Potential role of skin in SARS-CoV-2 infection
皮肤在 SARS-CoV-2 感染中的潜在作用
基本信息
- 批准号:10593622
- 负责人:
- 金额:$ 24.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-21 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:2019-nCoV3-DimensionalACE2AcuteAddressAfrican AmericanAfrican American populationAtopic DermatitisBindingBiological FactorsBiologyBiopsyCOVID-19COVID-19 cytokine stormCOVID-19 impactCOVID-19 pathogenesisCOVID-19 patientCOVID-19 riskCOVID-19 vaccineCapsid ProteinsCellsChickenpoxChronicCommunitiesCoronavirusDataDeath RateDermatologicDevelopmentDisparityEpidermisEpithelial CellsEthnic OriginEthnic PopulationEyeFutureGene ExpressionGenesGlycoproteinsHeartHerpes Simplex InfectionsHerpes zoster diseaseHispanicHumanIL17 geneIL4 geneImmune EvasionIn VitroIndividualInfectionInfectious Skin DiseasesInflammationInflammatoryInflammatory ResponseInterferon Type IIInterleukin-1 betaInterleukin-13Interleukin-6KidneyKnowledgeLatinoLentivirusMessenger RNAModelingMolecularMolluscum contagiosum virusMorphologyMultiple Organ FailureMutateMutationNoseNot Hispanic or LatinoOrganPancreasPathogenesisPatientsPeptide HydrolasesPopulationPreventionPropertyProteinsPsoriasisRNARaceReceptor CellRecoveryReporterReportingRoleRouteSARS-CoV-2 infectionSARS-CoV-2 variantSamplingSignal TransductionSkinSkin ManifestationsSocioeconomic FactorsSurfaceSymptomsTMPRSS2 geneTNF geneTestingTissuesTomatoesVariantViralViremiaVirusWorkairway epitheliumcytokinecytokine release syndromeexperimental studyhospitalization ratesin vitro Modelinfection rateinnovationinterleukin-22keratinocytemutantnovelprogramsracial populationreceptor bindingresponseskin disorderskin woundthree dimensional cell culturetranscriptome sequencingtransmission processvaccine accessvaccine hesitancyviral RNAwoundwound healing
项目摘要
COVID-19 continues to be a global catastrophe despite development of anti-SARS-CoV-2 vaccines. This is due
to the worldwide limited vaccine availability, vaccination hesitancy, and the emergence of new variants of SARS-
CoV-2. Moreover, there is a lack of complete knowledge about SARS-CoV-2 biology, including potential
transmission routes and variable pathogenesis, especially in ethnic groups, such as African American (AA) and
Hispanic/Latino that were disproportionally affected by COVID-19 compared to White Non-Hispanic (WNH)
population. The role of biological factors contributing to high infection, hospitalization, and death rates in these
groups remains to be investigated. Cell entry of SARS-CoV-2 depends on binding of the viral spike (S) protein
to the host cell receptor ACE2 and its priming/cleavage by host protease TMPRSS2. It is well accepted that the
main route of the SARS CoV-2 entry into the body is via respiratory epithelial cells. However, cells in other
tissues/organs including the heart, kidney, pancreas, eye and skin (mostly epidermis) also express ACE2 and
TMPRSS2. Some recent studies indicate that skin could be directly targeted by SARS-CoV-2. Indeed, viral RNA
and capsid proteins were detectable in skin biopsies. Importantly, some inflammatory skin diseases, such as
psoriasis and atopic dermatitis, significantly increased the risk of COVID-19. This correlates with the findings
that ACE2 and TMPRSS2 expression was increased in lesional skin of psoriasis patients as well as in wounded
skin. In addition, COVID-19 is associated with dermatological immediate or sometimes persistent manifestations
which could occur because of direct (topical) or systemic (via circulating virus) infection by SARS-CoV-2.
Nevertheless, the potential role of human healthy or inflamed skin in SARS-CoV-2 entry and COVID-19
pathogenesis has not been addressed. It is known that TNF-α, IL-6, IL-1β, and IFN-γ cytokines are involved in
the development of different inflammatory skin diseases and their level is increased during cytokine storm
frequently associated with viremia, multi-organ failure, and development of severe deadly COVID-19
.
