Browsing by Author "Giroux, Nicholas S"

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    Chromatin remodeling in peripheral blood cells reflects COVID-19 symptom severity.
    (bioRxiv, 2020-12-05) Giroux, Nicholas S; Ding, Shengli; McClain, Micah T; Burke, Thomas W; Petzold, Elizabeth; Chung, Hong A; Palomino, Grecia R; Wang, Ergang; Xi, Rui; Bose, Shree; Rotstein, Tomer; Nicholson, Bradly P; Chen, Tianyi; Henao, Ricardo; Sempowski, Gregory D; Denny, Thomas N; Ko, Emily R; Ginsburg, Geoffrey S; Kraft, Bryan D; Tsalik, Ephraim L; Woods, Christopher W; Shen, Xiling
    SARS-CoV-2 infection triggers highly variable host responses and causes varying degrees of illness in humans. We sought to harness the peripheral blood mononuclear cell (PBMC) response over the course of illness to provide insight into COVID-19 physiology. We analyzed PBMCs from subjects with variable symptom severity at different stages of clinical illness before and after IgG seroconversion to SARS-CoV-2. Prior to seroconversion, PBMC transcriptomes did not distinguish symptom severity. In contrast, changes in chromatin accessibility were associated with symptom severity. Furthermore, single-cell analyses revealed evolution of the chromatin accessibility landscape and transcription factor motif occupancy for individual PBMC cell types. The most extensive remodeling occurred in CD14+ monocytes where sub-populations with distinct chromatin accessibility profiles were associated with disease severity. Our findings indicate that pre-seroconversion chromatin remodeling in certain innate immune populations is associated with divergence in symptom severity, and the identified transcription factors, regulatory elements, and downstream pathways provide potential prognostic markers for COVID-19 subjects.
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    Differential chromatin accessibility in peripheral blood mononuclear cells underlies COVID-19 disease severity prior to seroconversion.
    (Res Sq, 2022-04-07) Giroux, Nicholas S; Ding, Shengli; McClain, Micah T; Burke, Thomas W; Petzold, Elizabeth; Chung, Hong A; Rivera, Grecia O; Wang, Ergang; Xi, Rui; Bose, Shree; Rotstein, Tomer; Nicholson, Bradly P; Chen, Tianyi; Henao, Ricardo; Sempowski, Gregory D; Denny, Thomas N; De Ussel, Maria Iglesias; Satterwhite, Lisa L; Ko, Emily R; Ginsburg, Geoffrey S; Kraft, Bryan D; Tsalik, Ephraim L; Shen, Xiling; Woods, Christopher
    SARS-CoV-2 infection triggers profound and variable immune responses in human hosts. Chromatin remodeling has been observed in individuals severely ill or convalescing with COVID-19, but chromatin remodeling early in disease prior to anti-spike protein IgG seroconversion has not been defined. We performed the Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) and RNA-seq on peripheral blood mononuclear cells (PBMCs) from outpatients with mild or moderate symptom severity at different stages of clinical illness. Early in the disease course prior to IgG seroconversion, modifications in chromatin accessibility associate with mild or moderate symptoms are already robust and include severity-associated changes in accessibility of genes in interleukin signaling, regulation of cell differentiation and cell morphology. Furthermore, single-cell analyses revealed evolution of the chromatin accessibility landscape and transcription factor motif accessibility for individual PBMC cell types over time. The most extensive remodeling occurred in CD14+ monocytes, where sub-populations with distinct chromatin accessibility profiles were observed prior to seroconversion. Mild symptom severity is marked by upregulation classical antiviral pathways including those regulating IRF1 and IRF7, whereas in moderate disease these classical antiviral signals diminish suggesting dysregulated and less effective responses. Together, these observations offer novel insight into the epigenome of early mild SARS-CoV-2 infection and suggest that detection of chromatin remodeling in early disease may offer promise for a new class of diagnostic tools for COVID-19.
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    Differential chromatin accessibility in peripheral blood mononuclear cells underlies COVID-19 disease severity prior to seroconversion.
    (Scientific reports, 2022-07-09) Giroux, Nicholas S; Ding, Shengli; McClain, Micah T; Burke, Thomas W; Petzold, Elizabeth; Chung, Hong A; Rivera, Grecia O; Wang, Ergang; Xi, Rui; Bose, Shree; Rotstein, Tomer; Nicholson, Bradly P; Chen, Tianyi; Henao, Ricardo; Sempowski, Gregory D; Denny, Thomas N; De Ussel, Maria Iglesias; Satterwhite, Lisa L; Ko, Emily R; Ginsburg, Geoffrey S; Kraft, Bryan D; Tsalik, Ephraim L; Shen, Xiling; Woods, Christopher W
    SARS-CoV-2 infection triggers profound and variable immune responses in human hosts. Chromatin remodeling has been observed in individuals severely ill or convalescing with COVID-19, but chromatin remodeling early in disease prior to anti-spike protein IgG seroconversion has not been defined. We performed the Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) and RNA-seq on peripheral blood mononuclear cells (PBMCs) from outpatients with mild or moderate symptom severity at different stages of clinical illness. Early in the disease course prior to IgG seroconversion, modifications in chromatin accessibility associated with mild or moderate symptoms were already robust and included severity-associated changes in accessibility of genes in interleukin signaling, regulation of cell differentiation and cell morphology. Furthermore, single-cell analyses revealed evolution of the chromatin accessibility landscape and transcription factor motif accessibility for individual PBMC cell types over time. The most extensive remodeling occurred in CD14+ monocytes, where sub-populations with distinct chromatin accessibility profiles were observed prior to seroconversion. Mild symptom severity was marked by upregulation of classical antiviral pathways, including those regulating IRF1 and IRF7, whereas in moderate disease, these classical antiviral signals diminished, suggesting dysregulated and less effective responses. Together, these observations offer novel insight into the epigenome of early mild SARS-CoV-2 infection and suggest that detection of chromatin remodeling in early disease may offer promise for a new class of diagnostic tools for COVID-19.
