Leber Congenital Amaurosis and associated gene therapy with expansion microscopy

Leber Congenital Amaurosis (LCA) is a group of Inherited Retinal Diseases (IRDs) characterized by the early onset and rapid loss of photoreceptor cells. Despite the discovery of a growing number of genes associated with this disease, the molecular mechanisms of photoreceptor cell degeneration of most LCA subtypes remain poorly understood. Here, using retina-specific affinity proteomics combined with Ultrastructure Expansion Microscopy (U-ExM), we revealed the structural and molecular defects underlying LCA type 5 (LCA5) with unprecedented resolution. We showed that LCA5-encoded lebercilin, together with Retinitis Pigmentosa 1 protein (RP1) and the intraflagellar transport (IFT) proteins IFT81 and IFT88, localize at the bulge region of the photoreceptor outer segment (OS), a region crucial for OS membrane disc formation. Next, we demonstrated that mutant mice deficient for lebercilin exhibit early axonemal defects at the bulge region and the distal OS, accompanied by reduced level of RP1 and IFT proteins, affecting membrane disc formation and presumably leading to photoreceptor death. Finally, we probed the LCA5 gene augmentation therapy strategy using U-ExM by monitoring its subcellular outcome. We found that, expression of LCA5 partially restores the bulge region, preserves OS axoneme structure and membrane disc formation, as well as photoreceptor survival.

molecular biology↗