In our pilot
experiments, we showed that combination of TNF-α + IL-6 + IL-1β + INF-γ strongly induced expression of ACE2
and TMPRSS2 in 3D human skin equivalents (3D-HSE) made from primary human epidermal keratinocytes
(NHEK). Based on these novel findings, we hypothesize that inflamed skin could be infected by wild type SARS-
CoV-2 virus and its emerging mutated variants, and that higher infection rates reported for specific ethnic
populations may depend on higher expression levels of proteins involved in SARS-CoV-2 cell entry. To test these
hypotheses, we will use pseudotyped Spike (S) protein-containing reporter lentiviruses, 2D- and 3D-HSE
cultures made from AA, Hispanic and WNH keratinocytes pretreated with cytokine cocktails related to COVID-
19 cytokine storm (TNF-α+IL-6+IL-1b+INF-γ) or cytokines proven to induce pro-psoriasis (IL17+IL22+TNFa) or
pro-atopic dermatitis (IL4+IL13) molecular and morphological changes in in vitro skin models.
尽管抗SARS-CoV-2疫苗已开发出来,COVID-19仍是全球性灾难。这是由于
由于全球疫苗供应有限,疫苗接种犹豫不决,以及SARS新变种的出现,
二型冠状病毒此外,缺乏关于SARS-CoV-2生物学的完整知识,包括潜在的
传播途径和可变的发病机制,特别是在种族群体中,如非洲裔美国人(AA)和
与白色非西班牙裔(WNH)相比,受COVID-19影响较大的西班牙裔/拉丁裔
人口生物学因素在这些疾病中的作用是导致高感染率、住院率和死亡率。
团体仍有待调查。SARS-CoV-2进入细胞依赖于病毒S蛋白的结合
与宿主细胞受体ACE 2的结合及其被宿主蛋白酶TMPRSS 2引发/切割。人们普遍认为,
SARS CoV-2进入人体的主要途径是通过呼吸道上皮细胞。然而,其他细胞
包括心脏、肾脏、胰腺、眼睛和皮肤(主要是表皮)在内的组织/器官也表达ACE 2,
TMPRSS 2.最近的一些研究表明,皮肤可能是SARS-CoV-2的直接靶点。事实上,病毒RNA
在皮肤活检中可检测到衣壳蛋白。重要的是,一些炎症性皮肤病,如
银屑病和特应性皮炎,显著增加了COVID-19的风险。这与研究结果相关,
ACE 2和TMPRSS 2在银屑病患者皮损中的表达增加,
皮肤此外,COVID-19与皮肤病的即时或有时持续的表现有关
这可能是由于SARS-CoV-2的直接(局部)或全身(通过循环病毒)感染而发生的。
然而,人类健康或发炎皮肤在SARS-CoV-2进入和COVID-19中的潜在作用
发病机制尚未解决。已知TNF-α、IL-6、IL-1β和IFN-γ细胞因子参与了
在细胞因子风暴期间,不同炎症性皮肤病的发展及其水平增加
经常与病毒血症、多器官衰竭和严重致命COVID-19的发展相关
.
在我们的试播集里
实验结果表明,TNF-α + IL-6 + IL-1β + INF-γ联合作用可强烈诱导ACE 2的表达,
和TMPRSS 2在由原代人表皮角质形成细胞制成的3D人皮肤等同物(3D-HSE)中
(NHEK)。基于这些新的发现,我们假设发炎的皮肤可能被野生型SARS感染-
CoV-2病毒及其新出现的突变变体,以及特定种族报告的较高感染率,
群体可能依赖于参与SARS-CoV-2细胞进入的蛋白质的较高表达水平。测试这些
假设,我们将使用含有假型刺突(S)蛋白的报告慢病毒,2D和3D-HSE
由用COVID相关细胞因子混合物预处理的AA、西班牙裔和WNH角质形成细胞制成的培养物-
19细胞因子风暴(TNF-α+IL-6+IL-1b+INF-γ)或经证实可诱导促银屑病的细胞因子(IL 17 + IL 22 + TNF α),或
在体外皮肤模型中的促特应性皮炎(IL 4 + IL 13)分子和形态学变化。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Irina Budunova其他文献
Irina Budunova的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Irina Budunova', 18)}}的其他基金
Role of healthy skin molecular phenotype in the switch to specific skin diseases
健康皮肤分子表型在向特定皮肤病转变中的作用
- 批准号:
10511569 - 财政年份:2022
- 资助金额:
$ 24.74万 - 项目类别:
Role of healthy skin molecular phenotype in the switch to specific skin diseases
健康皮肤分子表型在向特定皮肤病转变中的作用
- 批准号:
10709874 - 财政年份:2022
- 资助金额:
$ 24.74万 - 项目类别:
Integrative informatics approach to develop safe glucocorticoid therapies
