scholarly journals Smoking Modulates Different Secretory Subpopulations Expressing SARS-CoV-2 Entry Genes in the Nasal and Bronchial Airways

2021 ◽  
Author(s):  
Ke Xu ◽  
Xingyi Shi ◽  
Christopher Husted ◽  
Rui Hong ◽  
Yichen Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Severe Disease ◽  
Expression Patterns ◽  
Goblet Cells ◽  
Current Smoker ◽  
Secretory Cells ◽  
Cell Populations ◽  
Clinical Factor ◽  
Minimal Impact ◽  
Ve Gene

Abstract Background: SARS-CoV-2 infection and disease severity are influenced by viral entry (VE) gene expression patterns in airway epithelium. The similarities and differences of VE gene expression (ACE2, TMPRSS2, and CTSL) across nasal and bronchial compartments has not been fully characterized using matched samples from large cohorts. Results: Gene expression data from 793 nasal and 1,673 bronchial brushes obtained from individuals participating in lung cancer screening or diagnostic workup revealed that smoking was the only clinical factor significantly and reproducibly associated with VE gene expression. ACE2 and TMPRSS2 expression were higher in smokers in the bronchus but not in the nose. scRNA-seq of nasal brushings indicated that ACE2 co-expressed genes were highly expressed in club and C15orf48+ secretory cells while TMPRSS2 co-expressed genes were highly expressed in keratinizing epithelial cells. In contrast, these ACE2 and TMPRSS2 modules were highly expressed in goblet cells in scRNA-seq from bronchial brushings. Cell-type deconvolution of the RNA-seq confirmed that smoking increased the abundance of several secretory cell populations in the bronchus, but only goblet cells in the nose. Conclusions: The association of ACE2 and TMPRSS2 with smoking in the bronchus is due to their high expression in goblet cells which increase in abundance in current smoker airways. In contrast, in the nose these genes are not predominantly expressed in cell populations modulated by smoking. Smoking-induced VE gene expression changes in the nose likely has minimal impact on SARS-CoV-2 infection, but in the bronchus, smoking may lead to higher viral loads and more severe disease.

scholarly journals Smoking modulates different secretory subpopulations expressing SARS-CoV-2 entry genes in the nasal and bronchial airways

2021 ◽  
Author(s):  
Ke Xu ◽  
Xingyi Shi ◽  
Chris Husted ◽  
Rui Hong ◽  
Yichen Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Risk Factors ◽  
Epithelial Cells ◽  
Viral Infection ◽  
Single Cell ◽  
Goblet Cells ◽  
Secretory Cells ◽  
Gene Module ◽  
Rna Seq ◽  
Ve Gene

AbstractCoronavirus Disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 SARS-CoV-2), which infects host cells with help from the Viral Entry (VE) proteins ACE2, TMPRSS2, and CTSL1–4. Proposed risk factors for viral infection, as well as the rate of disease progression, include age5,6, sex7, chronic obstructive pulmonary disease7,8, cancer9, and cigarette smoking10–13. To investigate whether the proposed risk factors increase viral infection by modulation of the VE genes, we examined gene expression profiles of 796 nasal and 1,673 bronchial samples across four lung cancer screening cohorts containing individuals without COVID-19. Smoking was the only clinical factor reproducibly associated with the expression of any VE gene across cohorts. ACE2 expression was significantly up-regulated with smoking in the bronchus but significantly down-regulated with smoking in the nose. Furthermore, expression of individual VE genes were not correlated between paired nasal and bronchial samples from the same patients. Single-cell RNA-seq of nasal brushings revealed that an ACE2 gene module was detected in a variety of nasal secretory cells with the highest expression in the C15orf48+ secretory cells, while a TMPRSS2 gene module was most highly expressed in nasal keratinizing epithelial cells. In contrast, single-cell RNA-seq of bronchial brushings revealed that ACE2 andTMPRSS2 gene modules were most enriched in MUC5AC+ bronchial goblet cells. The CTSL gene module was highly expressed in immune populations of both nasal and bronchial brushings. Deconvolution of bulk RNA-seq showed that the proportion of MUC5AC+ goblet cells was increased in current smokers in both the nose and bronchus but proportions of nasal keratinizing epithelial cells, C15orf48+ secretory cells, and immune cells were not associated with smoking status. The complex association between VE gene expression and smoking in the nasal and bronchial epithelium revealed by our results may partially explain conflicting reports on the association between smoking and SARS-CoV-2 infection.