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    Epigenetic and transcriptional responses in circulating leukocytes are associated with future decompensation during SARS-CoV-2 infection.
    (iScience, 2024-01) McClain, Micah T; Zhbannikov, Ilya; Satterwhite, Lisa L; Henao, Ricardo; Giroux, Nicholas S; Ding, Shengli; Burke, Thomas W; Tsalik, Ephraim L; Nix, Christina; Balcazar, Jorge Prado; Petzold, Elizabeth A; Shen, Xiling; Woods, Christopher W
    To elucidate host response elements that define impending decompensation during SARS-CoV-2 infection, we enrolled subjects hospitalized with COVID-19 who were matched for disease severity and comorbidities at the time of admission. We performed combined single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq) on peripheral blood mononuclear cells (PBMCs) at admission and compared subjects who improved from their moderate disease with those who later clinically decompensated and required invasive mechanical ventilation or died. Chromatin accessibility and transcriptomic immune profiles were markedly altered between the two groups, with strong signals in CD4+ T cells, inflammatory T cells, dendritic cells, and NK cells. Multiomic signature scores at admission were tightly associated with future clinical deterioration (auROC 1.0). Epigenetic and transcriptional changes in PBMCs reveal early, broad immune dysregulation before typical clinical signs of decompensation are apparent and thus may act as biomarkers to predict future severity in COVID-19.
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    fastMitoCalc: an ultra-fast program to estimate mitochondrial DNA copy number from whole-genome sequences
    (Bioinformatics, 2017-05-01) Qian, Yong; Butler, Thomas J; Opsahl-Ong, Krista; Giroux, Nicholas S; Sidore, Carlo; Nagaraja, Ramaiah; Cucca, Francesco; Ferrucci, Luigi; Abecasis, Gonçalo R; Schlessinger, David; Ding, Jun
    Abstract Mitochondrial DNA (mtDNA) copy number is tightly regulated in tissues, and is both a critical determinant of mitochondrial function and a potential biomarker for disease. We and other groups have shown that the mtDNA copy number per cell can be directly estimated from whole-genome sequencing. The computation is based on the rationale that sequencing coverage should be proportional to the underlying DNA copy number for autosomal and mitochondrial DNA, and most computing time is spent calculating the average autosomal DNA coverage across ∼3 billion bases. That makes analyzing tens of thousands of available samples very slow. Here we present fastMitoCalc, which takes advantage of the indexing of sequencing alignment files and uses a randomly selected small subset (0.1%) of the nuclear genome to estimate autosomal DNA coverage accurately. It is more than 100 times faster than current programs. fastMitoCalc also provides an option to estimate copy number using a single autosomal chromosome, which could also achieve high accuracy but is slower. Using fastMitoCalc, it becomes much more feasible now to conduct analyses on large-scale consortium data to test for association of mtDNA copy number with quantitative traits or nuclear variants. Availability and Implementation fastMitoCalc is available at https://lgsun.irp.nia.nih.gov/hsgu/software/mitoAnalyzer/index.html Supplementary information Supplementary data are available at Bioinformatics online.
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    Mucosal Associated Invariant T (MAIT) Cell Responses Differ by Sex in COVID-19.
    (Med (New York, N.Y.), 2021-04-13) Yu, Chen; Littleton, Sejiro; Giroux, Nicholas S; Mathew, Rose; Ding, Shengli; Kalnitsky, Joan; Yang, Yuchen; Petzold, Elizabeth; Chung, Hong A; Rivera, Grecia O; Rotstein, Tomer; Xi, Rui; Ko, Emily R; Tsalik, Ephraim L; Sempowski, Gregory D; Denny, Thomas N; Burke, Thomas W; McClain, Micah T; Woods, Christopher W; Shen, Xiling; Saban, Daniel R
    Sexual dimorphisms in immune responses contribute to coronavirus disease 2019 (COVID-19) outcomes, yet the mechanisms governing this disparity remain incompletely understood. We carried out sex-balanced sampling of peripheral blood mononuclear cells from confirmed COVID-19 inpatients and outpatients, uninfected close contacts, and healthy controls for 36-color flow cytometry and single cell RNA-sequencing. Our results revealed a pronounced reduction of circulating mucosal associated invariant T (MAIT) cells in infected females. Integration of published COVID-19 airway tissue datasets implicate that this reduction represented a major wave of MAIT cell extravasation during early infection in females. Moreover, female MAIT cells possessed an immunologically active gene signature, whereas male counterparts were pro-apoptotic. Collectively, our findings uncover a female-specific protective MAIT profile, potentially shedding light on reduced COVID-19 susceptibility in females.