PMC:7652766 / 20405-26795 JSONTXT

{"project":"LitCovid-PD-HP","denotations":[{"id":"T13","span":{"begin":1759,"end":1776},"obj":"Phenotype"},{"id":"T14","span":{"begin":2496,"end":2512},"obj":"Phenotype"},{"id":"T15","span":{"begin":2556,"end":2575},"obj":"Phenotype"},{"id":"T16","span":{"begin":4601,"end":4613},"obj":"Phenotype"},{"id":"T17","span":{"begin":4629,"end":4666},"obj":"Phenotype"},{"id":"T18","span":{"begin":4668,"end":4672},"obj":"Phenotype"},{"id":"T19","span":{"begin":4791,"end":4803},"obj":"Phenotype"},{"id":"T20","span":{"begin":5449,"end":5453},"obj":"Phenotype"},{"id":"T21","span":{"begin":5458,"end":5464},"obj":"Phenotype"},{"id":"T22","span":{"begin":5613,"end":5617},"obj":"Phenotype"},{"id":"T23","span":{"begin":5689,"end":5698},"obj":"Phenotype"},{"id":"T24","span":{"begin":6054,"end":6058},"obj":"Phenotype"},{"id":"T25","span":{"begin":6289,"end":6311},"obj":"Phenotype"}],"attributes":[{"id":"A13","pred":"hp_id","subj":"T13","obj":"http://www.orpha.net/ORDO/Orphanet_178320"},{"id":"A14","pred":"hp_id","subj":"T14","obj":"http://purl.obolibrary.org/obo/HP_0100598"},{"id":"A15","pred":"hp_id","subj":"T15","obj":"http://purl.obolibrary.org/obo/HP_0002878"},{"id":"A16","pred":"hp_id","subj":"T16","obj":"http://purl.obolibrary.org/obo/HP_0000822"},{"id":"A17","pred":"hp_id","subj":"T17","obj":"http://purl.obolibrary.org/obo/HP_0006510"},{"id":"A18","pred":"hp_id","subj":"T18","obj":"http://purl.obolibrary.org/obo/HP_0006510"},{"id":"A19","pred":"hp_id","subj":"T19","obj":"http://purl.obolibrary.org/obo/HP_0000822"},{"id":"A20","pred":"hp_id","subj":"T20","obj":"http://purl.obolibrary.org/obo/HP_0006510"},{"id":"A21","pred":"hp_id","subj":"T21","obj":"http://purl.obolibrary.org/obo/HP_0002099"},{"id":"A22","pred":"hp_id","subj":"T22","obj":"http://purl.obolibrary.org/obo/HP_0006510"},{"id":"A23","pred":"hp_id","subj":"T23","obj":"http://purl.obolibrary.org/obo/HP_0002090"},{"id":"A24","pred":"hp_id","subj":"T24","obj":"http://purl.obolibrary.org/obo/HP_0006510"},{"id":"A25","pred":"hp_id","subj":"T25","obj":"http://purl.obolibrary.org/obo/HP_0011947"}],"text":"Pathogenic Mechanisms\nConsidering the similarity between SARS-CoV-1 and SARS-CoV-2, it is likely that their biochemical interactions and pathogenesis are also similar (80, 81). Once SARS-CoV-2 was reported to use ACE2 to enter host cells, it is suggested that the virus may target a cell spectrum similar to SARS-CoV-1 (38, 82, 83). SARS-CoV-1 is known to mainly infect macrophages and pneumocytes in the lungs, as well as other extrapulmonary tissues that express ACE2, which can also be expected for SARS-CoV-2 (82–84). However, the affinity of SARS-CoV-2 to ACE2 is 10–20-fold higher than that of SARS-CoV-1, which could explain its higher transmissibility and demonstrate that it can bind more efficiently to host cells, having a robust infection in ACE2+ cells in the upper respiratory tract (7).\nACE2 is an enzyme belonging to the renin-angiotensin system, located on the cell surface of type II alveolar epithelial cells in the lungs and cells of other tissues, and plays a crucial role in controlling vasoactive effects in the body. Despite their similarities, ACE and ACE2 have different substrate specificities with distinct functionalities that perform opposite actions in the body. In brief, ACE cleaves angiotensin I to generate angiotensin II, the peptide that binds and activates angiotensin type 1 receptor (AT1R) to constrict blood vessels, thereby raising blood pressure. In contrast, ACE2 inactivates angiotensin II (Ang-II) while generating angiotensin 1-7 (Ang-1-7), a potent heptapeptide that acts in vasodilation and attenuation of inflammation (85).