Biology subjects

Kowarsky, M.

Publications and source records attributed to Kowarsky, M..

6 recordsLinked to original sources

bioRxiv2025

Cell-free RNA reveals host and microbial correlates of broadly neutralizing antibody development against HIV

A small number of people living with HIV (PLWH) develop broadly neutralizing antibodies (bNAbs) targeting multiple HIV strains. Although several viral and immune factors contribute to bNAb development, the genetic and environmental factors driving this response remain largely unknown. We performed combined cell-free DNA (cfDNA) and cell-free RNA (cfRNA) sequencing in 42 plasma samples from a longitudinal cohort of 14 PLWH (7 who develop bNAbs and 7 matched controls). This approach enabled us to non-invasively monitor the host transcriptome, viral genetic variation, and microbiome composition during HIV infection, and to identify molecular correlates of bNAb development. We find that development of bNAbs is associated with a transcriptomic signature of early immune activation characterized by elevated levels of MHC class I antigen presentation genes. This signature is independent of viral load or CD4 count and declines over time. In addition to host features, we recovered sufficient viral reads to reconstruct HIV consensus sequences, supporting the utility of cfRNA for viral genotyping. Finally, we also identified an enrichment of several microbial taxa in bNAb producers and increased levels of GB virus C (GBV-C), a non-pathogenic lymphotropic virus. Our findings suggest a distinct early immune activation profile in PLWH who develop bNAbs. More broadly, we show that combined cfDNA/cfRNA sequencing can reveal relationships between a protective immunogenic response to HIV infection, the host immune system, and microbiome, highlighting its potential for biomarker discovery in future vaccine and therapeutic studies. Author SummaryA subset of people living with HIV develop broadly neutralizing antibodies (bNAbs), a phenomenon that remains poorly understood but relevant to vaccine development. We applied combined cell-free RNA and DNA sequencing to 42 longitudinal plasma samples (7 bNAb producers, 7 controls) to monitor the host transcriptome, viral variation, and microbiome composition during bNAb development. Early in infection, bNAb producers showed an MHC class I-linked immune activation signature that declined over time, alongside changes in commensal microbial sequences and increased levels of GB virus C in cfRNA. These findings support the use of cfDNA/cfRNA sequencing for biomarker discovery in HIV research.

genomics↗

bioRxiv2021

Revealing conserved mechanisms of neurodegeneration in a colonial chordate

Loss of the brains functional ability is a common symptom of aging and neurodegenerative diseases1,2. While the genetic and molecular mechanisms underlying human neurodegeneration are studied in-depth3-6, very little is known about the evolutionary origin of these traits and their involvement in loss of nervous system function in aged invertebrate species. Here we study evolutionarily conserved elements of brain degeneration using the colonial chordate model species Botryllus schlosseri. B. schlosseri reproduces both sexually and asexually7, with adult brains regenerating and degenerating multiple times throughout its adult life. Combining microscopy, transcriptomics and behavioral assays, we characterized adult brains from diverse stages and ages. We found that the number of neurons fluctuates each week, reaching a maximum of [~]1000 cells, and thereafter decreasing while the number of immunocytes increases. Comparing the number of neurons in the adult brains of young and old colonies, we found that older brains are smaller and contain fewer cells. Both during weekly degeneration cycles and overall with age, the decrease in neuron number correlates with reduced response to stimuli and with significant changes in the expression of genes with mammalian homologs associated with neural stem cells and neurodegenerative pathways. These results suggest persistent neural stem cell activity across ages and that cellular and molecular mechanisms of neurodegeneration are evolutionary conserved between tunicates and humans.

neuroscience↗

bioRxiv2020

Global Age-Specific Patterns of Cyclic Gene Expression Revealed by Tunicate Transcriptome Atlas