scholarly journals Gene Expression Risk Scores for COVID-19 Illness Severity

2021 ◽  
Author(s):  
Derick R Peterson ◽  
Andrea M Baran ◽  
Soumyaroop Bhattacharya ◽  
Angela Ramona Branche ◽  
Daniel P Croft ◽  
...  
Keyword(s):  
Gene Expression ◽  
Intensive Care ◽  
Severe Disease ◽  
Expression Patterns ◽  
Illness Severity ◽  
Risk Scores ◽  
Severe Illness ◽  
T Cell Signaling ◽  
Training Cohort ◽  
Peripheral Blood Gene Expression

Background: The correlates of COVID-19 illness severity following infection with SARS-Coronavirus 2 (SARS-CoV-2) are incompletely understood. Methods: We assessed peripheral blood gene expression in 53 adults with confirmed SARS-CoV-2-infection clinically adjudicated as having mild, moderate or severe disease. Supervised principal components analysis was used to build a weighted gene expression risk score (WGERS) to discriminate between severe and non-severe COVID. Results: Gene expression patterns in participants with mild and moderate illness were similar, but significantly different from severe illness. When comparing severe versus non-severe illness, we identified >4000 genes differentially expressed (FDR<0.05). Biological pathways increased in severe COVID-19 were associated with platelet activation and coagulation, and those significantly decreased with T cell signaling and differentiation. A WGERS based on 18 genes distinguished severe illness in our training cohort (cross-validated ROC-AUC=0.98), and need for intensive care in an independent cohort (ROC-AUC=0.85). Dichotomizing the WGERS yielded 100% sensitivity and 85% specificity for classifying severe illness in our training cohort, and 84% sensitivity and 74% specificity for defining the need for intensive care in the validation cohort. Conclusion: These data suggest that gene expression classifiers may provide clinical utility as predictors of COVID-19 illness severity.

scholarly journals Modulation of the expression of sirtuins and var genes by heat shock in the malaria parasite Plasmodium falciparum: a pattern emerges

2021 ◽  
Author(s):  
Linda O. Anagu ◽  
David R. Hulse ◽  
Paul D. Horrocks ◽  
Srabasti J Chakravorty
Keyword(s):  
Gene Expression ◽  
Plasmodium Falciparum ◽  
Heat Shock ◽  
Malaria Parasite ◽  
Severe Disease ◽  
Expression Patterns ◽  
Stress Factors ◽  
Virulence Gene Expression

Abstract Background: In the malaria parasite Plasmodium falciparum the expression of ‘var’ virulence genes is regulated through epigenetic mechanisms. Its sirtuin epigenetic regulators have a direct effect on var gene expression patterns, are increased in a laboratory strain of P. falciparum exposed to heat shock and are positively associated with fever. A Gambia study extended this association to blood lactate and var genes commonly expressed in severe malaria, and between PfSir2A and group B var. A Kenyan study extended this association to between PfSir2A and overall var transcript level. These observations suggest a mechanism through which stress phenotypes in the human host might be sensed via a parasite sirtuin, and virulence gene expression modulated accordingly. Methods: In vitro experiments were conducted using laboratory and recently-laboratory-adapted Kenyan isolates of P. falciparum to follow up the correlative findings of the field study. To investigate a potential cause-and-effect relationship between host stress factors and parasite gene expression, qPCR was used to measure the expression of sirtuins and var genes after highly synchronous cultured parasites had been exposed to 2h or 6h of heat shock at 40°C or elevated lactate.Results: Heat shock was shown to influence the expression of PfSir2B in the trophozoites, whereas exposure to lactate was not. After the ring stages were exposed to heat shock; sirtuins, severe-disease-associated upsA and upsB var genes and var genes in general were not altered. More biological replicate experiments will be needed to confirm our observations. Conclusions: This study demonstrates that heat stress in laboratory and recently-laboratory-adapted isolates of P. falciparum results in a small increase in PfSir2B transcripts in the trophozoite stages only. By contrast, the association between hyperlactataemia and sirtuin/var gene expression that was previously observed in vivo appears to be coincidental rather than causative.

