Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has emerged as a pandemic.... more Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has emerged as a pandemic. Paucity of information concerning the virus and therapeutic interventions have made SARS-CoV-2 infection a genuine threat to global public health. Therefore, there is a growing need for understanding the molecular mechanism of SARS-CoV-2 infection at cellular level. To address this, we undertook a systems biology approach by analyzing publicly available RNA-seq datasets of SARS-CoV-2 infection of different cells and compared with other lung pathogenic infections. Our study identified several key genes and pathways uniquely associated with SARS-CoV-2 infection. Genes such as interleukin (IL)-6, CXCL8, CCL20, CXCL1 and CXCL3 were upregulated, which in particular regulate the cytokine storm and IL-17 signaling pathway. Of note, SARS-CoV-2 infection strongly activated IL-17 signaling pathway compared with other respiratory viruses. Additionally, this transcriptomic signature was also analyz...
Biochemical and Biophysical Research Communications, 2019
RIG-I-like receptors (RLRs) are cytoplasmic sensors for viral RNA that elicit antiviral innate im... more RIG-I-like receptors (RLRs) are cytoplasmic sensors for viral RNA that elicit antiviral innate immune responses. RLR signaling culminates in the activation of the protein kinase TBK1, which mediates phosphorylation and nuclear translocation of IRF3 that regulates expression of type I interferon genes. Here, we found that Nucleoporin 93 (Nup93), components of nuclear pore complex (NPC), plays an important role in RLR-mediated antiviral responses. Nup93-deficient RAW264.7 macrophage cells exhibited decreased expression of Ifnb1 and Cxcl10 genes after treatment with a synthetic RLR agonist stimulation as well as Newcastle Disease Virus infection. Silencing Nup93 in murine primary macrophages and embryonic fibroblasts also resulted in reduced expression of these genes. IRF3 nuclear translocation during RLR signaling was impaired in Nup93-deficient RAW264.7 cells. Notably, the activation of TBK1 during RLR signaling was also decreased in Nup93-deficient cells. We found that Nup93 formed a complex with TBK1, and Nup93 overexpression enhanced TBK1-mediated IFNβ promoter activation. Taken together, our findings suggest that Nup93 regulates antiviral innate immunity by enhancing TBK1 activity and IRF3 nuclear translocation.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has resulted in the global... more Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has resulted in the global coronavirus disease 2019 (COVID-19) pandemic. Despite several single-cell RNA sequencing (RNA-seq) studies, conclusions cannot be reached owing to the small number of available samples and the differences in technology and tissue types used in the studies. To better understand the cellular landscape and disease severity in COVID-19, we performed a meta-analysis of publicly available single-cell RNA-seq data from peripheral blood and lung samples of COVID-19 patients with varying degrees of severity. Patients with severe disease showed increased numbers of M1 macrophages in lung tissue, while the number of M2 macrophages was depleted. Cellular profiling of the peripheral blood showed a marked increase of CD14+, CD16+ monocytes and a concomitant depletion of overall B cells and CD4+, CD8+ T cells in severe patients when compared with moderate patients. Our analysis indicates the presence of faulty innate-to-adaptive switching, marked by a prolonged innate immune response and a dysregulated adaptive immune response in severe COVID-19 patients. Furthermore, we identified cell types with a transcriptome signature that can be used as a prognostic biomarker for disease state prediction and the effective therapeutic management of COVID-19 patients.
Abnormal levels of High temperature requirement A1 (HtrA1) protein have been repeatedly observed ... more Abnormal levels of High temperature requirement A1 (HtrA1) protein have been repeatedly observed in sera and placentas of preeclampsia patients. To understand the functions of HtrA1 in placentation and in the etiology of preeclampsia, we established HtrA1(-/-) mice. HtrA1(-/-) mice show intrauterine growth retardation, and their placentas are small due to a reduced size of the junctional zone and aberrant vascularization in the labyrinth at the mid-gestation stage. HtrA1 is expressed by Tpbpa-positive trophoblast precursors in the outer ectoplacental cone and junctional zone from embryonic day 7.5 to 10.5. In the HtrA1(-/-) placenta, Tpbpa-positive cell precursors are decreased in the early stage. Spongiotrophoblasts and glycogen trophoblast cells, both of which differentiate from Tpbpa-positive precursors, are consequently decreased in the junctional zone. Fewer spiral artery-associated trophoblast giant cells, another cell type derived from Tpbpa-positive precursors, invade the decidua and associate with maternal arteries in the HtrA1(-/-) placenta than in the wild type placenta. Maternal arteries in the HtrA1(-/-) decidua have narrower lumens, thicker arterial walls, and more vascular smooth muscle cells remaining in the walls than those in the wild type decidua, indicating impaired remodeling of maternal arteries. These results indicate that HtrA1 plays important roles in the differentiation of trophoblasts from Tpbpa-positive precursors in the ectoplacental cone. Insufficient levels of HtrA1 cause poor placental development and intrauterine growth retardation, due to aberrant trophoblast differentiation and consequent defects in maternal artery remodeling, and may contribute to the onset of preeclampsia.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has emerged as a pandemic.... more Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has emerged as a pandemic. Paucity of information concerning the virus and therapeutic interventions have made SARS-CoV-2 infection a genuine threat to global public health. Therefore, there is a growing need for understanding the molecular mechanism of SARS-CoV-2 infection at cellular level. To address this, we undertook a systems biology approach by analyzing publicly available RNA-seq datasets of SARS-CoV-2 infection of different cells and compared with other lung pathogenic infections. Our study identified several key genes and pathways uniquely associated with SARS-CoV-2 infection. Genes such as interleukin (IL)-6, CXCL8, CCL20, CXCL1 and CXCL3 were upregulated, which in particular regulate the cytokine storm and IL-17 signaling pathway. Of note, SARS-CoV-2 infection strongly activated IL-17 signaling pathway compared with other respiratory viruses. Additionally, this transcriptomic signature was also analyz...
