Association between ACE2 and TMPRSS2 nasopharyngeal expression and COVID-19 respiratory distress

Rossi, Átila Duque; Araújo, João Locke Ferreira de; Almeida, Tailah Bernardo de; Ribeiro-Alves, Marcelo; Velozo, Camila de Almeida; Almeida, Jéssica Maciel de; Leitão, Isabela de Carvalho; Ferreira, Sâmila Natiane; Oliveira, Jéssica da Silva; Alves, Hugo José; Scheid, Helena Toledo; Faffe, Débora S.; Galliez, Rafael Mello; Ávila, Renata Eliane de; Resende, Gustavo Gomes; Teixeira, Mauro Martins; Herlinger, Alice Laschuk; Carvalho, Aliny dos Santos; Santos, André F.; Castiñeiras, Anna Carla Pinto; Teixeira, Bianca Isabelle Barreto; Silva, Bianca Ortiz da; Clarkson, Bruno; Dematté, Bruno Eduardo; Nacif, Camila Leitão; Silva, Camille Victória Leal Correia de; Voloch, Carolina M.; Nascimento, Caroline Macedo; Graça, Carolyne Lalucha Alves L. da; Gonçalves, Cássia Cristina Alves; Policarpo, Cíntia; Mariani, Diana; Goudouri, Ekaterini Simões; Costa, Elaine Sobral da; Silva, Elisangela Costa da; Riscarolli, Enrico Bruno; Nascimento, Érica Ramos dos Santos; Medeiros, Fabio Hecht Castro; Monteiro, Fábio L.; Santos, Fernanda Nunes; Castro, Fernando Luz de; Moreira, Filipe Romero Rebello; Schiffler, Francine Bittencourt; Kraychete, Gabriela Bergiante; Cunha, Gabriele Silveira da; Cunha, Gisely Novaes Borges da; Lira, Guilherme S; Silva, Gustavo Peixoto Duarte da; Westgarth, Harrison James; Oliveira, Helena D.’Anunciação de; Toma, Helena Keito; Fang, Huang; Gonçalves, Inês Corrêa; Silva, Ingrid Camelo da; Almeida, Isabela Labarba Carvalho de; Oliveira, Joissy Aprigio de; Menezes, Juliana Cazarin de; Fortuna, Juliana T.S.; Monteiro, Karyne Ferreira; França, Kíssyla Harley Della Pascôa; Renault, Laura Zalcberg; Costa, Lendel Correia da; Correa, Leticia Averbug; Ribeiro, Liane de Jesus; Boullosa, Lídia Theodoro; Cavalcante, Liliane Tavares de Faria; Costa, Luana dos Santos; Millioni, Lucas Matos; Costa, Luciana Jesus da; Higa, Luiza M.; Durães, Marcela dos Santos; Souza, Marcelo Amaral de; Tôrres, Marcelo Calado de Paula; Campos, Mariana Freire; Quinto, Mariana; Menezes, Mariane Talon de; Correia, Marisa Souza; Queiroz, Mateus Rodrigues de; Cosentino, Matheus Augusto Calvano; Melo, Mayla Gabryele Miranda de; Costa, Mirela D’arc Ferreira da; Paz, Pedro; Costa, Raissa Mirella dos Santos Cunha da; Coelho, Raquel Fernandes; Maia, Richard Araujo; Brindeiro, Rodrigo de Moraes; Ferreira, Romina Carvalho; Lisboa, Sérgio Machado; Miranda, Thamiris dos Santos; Ota, Victor Akira; Bastos, Victoria Cortes; Gomes, Viviane Guimarães; Júnior, Orlando da Costa Ferreira; Castiñeiras, Terezinha Marta Pereira Pinto; Souza, Renan Pedra de; Tanuri, Amílcar; Aguiar, Renato Santana; Barroso, Shana Priscila Coutinho; Cardoso, Cynthia Chester

doi:10.1038/s41598-021-88944-8

Cited by 35 publications

(30 citation statements)

References 27 publications

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“…In the study published by Lamers et al [ 34 ], a drop in ACE2 mRNA levels was observed in SARS-CoV2-infected human enterocytes at 24 h post-infection. This finding, which needs to be further replicated, is in line with previous reports obtained in SARS-CoV2-infected airway epithelial cells [ 57 , 58 ]. Authors from these studies and other researchers in the field proposed that the SARS-CoV2-induced dysregulation of ACE2 plays a major role in COVID-19 pathophysiology.…”

Section: Discussionsupporting

confidence: 92%

Molecular Insights into SARS-CoV2-Induced Alterations of the Gut/Brain Axis

Nataf

Pays

2021

IJMS

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For a yet unknown reason, a substantial share of patients suffering from COVID-19 develop long-lasting neuropsychiatric symptoms ranging from cognitive deficits to mood disorders and/or an extreme fatigue. We previously reported that in non-neural cells, angiotensin-1 converting enzyme 2 (ACE2), the gene coding for the SARS-CoV2 host receptor, harbors tight co-expression links with dopa-decarboxylase (DDC), an enzyme involved in the metabolism of dopamine. Here, we mined and integrated data from distinct human expression atlases and found that, among a wide range of tissues and cells, enterocytes of the small intestine express the highest expression levels of ACE2, DDC and several key genes supporting the metabolism of neurotransmitters. Based on these results, we performed co-expression analyses on a recently published set of RNA-seq data obtained from SARS-CoV2-infected human intestinal organoids. We observed that in SARS-CoV2-infected enterocytes, ACE2 co-regulates not only with DDC but also with a specific group of genes involved in (i) the dopamine/trace amines metabolic pathway, (ii) the absorption of microbiota-derived L-DOPA and (iii) the absorption of neutral amino acids serving as precursors to neurotransmitters. We conclude that in patients with long COVID, a chronic infection and inflammation of small intestine enterocytes might be indirectly responsible for prolonged brain alterations.

