scholarly journals Transcriptome of nasopharyngeal samples from COVID-19 patients and a comparative analysis with other SARS-CoV-2 infection models reveal disparate host responses against SARS-CoV-2

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Abul Bashar Mir Md. Khademul Islam ◽  
Md. Abdullah-Al-Kamran Khan ◽  
Rasel Ahmed ◽  
Md. Sabbir Hossain ◽  
Shah Md. Tamim Kabir ◽  
...  
Keyword(s):  
Functional Enrichment ◽  
Host Responses ◽  
Cytokine Signaling ◽  
Missense Mutations ◽  
Structural Protein ◽  
Differential Host ◽  
Genomic Features ◽  
Infection Models ◽  
Cytokine Stimulation ◽  
Respective Host

Abstract Background Although it is becoming evident that individual’s immune system has a decisive influence on SARS-CoV-2 disease progression, pathogenesis is largely unknown. In this study, we aimed to profile the host transcriptome of COVID-19 patients from nasopharyngeal samples along with virus genomic features isolated from respective host, and a comparative analyses of differential host responses in various SARS-CoV-2 infection systems. Results Unique and rare missense mutations in 3C-like protease observed in all of our reported isolates. Functional enrichment analyses exhibited that the host induced responses are mediated by innate immunity, interferon, and cytokine stimulation. Surprisingly, induction of apoptosis, phagosome, antigen presentation, hypoxia response was lacking within these patients. Upregulation of immune and cytokine signaling genes such as CCL4, TNFA, IL6, IL1A, CCL2, CXCL2, IFN, and CCR1 were observed in lungs. Lungs lacked the overexpression of ACE2 as suspected, however, high ACE2 but low DPP4 expression was observed in nasopharyngeal cells. Interestingly, directly or indirectly, viral proteins specially non-structural protein mediated overexpression of integrins such as ITGAV, ITGA6, ITGB7, ITGB3, ITGA2B, ITGA5, ITGA6, ITGA9, ITGA4, ITGAE, and ITGA8 in lungs compared to nasopharyngeal samples suggesting the possible way of enhanced invasion. Furthermore, we found comparatively highly expressed transcription factors such as CBP, CEBP, NFAT, ATF3, GATA6, HDAC2, TCF12 which have pivotal roles in lung injury. Conclusions Even though this study incorporates a limited number of cases, our data will provide valuable insights in developing potential studies to elucidate the differential host responses on the viral pathogenesis in COVID-19, and incorporation of further data will enrich the search of an effective therapeutics.

scholarly journals Regulation of Jak2 Function by Phosphorylation of Tyr317 and Tyr637 during Cytokine Signaling

2009 ◽  
Vol 29 (12) ◽  
pp. 3367-3378 ◽  
Author(s):  
Scott A. Robertson ◽  
Rositsa I. Koleva ◽  
Lawrence S. Argetsinger ◽  
Christin Carter-Su ◽  
Jarrod A. Marto ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Activity ◽  
Feedback Inhibition ◽  
Dominant Role ◽  
Kinase Domain ◽  
Cytokine Signaling ◽  
Tyrosine Kinase Domain ◽  
Phosphorylation Sites ◽  
Cytokine Stimulation

ABSTRACT Jak2, the cognate tyrosine kinase for numerous cytokine receptors, undergoes multisite phosphorylation during cytokine stimulation. To understand the role of phosphorylation in Jak2 regulation, we used mass spectrometry to identify numerous Jak2 phosphorylation sites and characterize their significance for Jak2 function. Two sites outside of the tyrosine kinase domain, Tyr317 in the FERM domain and Tyr637 in the JH2 domain, exhibited strong regulation of Jak2 activity. Mutation of Tyr317 promotes increased Jak2 activity, and the phosphorylation of Tyr317 during cytokine signaling requires prior activation loop phosphorylation, which is consistent with a role for Tyr317 in the feedback inhibition of Jak2 kinase activity after receptor stimulation. Comparison to several previously identified regulatory phosphorylation sites on Jak2 revealed a dominant role for Tyr317 in the attenuation of Jak2 signaling. In contrast, mutation of Tyr637 decreased Jak2 signaling and activity and partially suppressed the activating JH2 V617F mutation, suggesting a role for Tyr637 phosphorylation in the release of JH2 domain-mediated suppression of Jak2 kinase activity during cytokine stimulation. The phosphorylation of Tyr317 and Tyr637 act in concert with other regulatory events to maintain appropriate control of Jak2 activity and cytokine signaling.