scholarly journals GENE-47. A 3D ATLAS TO EVALUATE THE SPATIAL PATTERNING OF GENETIC ALTERATIONS AND TUMOR CELL STATES IN GLIOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi107-vi108
Author(s):  
Stephanie Hilz ◽  
Chibo Hong ◽  
Llewellyn Jalbert ◽  
Tali Mazor ◽  
Michael Martin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Gene Expression Profiles ◽  
Genetic Alterations ◽  
Cell Populations ◽  
Low Grade ◽  
Lower Grade ◽  
Diffuse Glioma ◽  
Spatial Patterning

Abstract BACKGROUND Previous studies of solid tumors have been restricted in their ability to map how heterogeneous cell populations evolved within the tumor in three-dimensional (3D) space due to insufficient sampling, typically one sample per tumor, and a lack of knowledge of where within the tumor the sample was obtained. Knowledge of the extensivity of heterogeneity and how it is spatially distributed is crucial for assessing whether a therapeutic target is truly tumor-wide, and for exploring how mutations relate to heterogeneity in the local microenvironment. METHODS We developed a novel platform to integrate and visualize in 3D multi-omics data generated from each of 8–10 spatially mapped samples per tumor. Together, the 171 samples collected using this approach from 16 adult diffuse glioma at diagnosis and recurrence form a novel resource – the 3D Glioma Atlas. RESULTS By maximally sampling the tumor geography without excluding samples based on low cancer cell fraction (CCF), we identify a subpopulation of glioblastoma with pervasively lower CCF likely excluded by other atlases, such as the TCGA, that used stringent CCF cutoffs. Exome sequencing of 3D-mapped samples from lower-grade tumors revealed that clonal expansions are typically spatially segregated, implying minimal tumor-wide intermixing of genetically heterogenous cells. Heterogeneity is less spatially segregated for faster-growing high-grade tumors, suggesting that cell populations expand in these tumors differently. Recurrent low-grade tumors have greater intratumoral mutational heterogeneity than newly diagnosed tumors, though this did not translate into greater dissimilarity in gene expression profiles for recurrent tumors, suggesting minimal functional impact of this additional mutational diversity on gene expression. CONCLUSIONS The delineation of spatial patterns of heterogeneity that our work provides enables more informed interpretation of biopsies and greater insight into the factors shaping intratumoral variation of gene expression patterns. Ongoing work is exploring the spatial patterning of amplification events and the tumor microenvironment.

scholarly journals Alteration of the expression of sirtuins and var genes by heat shock in the malaria parasite Plasmodium falciparum: a pattern emerges

2021 ◽  
Author(s):  
Linda O. Anagu ◽  
David R. Hulse ◽  
Paul D. Horrocks ◽  
Srabasti J Chakravorty
Keyword(s):  
Gene Expression ◽  
Plasmodium Falciparum ◽  
Heat Shock ◽  
Blood Lactate ◽  
Malaria Parasite ◽  
Severe Disease ◽  
Expression Patterns ◽  
Stress Factors

Abstract Background In the malaria parasite Plasmodium falciparum the expression of ‘var’ virulence genes is regulated through epigenetic mechanisms. P. falciparum sirtuin epigenetic regulators have a direct effect on their var gene expression patterns, are increased in the 3D7 laboratory strain on exposure to heat shock. A Gambia study showed an association with fever, blood lactate and var genes commonly expressed in severe malaria, and between PfSir2A and group B var. A Kenyan study extended this association to between PfSir2A and overall var transcript level. We investigated a causal link between heat shock or lactate levels and sirtuins or var expression. Methods In vitro experiments were conducted using laboratory and recently-laboratory-adapted Kenyan isolates of P. falciparum to follow up the correlative findings of the field study. To investigate a potential cause-and-effect relationship between host stress factors and parasite gene expression, qPCR was used to measure the expression of sirtuins and var genes after highly synchronous cultured parasites had been exposed to 2h or 6h of heat shock at 40°C or elevated lactate. Results Heat shock was shown to increase the expression of PfSir2B in the trophozoites, whereas exposure to lactate was not. After the ring stages were exposed to heat shock and lactate, there was no alteration in the expression of sirtuins and severe-disease-associated upsA and upsB var genes. The association between high blood lactate and sirtuin/var gene expression that was previously observed in vivo appears to be coincidental rather than causative. Conclusions This study demonstrates that heat stress in laboratory and recently-laboratory-adapted isolates of P. falciparum results in a small increase in PfSir2B transcripts in the trophozoite stages only. This finding adds to our understanding of how patient factors can influence the outcome of Plasmodium falciparum infections.