Biochemical and Biophysical Research Communications, 2019
RIG-I-like receptors (RLRs) are cytoplasmic sensors for viral RNA that elicit antiviral innate im... more RIG-I-like receptors (RLRs) are cytoplasmic sensors for viral RNA that elicit antiviral innate immune responses. RLR signaling culminates in the activation of the protein kinase TBK1, which mediates phosphorylation and nuclear translocation of IRF3 that regulates expression of type I interferon genes. Here, we found that Nucleoporin 93 (Nup93), components of nuclear pore complex (NPC), plays an important role in RLR-mediated antiviral responses. Nup93-deficient RAW264.7 macrophage cells exhibited decreased expression of Ifnb1 and Cxcl10 genes after treatment with a synthetic RLR agonist stimulation as well as Newcastle Disease Virus infection. Silencing Nup93 in murine primary macrophages and embryonic fibroblasts also resulted in reduced expression of these genes. IRF3 nuclear translocation during RLR signaling was impaired in Nup93-deficient RAW264.7 cells. Notably, the activation of TBK1 during RLR signaling was also decreased in Nup93-deficient cells. We found that Nup93 formed a complex with TBK1, and Nup93 overexpression enhanced TBK1-mediated IFNβ promoter activation. Taken together, our findings suggest that Nup93 regulates antiviral innate immunity by enhancing TBK1 activity and IRF3 nuclear translocation.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has resulted in the global... more Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has resulted in the global coronavirus disease 2019 (COVID-19) pandemic. Despite several single-cell RNA sequencing (RNA-seq) studies, conclusions cannot be reached owing to the small number of available samples and the differences in technology and tissue types used in the studies. To better understand the cellular landscape and disease severity in COVID-19, we performed a meta-analysis of publicly available single-cell RNA-seq data from peripheral blood and lung samples of COVID-19 patients with varying degrees of severity. Patients with severe disease showed increased numbers of M1 macrophages in lung tissue, while the number of M2 macrophages was depleted. Cellular profiling of the peripheral blood showed a marked increase of CD14+, CD16+ monocytes and a concomitant depletion of overall B cells and CD4+, CD8+ T cells in severe patients when compared with moderate patients. Our analysis indicates the presence of faulty innate-to-adaptive switching, marked by a prolonged innate immune response and a dysregulated adaptive immune response in severe COVID-19 patients. Furthermore, we identified cell types with a transcriptome signature that can be used as a prognostic biomarker for disease state prediction and the effective therapeutic management of COVID-19 patients.
Abnormal levels of High temperature requirement A1 (HtrA1) protein have been repeatedly observed ... more Abnormal levels of High temperature requirement A1 (HtrA1) protein have been repeatedly observed in sera and placentas of preeclampsia patients. To understand the functions of HtrA1 in placentation and in the etiology of preeclampsia, we established HtrA1(-/-) mice. HtrA1(-/-) mice show intrauterine growth retardation, and their placentas are small due to a reduced size of the junctional zone and aberrant vascularization in the labyrinth at the mid-gestation stage. HtrA1 is expressed by Tpbpa-positive trophoblast precursors in the outer ectoplacental cone and junctional zone from embryonic day 7.5 to 10.5. In the HtrA1(-/-) placenta, Tpbpa-positive cell precursors are decreased in the early stage. Spongiotrophoblasts and glycogen trophoblast cells, both of which differentiate from Tpbpa-positive precursors, are consequently decreased in the junctional zone. Fewer spiral artery-associated trophoblast giant cells, another cell type derived from Tpbpa-positive precursors, invade the decidua and associate with maternal arteries in the HtrA1(-/-) placenta than in the wild type placenta. Maternal arteries in the HtrA1(-/-) decidua have narrower lumens, thicker arterial walls, and more vascular smooth muscle cells remaining in the walls than those in the wild type decidua, indicating impaired remodeling of maternal arteries. These results indicate that HtrA1 plays important roles in the differentiation of trophoblasts from Tpbpa-positive precursors in the ectoplacental cone. Insufficient levels of HtrA1 cause poor placental development and intrauterine growth retardation, due to aberrant trophoblast differentiation and consequent defects in maternal artery remodeling, and may contribute to the onset of preeclampsia.
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Papers by Zobaer Hasan