scholarly journals A pan-cancer assessment of alterations of the kinase domain of ULK1, an upstream regulator of autophagy

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Mukesh Kumar ◽  
Elena Papaleo
Keyword(s):  
Catalytic Domain ◽  
Cancer Genomics ◽  
Three Dimensional ◽  
Kinase Domain ◽  
Structural Level ◽  
Missense Mutations ◽  
Structural Protein ◽  
Upstream Regulator ◽  
Functional Dynamics ◽  
Cancer Types

Abstract Autophagy is a key clearance process to recycle damaged cellular components. One important upstream regulator of autophagy is ULK1 kinase. Several three-dimensional structures of the ULK1 catalytic domain are available, but a comprehensive study, including molecular dynamics, is missing. Also, an exhaustive description of ULK1 alterations found in cancer samples is presently lacking. We here applied a framework which links -omics data to structural protein ensembles to study ULK1 alterations from genomics data available for more than 30 cancer types. We predicted the effects of mutations on ULK1 function and structural stability, accounting for protein dynamics, and the different layers of changes that a mutation can induce in a protein at the functional and structural level. ULK1 is down-regulated in gynecological tumors. In other cancer types, ULK2 could compensate for ULK1 downregulation and, in the majority of the cases, no marked changes in expression have been found. 36 missense mutations of ULK1, not limited to the catalytic domain, are co-occurring with mutations in a large number of ULK1 interactors or substrates, suggesting a pronounced effect of the upstream steps of autophagy in many cancer types. Moreover, our results pinpoint that more than 50% of the mutations in the kinase domain of ULK1, here investigated, are predicted to affect protein stability. Three mutations (S184F, D102N, and A28V) are predicted with only impact on kinase activity, either modifying the functional dynamics or the capability to exert effects from distal sites to the functional and catalytic regions. The framework here applied could be extended to other protein targets to aid the classification of missense mutations from cancer genomics studies, as well as to prioritize variants for experimental validation, or to select the appropriate biological readouts for experiments.

scholarly journals The Proinflammatory Response Induced by Wild-Type Yersinia pseudotuberculosis Infection Inhibits Survival of yop Mutants in the Gastrointestinal Tract and Peyer's Patches

2006 ◽  
Vol 74 (3) ◽  
pp. 1516-1527 ◽  
Author(s):  
Lauren K. Logsdon ◽  
Joan Mecsas
Keyword(s):  
Yersinia Pseudotuberculosis ◽  
Intestinal Inflammation ◽  
Peyer's Patches ◽  
Host Responses ◽  
Infection Model ◽  
Peyer’S Patches ◽  
Wild Type ◽  
Single Strain ◽  
Infection Models ◽  
Ifn Γ

ABSTRACT Single-strain infections and coinfections are frequently used to assess roles of virulence factors in infected tissues. After oral inoculation of mice, Yersinia pseudotuberculosis yopE and yopH mutants colonize the intestines and Peyer's patches in single-strain infections but fail to persist in competition with wild-type Y. pseudotuberculosis, indicating that these two infection models provide different insights into the roles of Yops. To determine how wild-type Y. pseudotuberculosis hinders yop mutant survival, yop mutant colonization and host responses were investigated in several different infection models that isolated specific features of wild-type Y. pseudotuberculosis infection. Infection with wild-type Y. pseudotuberculosis caused significantly more inflammation than yop mutants. Results from coinfections of gamma interferon (IFN-γ)−/− mice revealed that IFN-γ-regulated defenses target these mutants, suggesting that YopE and YopH protect Y. pseudotuberculosis from these defenses in BALB/c mice. We developed an oral-intraperitoneal infection model to evaluate the effects of spleen and liver colonization by Y. pseudotuberculosis on yop mutants in the intestines. Spleen and liver infection increased inflammation and decreased yop mutant survival in the intestines, indicating that infection of these organs has consequences in intestinal tissues. Finally, competition infections with Y. pseudotuberculosis mutants with various abilities to induce inflammation demonstrated that survival of the yopE, but not the yopH, mutant was consistently decreased in inflamed tissues. In summary, infection with Y. pseudotuberculosis in intestinal and systemic sites induces intestinal inflammation, which decreases yop mutant survival. Thus, competition studies with wild-type yersiniae reveal critical roles of Yops in combating host responses to a normal virulent infection.