scholarly journals Cellular Heterogeneity of Mesenchymal Stem/Stromal Cells in the Bone Marrow

2021 ◽  
Vol 9 ◽  
Author(s):  
Yo Mabuchi ◽  
Chikako Okawara ◽  
Simón Méndez-Ferrer ◽  
Chihiro Akazawa
Keyword(s):  
Gene Expression ◽  
Stromal Cells ◽  
Myeloproliferative Neoplasms ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Cellular Heterogeneity ◽  
Cell Populations ◽  
Complex Nature ◽  
Cell Surface Antigens ◽  
Body Tissues

Mesenchymal stem/stromal cells (MSCs) are present in various body tissues and help in maintaining homeostasis. The stemness of MSCs has been evaluated in vitro. In addition, analyses of cell surface antigens and gene expression patterns have shown that MSCs comprise a heterogeneous population, and the diverse and complex nature of MSCs makes it difficult to identify the specific roles in diseases. There is a lack of understanding regarding the classification of MSC properties. In this review, we explore the characteristics of heterogeneous MSC populations based on their markers and gene expression profiles. We integrated the contents of previously reported single-cell analysis data to better understand the properties of mesenchymal cell populations. In addition, the cell populations involved in the development of myeloproliferative neoplasms (MPNs) are outlined. Owing to the diversity of terms used to describe MSCs, we used the text mining technology to extract topics from MSC research articles. Recent advances in technology could improve our understanding of the diversity of MSCs and help us evaluate cell populations.

scholarly journals Heat shock modulates the expression of sirtuins and var genes in the malaria parasite Plasmodium falciparum

2020 ◽  
Author(s):  
Linda Anagu ◽  
David Hulse ◽  
Srabasti Chakravorty ◽  
Paul Horrocks ◽  
Catherine Jill Merrick
Keyword(s):  
Gene Expression ◽  
Plasmodium Falciparum ◽  
Heat Stress ◽  
Heat Shock ◽  
Malaria Parasite ◽  
Severe Disease ◽  
Expression Patterns ◽  
Stress Factors ◽  
High Expression ◽  
Human Host

Abstract Background: In the malaria parasite Plasmodium falciparum the expression of key ‘var’ virulence genes is regulated through epigenetic mechanisms. Two deacetylase enzymes of the sirtuin family have been implicated in this epigenetic control in laboratory-adapted parasites. A previous study of var gene expression in parasites isolated directly from Gambian malaria patients found that high expression levels of severe-disease-associated var variants correlated with high expression of the PfSir2A sirtuin, and these expression patterns also correlated with patient phenotypes of fever and hyperlactataemia. Together, the observations suggest a mechanism through which stress phenotypes in the human host might be sensed via a parasite sirtuin, and virulence gene expression modulated accordingly. Methods: In vitro experiments were conducted using recently-laboratory-adapted Kenyan isolates of P. falciparum to follow up the correlative findings of the field study. To investigate a potential cause-and-effect relationship between host stress factors and parasite gene expression, RT-PCR was used to measure the expression of sirtuins and var genes after cultured parasites had been exposed to 2h or 6h of heat shock at 40°C or elevated lactate at 5mM.Results: Heat shock was shown to influence the expression of both sirtuins and var genes, whereas exposure to lactate was not. Heat shock in the trophozoite stage resulted in modest upregulation of the expression of sirtuins, particularly PfSir2B, by 2-3 fold in all strains tested. Interestingly, when heat shock was applied in ring stages PfSir2A was still upregulated but PfSir2B was downregulated. This correlated with a general upregulation of ring-stage var transcription, and particularly of severe-disease-associated upsA and upsB var genes, but there was no clear pattern in the dominant var gene(s) ultimately expressed by heat-shocked parasites. Conclusions: This study demonstrates for the first time that heat stress in recently-laboratory-adapted patient isolates of P. falciparum results in altered sirtuin expression – PfSir2B as well as PfSir2A – and also the upregulation of var gene expression. These may be strategies evolved by the parasite to survive heat stress when a human host experiences malarial fevers. By contrast, the association between hyperlactataemia and sirtuin/var gene expression that was previously observed in vivo appears to be coincidental rather than causative.