\nTherefore, considering that SARS-CoV-2 uses ACE2 to enter cells, the main hypothesis of pulmonary pathology is that the increased activity of ACE (Ang-II) over ACE2 (Ang-1-7) may cause acute lung injury since the binding of the S protein to ACE2 leads to its blockage. Thus, the suppression of ACE2 occurs due to the increased internalization and release of ACE2 from the cell surface, which leads to a decrease in tissue ACE2 and the generation of Ang-1-7, and consequently higher Ang-II levels. Because of this, as shown in an experimental SARS-CoV-1 model, this process can drive an Ang II-AT1R-mediated inflammatory response in the lungs and potentially induce direct parenchymal injury (67, 80, 86, 87).\nAnother hypothesis states that SARS-CoV-2 infection blocks ACE2 function when binding to host cells, inhibiting its role of cleaving bradykinin and, as a consequence, bradykinin accumulates in the lung, promoting pulmonary edemas due to vasodilator activity and consequent respiratory failure. The increased bradykinin activation in the pulmonary endothelium can also induce neutrophil migration, enhancing tissue damage caused by the respiratory burst of these cells (88).\nACE2 is also highly expressed and co-expressed with TMPRSS2 in nasal epithelial cells, chalices, and hair cells (89). This finding is in accordance with the high detection of viral RNA in the upper airways present in nasal swabs and throats of both symptomatic and asymptomatic patients, demonstrating that the nasal epithelium is an important site for the infection to initiate and can represent an essential reservoir for viral dissemination and transmission (38).\nAlthough the virus mainly affects the lungs, there are reports that SARS-CoV-2 also has organotropism, accompanied by dysfunction, in multiple organs, including the kidneys, liver, heart, and brain, which can influence the course of the disease and possibly worsen pre-existing conditions. It has been reported that ACE2, TMPRSS2, and cathepsin L can be expressed on glial cells and neurons, cardiomyocytes, liver cells, bile duct cells, and renal tubular cells (90, 91).\nEvidence indicates that SARS-CoV-2 “neuroinvasion” can establish a direct entry along the olfactory nerve, mainly through the nasal olfactory epithelium, which expresses ACE2 and TMPRSS2, allowing access to the central nervous system (CNS). The spread of the virus through the hematogenous or transsynaptic pathway has also been widely discussed, however, it is known that the different levels of neurotropism and neurovirulence in patients with COVID-19 can be explained by a combination of viral factors and their interaction with the host (41, 92, 93).\nRegarding the evolution of infected individuals, aging, comorbidities, and weakening of the immune system are factors that generally cause the infection to intensify at the acute phase, leading to the manifestation of more severe conditions (6). Thus, according to epidemiological studies, it is known that patients with chronic conditions, such as hypertension, diabetes, and chronic obstructive pulmonary disease (COPD), are more likely to develop a critical form of the disease (94–96).\nThe risk of applying medication commonly used in hypertension treatments to COVID-19 patients (97, 98) has raised different hypotheses over the issue of invoking a higher expression of ACE2 (99–101). A systematic review assessing the clinical outcomes for SARS-CoV-2-infected individuals regarding treatment using angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) concluded that these types of drugs have no deleterious effects and should continue to be used in COVID-19 patients (102), reinforcing the recommendations of several medical societies, including the American Heart Association (103) and European Society of Cardiology (104).