Expression levels of circadian clock genes, which regulate 24-hour rhythms of behavior and physiology, have been shown to change with age. However, a study holistically linking aging and circadian gene expression is missing. Using the colonial chordate Botryllus schlosseri, we combined transcriptome sequencing and stem cell-mediated aging phenomena to test how circadian gene expression changes with age. This revealed that B. schlosseri clock and clock-controlled genes oscillate organism-wide, with daily, age-specific amplitudes and frequencies. These age-related, circadian patterns persist at the tissue level, where dramatic variations in cyclic gene expression of tissue profiles link to morphological and cellular aging phenotypes. Similar cyclical expression differences were found in hundreds of pathways associated with known hallmarks of aging, as well as pathways that were not previously linked to aging. The atlas we developed points to alterations in circadian gene expression as a key regulator of aging. One Sentence SummaryThe Ticking Clock: Systemic changes in circadian gene expression correlates with wide-ranging phenotypes of aging

developmental biology↗

bioRxiv2019

Molecular and Morphological Signatures of Chordate Development: Two Distinct Pathways, One Tunicate

All chordates, including urochordates such as tunicates, develop through embryogenesis. The chordate larvae of colonial tunicates metamorphose to lose all chordate structures such as notochord, neural tube, segmented musculature, and then develop by asexual reproduction [blastogenesis], whereby stem cells form tissues and organs. These two developmental pathways establish the same body axis, morphogenetic patterning and organ formation. It is unknown if this convergent morphology implies convergent cellular and molecular mechanisms, and whether the stem cells that mediate these processes differ. Using the colonial tunicate Botryllus schlosseri, we combined transcriptome sequencing and multiple microscopy techniques to study the molecular and morphological signatures of cells at each developmental stage of embryogenesis and blastogenesis. This revealed that the molecular programs are distinct, but the blastogenic tissue-specific stem cells and embryonic precursor populations share similar molecular profiles. By comparing embryogenesis in other chordates we found shared developmental principles, highlighting transcription factors as key evolutionary conserved elements. This study establishes a platform for advancing the science of stem cell biology and regulation of development and regeneration.

developmental biology↗

bioRxiv2018

Cell-free DNA Reveals Potential Zoonotic Reservoirs in Non-Human Primates

AbstractThe microbiome of non-human primates is relatively neglected compared with humans, and yet it is a source of many zoonotic diseases. We used high throughput sequencing of circulating cell-free DNA to identify the bacteria, archaea, eukaryotic parasites and viruses from over 200 individual non-human primates across 17 species from Africa. Many of the assembled sequences have low or no homology to previously sequenced microorganisms, while those that do have homology support prior observations of specific taxa present in primate microbiomes. The structure of the total microbiome is correlated with geographic location, even between distinct primate species which are co-located. However, we find that viruses have a particularly notable association with host taxa independent of geography. Numerous potentially zoonotic taxa were discovered in an unbiased manner, thereby expanding knowledge of host species diversity and strengthening the case for monitoring wildlife reservoirs.\n\nOne Sentence SummaryBlood from non-human primates provides insight into potential pathogens which might eventually infect humans.

microbiology↗

bioRxiv2017

Single-Cell RNAseq analysis of infiltrating neoplastic cells at the migrating front of human glioblastoma

Glioblastoma is the most common primary brain cancer in adults and is notoriously difficult to treat due to its diffuse nature. We performed single-cell RNAseq on 3589 cells in a cohort of four patients. We obtained cells from the tumor core as well as surrounding peripheral tissue. Our analysis revealed cellular variation in the tumors genome and transcriptome, We were able to identify infiltrating neoplastic cells in regions peripheral to the core lesions. Despite the existence of significant heterogeneity among neoplastic cells, we found that infiltrating GBM cells share a consistent gene signature between patients, suggesting a common mechanism of infiltration. Additionally, in investigating the immunological response to the tumors, we found transcriptionally distinct myeloid cell populations residing in the tumor core and the surrounding peritumoral space. Our data provide a detailed dissection of GBM cell types, revealing an abundance of novel information about tumor formation and migration.

cancer biology↗