开发安全糖皮质激素疗法的综合信息学方法
- 批准号:
8965299 - 财政年份:2015
- 资助金额:
$ 24.74万 - 项目类别:
Integrative informatics approach to develop safe glucocorticoid therapies
开发安全糖皮质激素疗法的综合信息学方法
- 批准号:
9265107 - 财政年份:2015
- 资助金额:
$ 24.74万 - 项目类别:
Integrative informatics approach to develop safe glucocorticoid therapies
开发安全糖皮质激素疗法的综合信息学方法
- 批准号:
9223338 - 财政年份:2015
- 资助金额:
$ 24.74万 - 项目类别:
Tumor suppressor effects of GR in skin: implication of stem cells
皮肤GR的抑癌作用:干细胞的意义
- 批准号:
8071063 - 财政年份:2007
- 资助金额:
$ 24.74万 - 项目类别:
相似海外基金
REU Site: Design, Create, and Innovate 3-Dimensional User Interfaces to Improve Human Sensory and Motor Performance in Virtual Environments (HUMANS MOVE)
REU 网站:设计、创建和创新 3 维用户界面,以提高虚拟环境中的人类感官和运动表现 (HUMANS MOVE)
- 批准号:
2349771 - 财政年份:2024
- 资助金额:
$ 24.74万 - 项目类别:
Standard Grant
CAREER: Atomic-level understanding of stability and transition kinetics of 3-dimensional interfaces under irradiation
职业:对辐照下 3 维界面的稳定性和转变动力学的原子水平理解
- 批准号:
2340085 - 财政年份:2024
- 资助金额:
$ 24.74万 - 项目类别:
Continuing Grant
Artificial fabrication of 3-dimensional noncollinear magnetic order and magnetization manipulation by spin torque
三维非共线磁序的人工制造和自旋转矩磁化操纵
- 批准号:
23H00232 - 财政年份:2023
- 资助金额:
$ 24.74万 - 项目类别:
Grant-in-Aid for Scientific Research (A)
Understanding of 3-dimensional seismic behavior of RC frame high-speed railway/highway viaducts using FE analysis
使用有限元分析了解 RC 框架高速铁路/公路高架桥的 3 维抗震性能
- 批准号:
23H01489 - 财政年份:2023
- 资助金额:
$ 24.74万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Modernization of 3-dimensional printing capabilities at the Aquatic Germplasm and Genetic Resource Center
水产种质和遗传资源中心 3 维打印能力的现代化
- 批准号:
10736961 - 财政年份:2023
- 资助金额:
$ 24.74万 - 项目类别:
The 3-dimensional nest of the honey bee: organization, development, and impact on colony function
蜜蜂的 3 维巢穴:组织、发育及其对蜂群功能的影响
- 批准号:
2216835 - 财政年份:2023
- 资助金额:
$ 24.74万 - 项目类别:
Standard Grant
Research on high-density 3-dimensional polymer optical waveguide device for photonics-electronics convergence
光电子融合高密度三维聚合物光波导器件研究
- 批准号:
23H01882 - 财政年份:2023
- 资助金额:
$ 24.74万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Scaff-Net: 3 Dimensional multiphoton polymerisation printed scaffolds for medium throughput recording from stem cell derived human cortical networks.
Scaff-Net:3 维多光子聚合打印支架,用于从干细胞衍生的人类皮质网络进行中等通量记录。
- 批准号:
EP/X018385/1 - 财政年份:2023
- 资助金额:
$ 24.74万 - 项目类别:
Research Grant
3-dimensional prompt gamma imaging for online proton beam dose verification
用于在线质子束剂量验证的 3 维瞬发伽马成像
- 批准号:
10635210 - 财政年份:2023
- 资助金额:
$ 24.74万 - 项目类别:
Equipment: MRI: Track 1 Acquisition of a 3-Dimensional Nanolithography Instrument
设备:MRI:轨道 1 获取 3 维纳米光刻仪器
- 批准号:
2320636 - 财政年份:2023
- 资助金额:
$ 24.74万 - 项目类别:
Standard Grant