\nRespiratory diseases, such as COPD and asthma, cause a reduced lung function and greater susceptibility to lung inflammation, and are expected to show a potentially critical course of COVID-19. COPD patients are already considered more susceptible to the development of pneumonia based on the clinical characteristics exhibited, such as lung structural damage, alterations in local/systemic inflammatory response, impaired host immunity, microbiome imbalance, persistent mucus production, and the presence of potentially pathogenic bacteria in the airways (105). Additionally, in the scenario of COVID-19, smokers and individuals with COPD have shown to have increased airway expressions of ACE-2 (106). It is still worth mentioning that patients who have this type of disorder often use corticosteroid immune-suppressing drugs, whose effect of reducing the immunity to respiratory infections may represent another contributing factor to a higher risk of infection (107)."}

{"project":"LitCovid-sentences","denotations":[{"id":"T108","span":{"begin":0,"end":21},"obj":"Sentence"},{"id":"T109","span":{"begin":22,"end":176},"obj":"Sentence"},{"id":"T110","span":{"begin":177,"end":332},"obj":"Sentence"},{"id":"T111","span":{"begin":333,"end":521},"obj":"Sentence"},{"id":"T112","span":{"begin":522,"end":801},"obj":"Sentence"},{"id":"T113","span":{"begin":802,"end":1040},"obj":"Sentence"},{"id":"T114","span":{"begin":1041,"end":1193},"obj":"Sentence"},{"id":"T115","span":{"begin":1194,"end":1389},"obj":"Sentence"},{"id":"T116","span":{"begin":1390,"end":1573},"obj":"Sentence"},{"id":"T117","span":{"begin":1574,"end":1842},"obj":"Sentence"},{"id":"T118","span":{"begin":1843,"end":2070},"obj":"Sentence"},{"id":"T119","span":{"begin":2071,"end":2282},"obj":"Sentence"},{"id":"T120","span":{"begin":2283,"end":2576},"obj":"Sentence"},{"id":"T121","span":{"begin":2577,"end":2756},"obj":"Sentence"},{"id":"T122","span":{"begin":2757,"end":2874},"obj":"Sentence"},{"id":"T123","span":{"begin":2875,"end":3223},"obj":"Sentence"},{"id":"T124","span":{"begin":3224,"end":3513},"obj":"Sentence"},{"id":"T125","span":{"begin":3514,"end":3695},"obj":"Sentence"},{"id":"T126","span":{"begin":3696,"end":3936},"obj":"Sentence"},{"id":"T127","span":{"begin":3937,"end":4251},"obj":"Sentence"},{"id":"T128","span":{"begin":4252,"end":4497},"obj":"Sentence"},{"id":"T129","span":{"begin":4498,"end":4741},"obj":"Sentence"},{"id":"T130","span":{"begin":4742,"end":4941},"obj":"Sentence"},{"id":"T131","span":{"begin":4942,"end":5418},"obj":"Sentence"},{"id":"T132","span":{"begin":5419,"end":5612},"obj":"Sentence"},{"id":"T133","span":{"begin":5613,"end":5981},"obj":"Sentence"},{"id":"T134","span":{"begin":5982,"end":6122},"obj":"Sentence"},{"id":"T135","span":{"begin":6123,"end":6390},"obj":"Sentence"}],"namespaces":[{"prefix":"_base","uri":"http://pubannotation.org/ontology/tao.owl#"}],"text":"Pathogenic Mechanisms\nConsidering the similarity between SARS-CoV-1 and SARS-CoV-2, it is likely that their biochemical interactions and pathogenesis are also similar (80, 81). Once SARS-CoV-2 was reported to use ACE2 to enter host cells, it is suggested that the virus may target a cell spectrum similar to SARS-CoV-1 (38, 82, 83). SARS-CoV-1 is known to mainly infect macrophages and pneumocytes in the lungs, as well as other extrapulmonary tissues that express ACE2, which can also be expected for SARS-CoV-2 (82–84). However, the affinity of SARS-CoV-2 to ACE2 is 10–20-fold higher than that of SARS-CoV-1, which could explain its higher transmissibility and demonstrate that it can bind more efficiently to host cells, having a robust infection in ACE2+ cells in the upper respiratory tract (7).