scholarly journals Role for Parasite Genetic Diversity in Differential Host Responses to Trypanosoma brucei Infection

2010 ◽  
Vol 78 (3) ◽  
pp. 1096-1108 ◽  
Author(s):  
Liam J. Morrison ◽  
Sarah McLellan ◽  
Lindsay Sweeney ◽  
Chi N. Chan ◽  
Annette MacLeod ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Interleukin 10 ◽  
Host Responses ◽  
Response Modulation ◽  
Product Analysis ◽  
Differential Host ◽  
Experimental Systems ◽  
Immune Response Modulation ◽  
Host Parasite ◽  
Host Genes

ABSTRACT The postgenomic era has revolutionized approaches to defining host-pathogen interactions and the investigation of the influence of genetic variation in either protagonist upon infection outcome. We analyzed pathology induced by infection with two genetically distinct Trypanosoma brucei strains and found that pathogenesis is partly strain specific, involving distinct host mechanisms. Infections of BALB/c mice with one strain (927) resulted in more severe anemia and greater erythropoietin production compared to infections with the second strain (247), which, contrastingly, produced greater splenomegaly and reticulocytosis. Plasma interleukin-10 (IL-10) and gamma interferon levels were significantly higher in strain 927-infected mice, whereas IL-12 was higher in strain 247-infected mice. To define mechanisms underlying these differences, expression microarray analysis of host genes in the spleen at day 10 postinfection was undertaken. Rank product analysis (RPA) showed that 40% of the significantly differentially expressed genes were specific to infection with one or the other trypanosome strain. RPA and pathway analysis identified LXR/RXR signaling, IL-10 signaling, and alternative macrophage activation as the most significantly differentially activated host processes. These data suggest that innate immune response modulation is a key determinant in trypanosome infections, the pattern of which can vary, dependent upon the trypanosome strain. This strongly suggests that a parasite genetic component is responsible for causing disease in the host. Our understanding of trypanosome infections is largely based on studies involving single parasite strains, and our results suggest that an integrated host-parasite approach is required for future studies on trypanosome pathogenesis. Furthermore, it is necessary to incorporate parasite variation into both experimental systems and models of pathogenesis.

scholarly journals A Pan-Cancer assessment of alterations of the kinase domain of ULK1, an upstream regulator of autophagy

2019 ◽  
Author(s):  
Mukesh Kumar ◽  
Elena Papaleo
Keyword(s):  
Cancer Genomics ◽  
Kinase Domain ◽  
Structural Level ◽  
Missense Mutations ◽  
Structural Protein ◽  
Upstream Regulator ◽  
Functional Dynamics ◽  
Cancer Types ◽  
Protein Ensembles ◽  
Cellular Components

ABSTRACTAutophagy is a key clearance process to recycle damaged cellular components. One important upstream regulator of autophagy is the ULK1 kinase. Several structures of the ULK1 kinase domain have been solved, but a comprehensive study, including molecular dynamics, is missing. Also, an exhaustive description of ULK1 alterations found in cancer samples is presently lacking. We here applied a framework which links -omics data to structural protein ensembles to study ULK1 alterations from genomics data available for more that 30 cancer types. Moreover, we predicted the effects of mutations on ULK1 function and structural stability, accounting for protein dynamics and the different layers of changes that a mutation can induce in a protein at the functional and structural level.We find that ULK1 is down-regulated in gynecological tumors. In other cancer types, ULK2 could compensate for ULK1 downregulation and, in the majority of the cases, no marked changes in expression have been found. 36 missense mutations of ULK1 are co-occurring with mutations in a large number of ULK1 interactors, suggesting a pronounced effect of the upstream steps of autophagy in many cancer types. Moreover, our results pinpoint that more than 50% of the ULK1 mutations that we studied are predicted to affect protein stability. Three mutations (S184F, D102N, and A28V) are predicted with only impact on kinase activity, either modifying the functional dynamics or the capability to exert effects from distal site to the functional and catalytic regions. The framework here applied could be extended to other protein targets to aid the classification of missense mutations from cancer genomics studies, as well as to prioritize variants for experimental validation, or to select the appropriate biological readouts for experiments.

scholarly journals Metatranscriptomic Characterization of Coronavirus Disease 2019 Identified a Host Transcriptional Classifier Associated With Immune Signaling