scholarly journals Heat Shock Modulates The Expression of Sirtuins and Var Genes in The Malaria Parasite Plasmodium Falciparum

2020 ◽  
Author(s):  
Linda O. Anagu ◽  
David R. Hulse ◽  
Srabasti J Chakravorty ◽  
Paul D. Horrocks ◽  
Catherine Jill Merrick
Keyword(s):  
Gene Expression ◽  
Plasmodium Falciparum ◽  
Heat Stress ◽  
Heat Shock ◽  
Malaria Parasite ◽  
Severe Disease ◽  
Expression Patterns ◽  
Stress Factors ◽  
High Expression ◽  
Human Host

Abstract Background: In the malaria parasite Plasmodium falciparum the expression of ‘var’ virulence genes is regulated through epigenetic mechanisms. Two deacetylase enzymes of the sirtuin family have been implicated in this epigenetic control in laboratory-adapted parasites. A previous study of var gene expression in parasites isolated directly from Gambian malaria patients found that high expression levels of severe-disease-associated var variants correlated with high expression of the PfSir2A sirtuin, and these expression patterns also correlated with patient phenotypes of fever and hyperlactataemia. Together, the observations suggest a mechanism through which stress phenotypes in the human host might be sensed via a parasite sirtuin, and virulence gene expression modulated accordingly. Methods: In vitro experiments were conducted using recently-laboratory-adapted Kenyan isolates of P. falciparum to follow up the correlative findings of the field study. To investigate a potential cause-and-effect relationship between host stress factors and parasite gene expression, qPCR was used to measure the expression of sirtuins and var genes after cultured parasites had been exposed to 2h or 6h of heat shock at 40°C or elevated lactate at 5mM.Results: Heat shock was shown to influence the expression of both sirtuins and var genes, whereas exposure to lactate was not. Heat shock in the trophozoite stage resulted in modest upregulation of the expression of sirtuins, particularly PfSir2B, by 2-3 fold in all strains tested. Interestingly, when heat shock was applied in ring stages PfSir2A was still upregulated but PfSir2B was downregulated. This correlated with a general upregulation of ring-stage var transcription, and particularly of severe-disease-associated upsA and upsB var genes, but there was no clear pattern in the dominant var gene(s) ultimately expressed by heat-shocked parasites. Conclusions: This study demonstrates for the first time that heat stress in recently-laboratory-adapted isolates of P. falciparum results in altered sirtuin expression – PfSir2B as well as PfSir2A – and also the upregulation of var gene expression. These may be strategies evolved by the parasite to survive heat stress when a human host experiences malarial fevers. By contrast, the association between hyperlactataemia and sirtuin/var gene expression that was previously observed in vivo appears to be coincidental rather than causative.

scholarly journals Differences in adherence and virulence gene expression between two outbreak strains of enterohaemorrhagic Escherichia coli O157 : H7

Microbiology ◽  
2010 ◽  
Vol 156 (2) ◽  
pp. 408-419 ◽  
Author(s):  
Galeb S. Abu-Ali ◽  
Lindsey M. Ouellette ◽  
Scott T. Henderson ◽  
Thomas S. Whittam ◽  
Shannon D. Manning
Keyword(s):  
Gene Expression ◽  
Escherichia Coli ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Severe Disease ◽  
Expression Patterns ◽  
Disease Process ◽  
Bacterial Attachment ◽  
Significant Differential Expression ◽  
Enterohaemorrhagic Escherichia Coli