\nACE2 is an enzyme belonging to the renin-angiotensin system, located on the cell surface of type II alveolar epithelial cells in the lungs and cells of other tissues, and plays a crucial role in controlling vasoactive effects in the body. Despite their similarities, ACE and ACE2 have different substrate specificities with distinct functionalities that perform opposite actions in the body. In brief, ACE cleaves angiotensin I to generate angiotensin II, the peptide that binds and activates angiotensin type 1 receptor (AT1R) to constrict blood vessels, thereby raising blood pressure. In contrast, ACE2 inactivates angiotensin II (Ang-II) while generating angiotensin 1-7 (Ang-1-7), a potent heptapeptide that acts in vasodilation and attenuation of inflammation (85).\nTherefore, considering that SARS-CoV-2 uses ACE2 to enter cells, the main hypothesis of pulmonary pathology is that the increased activity of ACE (Ang-II) over ACE2 (Ang-1-7) may cause acute lung injury since the binding of the S protein to ACE2 leads to its blockage. Thus, the suppression of ACE2 occurs due to the increased internalization and release of ACE2 from the cell surface, which leads to a decrease in tissue ACE2 and the generation of Ang-1-7, and consequently higher Ang-II levels. Because of this, as shown in an experimental SARS-CoV-1 model, this process can drive an Ang II-AT1R-mediated inflammatory response in the lungs and potentially induce direct parenchymal injury (67, 80, 86, 87).\nAnother hypothesis states that SARS-CoV-2 infection blocks ACE2 function when binding to host cells, inhibiting its role of cleaving bradykinin and, as a consequence, bradykinin accumulates in the lung, promoting pulmonary edemas due to vasodilator activity and consequent respiratory failure. The increased bradykinin activation in the pulmonary endothelium can also induce neutrophil migration, enhancing tissue damage caused by the respiratory burst of these cells (88).\nACE2 is also highly expressed and co-expressed with TMPRSS2 in nasal epithelial cells, chalices, and hair cells (89). This finding is in accordance with the high detection of viral RNA in the upper airways present in nasal swabs and throats of both symptomatic and asymptomatic patients, demonstrating that the nasal epithelium is an important site for the infection to initiate and can represent an essential reservoir for viral dissemination and transmission (38).\nAlthough the virus mainly affects the lungs, there are reports that SARS-CoV-2 also has organotropism, accompanied by dysfunction, in multiple organs, including the kidneys, liver, heart, and brain, which can influence the course of the disease and possibly worsen pre-existing conditions. It has been reported that ACE2, TMPRSS2, and cathepsin L can be expressed on glial cells and neurons, cardiomyocytes, liver cells, bile duct cells, and renal tubular cells (90, 91).\nEvidence indicates that SARS-CoV-2 “neuroinvasion” can establish a direct entry along the olfactory nerve, mainly through the nasal olfactory epithelium, which expresses ACE2 and TMPRSS2, allowing access to the central nervous system (CNS). The spread of the virus through the hematogenous or transsynaptic pathway has also been widely discussed, however, it is known that the different levels of neurotropism and neurovirulence in patients with COVID-19 can be explained by a combination of viral factors and their interaction with the host (41, 92, 93).\nRegarding the evolution of infected individuals, aging, comorbidities, and weakening of the immune system are factors that generally cause the infection to intensify at the acute phase, leading to the manifestation of more severe conditions (6). Thus, according to epidemiological studies, it is known that patients with chronic conditions, such as hypertension, diabetes, and chronic obstructive pulmonary disease (COPD), are more likely to develop a critical form of the disease (94–96).