2020 ◽  
Author(s):  
Haocheng Zhang ◽  
Jing-Wen Ai ◽  
Wenjiao Yang ◽  
Xian Zhou ◽  
Fusheng He ◽  
...  
Keyword(s):  
Disease Severity ◽  
Area Under The Curve ◽  
Alpha Diversity ◽  
Host Gene ◽  
Host Responses ◽  
Cytokine Signaling ◽  
Transcriptional Signature ◽  
Airway Microbiome ◽  
Core Elements ◽  
Novel Coronavirus

Abstract Background The recent identification of a novel coronavirus, also known as severe acute respiratory syndrome coronavirus 2, has caused a global outbreak of respiratory illnesses. The rapidly developing pandemic has posed great challenges to diagnosis of this novel infection. However, little is known about the metatranscriptomic characteristics of patients with coronavirus disease 2019 (COVID-19). Methods We analyzed metatranscriptomics in 187 patients (62 cases with COVID-19 and 125 with non–COVID-19 pneumonia). Transcriptional aspects of 3 core elements, pathogens, the microbiome, and host responses, were evaluated. Based on the host transcriptional signature, we built a host gene classifier and examined its potential for diagnosing COVID-19 and indicating disease severity. Results The airway microbiome in COVID-19 patients had reduced alpha diversity, with 18 taxa of differential abundance. Potentially pathogenic microbes were also detected in 47% of the COVID-19 cases, 58% of which were respiratory viruses. Host gene analysis revealed a transcriptional signature of 36 differentially expressed genes significantly associated with immune pathways, such as cytokine signaling. The host gene classifier built on such a signature exhibited the potential for diagnosing COVID-19 (area under the curve of 0.75–0.89) and indicating disease severity. Conclusions Compared with those with non–COVID-19 pneumonias, COVID-19 patients appeared to have a more disrupted airway microbiome with frequent potential concurrent infections and a special trigger host immune response in certain pathways, such as interferon-gamma signaling. The immune-associated host transcriptional signatures of COVID-19 hold promise as a tool for improving COVID-19 diagnosis and indicating disease severity.

scholarly journals Genome Sequence of Verticillium dahliae Race 1 Isolate VdLs.16 From Lettuce

2020 ◽  
Vol 33 (11) ◽  
pp. 1265-1269
Author(s):  
Jie-Yin Chen ◽  
Dan-Dan Zhang ◽  
Jin-Qun Huang ◽  
Dan Wang ◽  
Shi-Jun Hao ◽  
...  
Keyword(s):  
Verticillium Dahliae ◽  
Genetic Basis ◽  
Reference Genome ◽  
Genomic Diversity ◽  
Host Responses ◽  
Ongoing Research ◽  
Differential Host ◽  
Population Genomic ◽  
Race 1 ◽  
Race 2

Verticillium dahliae is a widespread fungal pathogen that causes Verticillium wilt on many economically important crops and ornamentals worldwide. Populations of V. dahliae have been divided into two distinct races based upon differential host responses in tomato and lettuce. Recently, the contemporary race 2 isolates were further divided into an additional race in tomato. Herein, we provide a high-quality reference genome for the race 1 strain VdLs.16 isolated from lettuce in California, U.S.A. This resource will contribute to ongoing research that aims to elucidate the genetic basis of V. dahliae pathogenicity and population genomic diversity.

scholarly journals Emerging SARS-CoV-2 variants of concern and potential intervention approaches

Critical Care ◽  
2021 ◽  
Vol 25 (1) ◽  
Author(s):  
Jasmin Khateeb ◽  
Yuchong Li ◽  
Haibo Zhang
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Clinical Outcome ◽  
Therapeutic Strategies ◽  
Spike Protein ◽  
Host Responses ◽  
Structural Protein ◽  
Potential Intervention ◽  
Viral Virulence ◽  
Protein Mutations ◽  
Spike Proteins

AbstractThe major variant of concerns (VOCs) have shared mutations in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike proteins, mostly on the S1 unit and resulted in higher transmissibility rate and affect viral virulence and clinical outcome. The spike protein mutations and other non-structural protein mutations in the VOCs may lead to escape approved vaccinations in certain extend. We will discuss these VOC mutations and discuss the need for combination therapeutic strategies targeting viral cycle and immune host responses.

Sign in / Sign up

Export Citation Format

Share Document