The Escherichia coli O157 : H7 TW14359 strain was implicated in a multi-state outbreak in North America in 2006, which resulted in high rates of severe disease. Similarly, the O157 : H7 RIMD0509952 (Sakai) strain caused the largest O157 : H7 outbreak to date. Both strains were shown to represent divergent phylogenetic lineages. Here we compared global gene expression patterns before and after epithelial cell exposure, as well as the ability to adhere to and invade epithelial cells, between the two outbreak strains. Epithelial cell assays demonstrated a 2.5-fold greater adherence of the TW14359 strain relative to Sakai, while whole-genome microarrays detected significant differential expression of 914 genes, 206 of which had a fold change ≥1.5. Interestingly, most locus of enterocyte effacement (LEE) genes were upregulated in TW14359, whereas flagellar and chemotaxis genes were primarily upregulated in Sakai, suggesting discordant expression of these genes between the two strains. The Shiga toxin 2 genes were also upregulated in the TW14359 strain, as were several pO157-encoded genes that promote adherence, including type II secretion genes and their effectors stcE and adfO. Quantitative RT-PCR confirmed the expression differences detected in the microarray analysis, and expression levels were lower for a subset of LEE genes before versus after exposure to epithelial cells. In all, this study demonstrated the upregulation of major and ancillary virulence genes in TW14359 and of flagellar and chemotaxis genes in Sakai, under conditions that precede intimate bacterial attachment to epithelial cells. Differences in the level of adherence to epithelial cells were also observed, implying that these two phylogenetically divergent O157 : H7 outbreak strains vary in their ability to colonize, or initiate the disease process.

scholarly journals Differential Gene Expression in Host Ubiquitination Processes in Childhood Malarial Anemia

2021 ◽  
Vol 12 ◽  
Author(s):  
Samuel B. Anyona ◽  
Evans Raballah ◽  
Qiuying Cheng ◽  
Ivy Hurwitz ◽  
Caroline Ndege ◽  
...  
Keyword(s):  
Gene Expression ◽  
Differential Gene Expression ◽  
Expression Profiles ◽  
Severe Disease ◽  
Expression Patterns ◽  
Gene Expression Profiles ◽  
Protein Coding ◽  
Childhood Morbidity ◽  
Differential Gene ◽  
Malarial Anemia

Background: Malaria remains one of the leading global causes of childhood morbidity and mortality. In holoendemic Plasmodium falciparum transmission regions, such as western Kenya, severe malarial anemia [SMA, hemoglobin (Hb) &lt; 6.0 g/dl] is the primary form of severe disease. Ubiquitination is essential for regulating intracellular processes involved in innate and adaptive immunity. Although dysregulation in ubiquitin molecular processes is central to the pathogenesis of multiple human diseases, the expression patterns of ubiquitination genes in SMA remain unexplored.Methods: To examine the role of the ubiquitination processes in pathogenesis of SMA, differential gene expression profiles were determined in Kenyan children (n = 44, aged &lt;48 mos) with either mild malarial anemia (MlMA; Hb ≥9.0 g/dl; n = 23) or SMA (Hb &lt;6.0 g/dl; n = 21) using the Qiagen Human Ubiquitination Pathway RT2 Profiler PCR Array containing a set of 84 human ubiquitination genes.Results: In children with SMA, 10 genes were down-regulated (BRCC3, FBXO3, MARCH5, RFWD2, SMURF2, UBA6, UBE2A, UBE2D1, UBE2L3, UBR1), and five genes were up-regulated (MDM2, PARK2, STUB1, UBE2E3, UBE2M). Enrichment analyses revealed Ubiquitin-Proteasomal Proteolysis as the top disrupted process, along with altered sub-networks involved in proteasomal, protein, and ubiquitin-dependent catabolic processes.Conclusion: Collectively, these novel results show that protein coding genes of the ubiquitination processes are involved in the pathogenesis of SMA.

Sign in / Sign up

Export Citation Format

Share Document