\nThe risk of applying medication commonly used in hypertension treatments to COVID-19 patients (97, 98) has raised different hypotheses over the issue of invoking a higher expression of ACE2 (99–101). A systematic review assessing the clinical outcomes for SARS-CoV-2-infected individuals regarding treatment using angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) concluded that these types of drugs have no deleterious effects and should continue to be used in COVID-19 patients (102), reinforcing the recommendations of several medical societies, including the American Heart Association (103) and European Society of Cardiology (104).\nRespiratory diseases, such as COPD and asthma, cause a reduced lung function and greater susceptibility to lung inflammation, and are expected to show a potentially critical course of COVID-19. COPD patients are already considered more susceptible to the development of pneumonia based on the clinical characteristics exhibited, such as lung structural damage, alterations in local/systemic inflammatory response, impaired host immunity, microbiome imbalance, persistent mucus production, and the presence of potentially pathogenic bacteria in the airways (105). Additionally, in the scenario of COVID-19, smokers and individuals with COPD have shown to have increased airway expressions of ACE-2 (106). It is still worth mentioning that patients who have this type of disorder often use corticosteroid immune-suppressing drugs, whose effect of reducing the immunity to respiratory infections may represent another contributing factor to a higher risk of infection (107)."}

{"project":"LitCovid-PubTator","denotations":[{"id":"760","span":{"begin":213,"end":217},"obj":"Gene"},{"id":"761","span":{"begin":465,"end":469},"obj":"Gene"},{"id":"762","span":{"begin":561,"end":565},"obj":"Gene"},{"id":"763","span":{"begin":754,"end":758},"obj":"Gene"},{"id":"764","span":{"begin":710,"end":712},"obj":"Gene"},{"id":"765","span":{"begin":558,"end":560},"obj":"Gene"},{"id":"766","span":{"begin":353,"end":355},"obj":"Gene"},{"id":"767","span":{"begin":305,"end":307},"obj":"Gene"},{"id":"768","span":{"begin":218,"end":220},"obj":"Gene"},{"id":"769","span":{"begin":206,"end":208},"obj":"Gene"},{"id":"770","span":{"begin":57,"end":65},"obj":"Species"},{"id":"771","span":{"begin":72,"end":82},"obj":"Species"},{"id":"772","span":{"begin":182,"end":192},"obj":"Species"},{"id":"773","span":{"begin":308,"end":316},"obj":"Species"},{"id":"774","span":{"begin":333,"end":341},"obj":"Species"},{"id":"775","span":{"begin":502,"end":512},"obj":"Species"},{"id":"776","span":{"begin":547,"end":557},"obj":"Species"},{"id":"777","span":{"begin":600,"end":608},"obj":"Species"},{"id":"778","span":{"begin":779,"end":790},"obj":"Species"},{"id":"779","span":{"begin":732,"end":733},"obj":"Gene"},{"id":"780","span":{"begin":281,"end":282},"obj":"Gene"},{"id":"781","span":{"begin":741,"end":750},"obj":"Disease"},{"id":"800","span":{"begin":802,"end":806},"obj":"Gene"},{"id":"801","span":{"begin":1069,"end":1072},"obj":"Gene"},{"id":"802","span":{"begin":1077,"end":1081},"obj":"Gene"},{"id":"803","span":{"begin":1204,"end":1207},"obj":"Gene"},{"id":"804","span":{"begin":1216,"end":1229},"obj":"Gene"},{"id":"805","span":{"begin":1242,"end":1256},"obj":"Gene"},{"id":"806","span":{"begin":1295,"end":1322},"obj":"Gene"},{"id":"807","span":{"begin":1324,"end":1328},"obj":"Gene"},{"id":"808","span":{"begin":1403,"end":1407},"obj":"Gene"},{"id":"809","span":{"begin":1420,"end":1434},"obj":"Gene"},{"id":"810","span":{"begin":1436,"end":1442},"obj":"Gene"},{"id":"811","span":{"begin":1478,"end":1485},"obj":"Gene"},{"id":"812","span":{"begin":1330,"end":1332},"obj":"Gene"},{"id":"813","span":{"begin":1230,"end":1232},"obj":"Gene"},{"id":"814","span":{"begin":830,"end":832},"obj":"Gene"},{"id":"815","span":{"begin":1488,"end":1489},"obj":"Gene"},{"id":"816","span":{"begin":979,"end":980},"obj":"Gene"},{"id":"817","span":{"begin":1555,"end":1567},"obj":"Disease"},{"id":"841","span":{"begin":1618,"end":1622},"obj":"Gene"},{"id":"842","span":{"begin":1716,"end":1719},"obj":"Gene"},{"id":"843","span":{"begin":1721,"end