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Section: Discussionsupporting

confidence: 92%

Molecular Insights into SARS-CoV2-Induced Alterations of the Gut/Brain Axis

Nataf

Pays

2021

IJMS

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“…A previous report showed that by binding to the ACE2 receptor in EC, spike causes the downregulation of ACE2 protein levels and the subsequent inhibition of mitochondrial function and eNOS activity leading to EC damage ( 9 ). Because ACE2 is anti-inflammatory ( 24 ), and its overexpression protects against severe COVID-19 symptoms ( 45 ) , spike-induced downregulation of ACE2 would cause inflammation to thrive. Paradoxically, we found that the spike activation of ⍺5β1-NF-κB signaling in ECs increases ACE2 mRNA levels.…”

Section: Discussionmentioning

confidence: 99%

The spike protein of SARS-CoV-2 induces endothelial inflammation through integrin α5β1 and NF-κB signaling

Robles¹,

Zamora²,

Adán‐Castro

et al. 2022

Journal of Biological Chemistry

100

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Vascular endothelial cells (ECs) form a critical interface between blood and tissues that maintains whole-body homeostasis. In COVID-19, disruption of the EC barrier results in edema, vascular inflammation, and coagulation, hallmarks of this severe disease. However, the mechanisms by which ECs are dysregulated in COVID-19 are unclear. Here, we show that the spike protein of SARS-CoV-2 alone activates the EC inflammatory phenotype in a manner dependent on integrin ⍺5β1 signaling. Incubation of human umbilical vein ECs with whole spike protein, its receptor-binding domain, or the integrin-binding tripeptide RGD induced the nuclear translocation of NF-κB and subsequent expression of leukocyte adhesion molecules (VCAM1 and ICAM1), coagulation factors (TF and FVIII), proinflammatory cytokines (TNF⍺, IL-1β, and IL-6), and ACE2, as well as the adhesion of peripheral blood leukocytes and hyperpermeability of the EC monolayer. In addition, inhibitors of integrin ⍺5β1 activation prevented these effects. Furthermore, these vascular effects occur in vivo , as revealed by the intravenous administration of spike, which increased expression of ICAM1, VCAM1, CD45, TNFα, IL-1β, and IL-6 in the lung, liver, kidney, and eye, and the intravitreal injection of spike, which disrupted the barrier function of retinal capillaries. We suggest that the spike protein, through its RGD motif in the receptor-binding domain, binds to integrin ⍺5β1 in ECs to activate the NF-κB target gene expression programs responsible for vascular leakage and leukocyte adhesion. These findings uncover a new direct action of SARS-CoV-2 on EC dysfunction and introduce integrin ⍺5β1 as a promising target for treating vascular inflammation in COVID-19.

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“…ACE2 and TMPRSS2 levels correlate with age and are strongly associated with respiratory distress. Increased nasopharyngeal ACE2 levels are protective and the TMPRSS2/ACE2 ratio is associated with risk of COVID-19 with prevalent symptomatology (cough, 70.42%; fever, 63.85%; headache, 61.50%; anosmia, 57.28%; myalgia, 55.87%) [212]. The imbalance between ACE1 and ACE2 activity is implicated in the pathogenesis of respiratory disorders and in COVID-19 severity.…”

Section: Covid-19mentioning

confidence: 99%

Genophenotypic Factors and Pharmacogenomics in Adverse Drug Reactions

Cacabelos

Naidoo

Corzo

et al. 2021

IJMS

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Adverse drug reactions (ADRs) rank as one of the top 10 leading causes of death and illness in developed countries. ADRs show differential features depending upon genotype, age, sex, race, pathology, drug category, route of administration, and drug–drug interactions. Pharmacogenomics (PGx) provides the physician effective clues for optimizing drug efficacy and safety in major problems of health such as cardiovascular disease and associated disorders, cancer and brain disorders. Important aspects to be considered are also the impact of immunopharmacogenomics in cutaneous ADRs as well as the influence of genomic factors associated with COVID-19 and vaccination strategies. Major limitations for the routine use of PGx procedures for ADRs prevention are the lack of education and training in physicians and pharmacists, poor characterization of drug-related PGx, unspecific biomarkers of drug efficacy and toxicity, cost-effectiveness, administrative problems in health organizations, and insufficient regulation for the generalized use of PGx in the clinical setting. The implementation of PGx requires: (i) education of physicians and all other parties involved in the use and benefits of PGx; (ii) prospective studies to demonstrate the benefits of PGx genotyping; (iii) standardization of PGx procedures and development of clinical guidelines; (iv) NGS and microarrays to cover genes with high PGx potential; and (v) new regulations for PGx-related drug development and PGx drug labelling.

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Association between ACE2 and TMPRSS2 nasopharyngeal expression and COVID-19 respiratory distress

Cited by 35 publications

References 27 publications

Molecular Insights into SARS-CoV2-Induced Alterations of the Gut/Brain Axis

Molecular Insights into SARS-CoV2-Induced Alterations of the Gut/Brain Axis

The spike protein of SARS-CoV-2 induces endothelial inflammation through integrin α5β1 and NF-κB signaling

Genophenotypic Factors and Pharmacogenomics in Adverse Drug Reactions

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