":1727},"obj":"Gene"},{"id":"844","span":{"begin":1734,"end":1738},"obj":"Gene"},{"id":"845","span":{"begin":1740,"end":1747},"obj":"Gene"},{"id":"846","span":{"begin":1815,"end":1819},"obj":"Gene"},{"id":"847","span":{"begin":1868,"end":1872},"obj":"Gene"},{"id":"848","span":{"begin":1932,"end":1936},"obj":"Gene"},{"id":"849","span":{"begin":1996,"end":2000},"obj":"Gene"},{"id":"850","span":{"begin":2023,"end":2030},"obj":"Gene"},{"id":"851","span":{"begin":2056,"end":2062},"obj":"Gene"},{"id":"852","span":{"begin":2167,"end":2171},"obj":"Gene"},{"id":"853","span":{"begin":2160,"end":2163},"obj":"Gene"},{"id":"854","span":{"begin":1972,"end":1974},"obj":"Gene"},{"id":"855","span":{"begin":1884,"end":1886},"obj":"Gene"},{"id":"856","span":{"begin":1826,"end":1828},"obj":"Gene"},{"id":"857","span":{"begin":1812,"end":1814},"obj":"Gene"},{"id":"858","span":{"begin":1623,"end":1625},"obj":"Gene"},{"id":"859","span":{"begin":1602,"end":1612},"obj":"Species"},{"id":"860","span":{"begin":2116,"end":2124},"obj":"Species"},{"id":"861","span":{"begin":1975,"end":1976},"obj":"Gene"},{"id":"862","span":{"begin":1759,"end":1776},"obj":"Disease"},{"id":"863","span":{"begin":2246,"end":2264},"obj":"Disease"},{"id":"875","span":{"begin":2342,"end":2346},"obj":"Gene"},{"id":"876","span":{"begin":2416,"end":2426},"obj":"Gene"},{"id":"877","span":{"begin":2450,"end":2460},"obj":"Gene"},{"id":"878","span":{"begin":2591,"end":2601},"obj":"Gene"},{"id":"879","span":{"begin":2517,"end":2519},"obj":"Gene"},{"id":"880","span":{"begin":2369,"end":2371},"obj":"Gene"},{"id":"881","span":{"begin":2718,"end":2729},"obj":"Species"},{"id":"882","span":{"begin":2435,"end":2436},"obj":"Gene"},{"id":"883","span":{"begin":2314,"end":2334},"obj":"Disease"},{"id":"884","span":{"begin":2496,"end":2512},"obj":"Disease"},{"id":"885","span":{"begin":2556,"end":2575},"obj":"Disease"},{"id":"891","span":{"begin":2757,"end":2761},"obj":"Gene"},{"id":"892","span":{"begin":2809,"end":2816},"obj":"Gene"},{"id":"893","span":{"begin":3124,"end":3126},"obj":"Gene"},{"id":"894","span":{"begin":3035,"end":3043},"obj":"Species"},{"id":"895","span":{"begin":3114,"end":3123},"obj":"Disease"},{"id":"901","span":{"begin":3540,"end":3544},"obj":"Gene"},{"id":"902","span":{"begin":3546,"end":3553},"obj":"Gene"},{"id":"903","span":{"begin":3559,"end":3570},"obj":"Gene"},{"id":"904","span":{"begin":3292,"end":3302},"obj":"Species"},{"id":"905","span":{"begin":3389,"end":3396},"obj":"Disease"},{"id":"915","span":{"begin":3866,"end":3870},"obj":"Gene"},{"id":"916","span":{"begin":3875,"end":3882},"obj":"Gene"},{"id":"917","span":{"begin":3900,"end":3902},"obj":"Gene"},{"id":"918","span":{"begin":3720,"end":3730},"obj":"Species"},{"id":"919","span":{"begin":4128,"end":4136},"obj":"Species"},{"id":"920","span":{"begin":4171,"end":4172},"obj":"Gene"},{"id":"921","span":{"begin":3761,"end":3762},"obj":"Gene"},{"id":"922","span":{"begin":4093,"end":4105},"obj":"Disease"},{"id":"923","span":{"begin":4142,"end":4150},"obj":"Disease"},{"id":"936","span":{"begin":4691,"end":4693},"obj":"Gene"},{"id":"937","span":{"begin":4514,"end":4516},"obj":"Gene"},{"id":"938","span":{"begin":4446,"end":4448},"obj":"Gene"},{"id":"939","span":{"begin":4405,"end":4407},"obj":"Gene"},{"id":"940","span":{"begin":4559,"end":4567},"obj":"Species"},{"id":"941","span":{"begin":4702,"end":4703},"obj":"Gene"},{"id":"942","span":{"begin":4279,"end":4287},"obj":"Disease"},{"id":"943","span":{"begin":4395,"end":4404},"obj":"Disease"},{"id":"944","span":{"begin":4601,"end":4613},"obj":"Disease"},{"id":"945","span":{"begin":4615,"end":4623},"obj":"Disease"},{"id":"946","span":{"begin":4629,"end":4666},"obj":"Disease"},{"id":"947","span":{"begin":4668,"end":4672},"obj":"Disease"},{"id":"960","span":{"begin":4927,"end":4931},"obj":"Gene"},{"id":"961","span":{"begin":5056,"end":5085},"obj":"Gene"},{"id":"962","span":{"begin":5229,"end":5231},"obj":"Gene"},{"id":"963","span":{"begin":4815,"end":4817},"obj":"Gene"},{"id":"964","span":{"begin":4827,"end":4835},"obj":"Species"},{"id":"965","span":{"begin":5252,"end":5260},"obj":"Species"},{"id":"966","span":{"begin":4942,"end":4943},"obj":"Gene"},{"id":"967","span":{"begin":4904,"end":4905},"obj":"Gene"},{"id":"968","span":{"begin":4791,"end":4803},"obj":"Disease"},{"id":"969","span":{"begin":4818,"end":4826},"obj":"Disease"},{"id":"970","span":{"begin":4998,"end":5017},"obj":"Disease"},{"id":"971","span":{"begin":5243,"end":5251},"obj":"Disease"},{"id":"996","span":{"begin":6110,"end":6115},"obj":"Gene"},{"id":"997","span":{"begin":6354,"end":6356},"obj":"Gene"},{"id":"998","span":{"begin":6286,"end":6288},"obj":"Gene"},{"id":"999","span":{"begin":6070,"end":6072},"obj":"Gene"},{"id":"1000","span":{"begin":5667,"end":5669},"obj":"Gene"},{"id":"1001","span":{"begin":5562,"end":5564},"obj":"Gene"},{"id":"1002","span":{"begin":5523,"end":5525},"obj":"Gene"},{"id":"1003","span":{"begin":5618,"end":5626},"obj":"Species"},{"id":"1004","span":{"begin":6157,"end":6165},"obj":"Species"},{"id":"1005","span":{"begin":6357,"end":6358},"obj":"Gene"},{"id":"1006","span":{"begin":5570,"end":5571},"obj":"Gene"},{"id":"1007","span":{"begin":5472,"end":5473},"obj":"Gene"},{"id":"1008","span":{"begin":5419,"end":5439},"obj":"Disease"},{"id":"1009","span":{"begin":5449,"end":5453},"obj":"Disease"},{"id":"1010","span":{"begin":5458,"end":5464},"obj":"Disease"},{"id":"1011","span":{"begin":5526,"end":5543},"obj":"Disease"},{"id":"1012","span":{"begin":5603,"end":5611},"obj":"Disease"},{"id":"1013","span":{"begin":5613,"end":5617},"obj":"Disease"},{"id":"1014","span":{"begin":5689,"end":5698},"obj":"Disease"},{"id":"1015","span":{"begin":5756,"end":5778},"obj":"Disease"},{"id":"1016","span":{"begin":6015,"end":6023},"obj":"Disease"},{"id":"1017","span":{"begin":6054,"end":6058},"obj":"Disease"},{"id":"1018","span":{"begin":6289,"end":6311},"obj":"Disease"},{"id":"1019","span":{"begin":6374,"end":6383},"obj":"Disease"}],"attributes":[{"id":"A760","pred":"tao:has_database_id","subj":"760","obj":"Gene:59272"},{"id":"A761","pred":"tao:has_database_id","subj":"761","obj":"Gene:59272"},{"id":"A762","pred":"tao:has_database_id","subj":"762","obj":"Gene:59272"},{"id":"A763","pred":"tao:has_database_id","subj":"763","obj":"Gene:59272"},{"id":"A764","pred":"tao:has_database_id","subj":"764","obj":"Gene:6999"},{"id":"A765","pred":"tao:has_database_id","subj":"765","obj":"Gene:6999"},{"id":"A766","pred":"tao:has_database_id","subj":"766","obj":"Gene:6999"},{"id":"A767","pred":"tao:has_database_id","subj":"767","obj":"Gene:6999"},{"id":"A768","pred":"tao:has_database_id","subj":"768","obj":"Gene:6999"},{"id":"A769","pred":"tao:has_database_id","subj":"769","obj":"Gene:6999"},{"id":"A770","pred":"tao:has_database_id","subj":"770","obj":"Tax:694009"},{"id":"A771","pred":"tao:has_database_id","subj":"771","obj":"Tax:2697049"},{"id":"A772","pred":"tao:has_database_id","subj":"772","obj":"Tax:2697049"},{"id":"A773","pred":"tao:has_database_id","subj":"773","obj":"Tax:694009"},{"id":"A774","pred":"tao:has_database_id","subj":"774","obj":"Tax:694009"},{"id":"A775","pred":"tao:has_database_id","subj":"775","obj":"Tax:2697049"},{"id":"A776","pred":"tao:has_database_id","subj":"776","obj":"Tax:2697049"},{"id":"A777","pred":"tao:has_database_id","subj":"777","obj":"Tax:694009"},{"id":"A778","pred":"tao:has_database_id","subj":"778","obj":"Tax:12814"},{"id":"A779","pred":"tao:has_database_id","subj":"779","obj":"Gene:351"},{"id":"A780","pred":"tao:has_database_id","subj":"780","obj":"Gene:351"},{"id":"A781","pred":"tao:has_database_id","subj":"781","obj":"MESH:D007239"},{"id":"A800","pred":"tao:has_database_id","subj":"800","obj":"Gene:59272"},{"id":"A801","pred":"tao:has_database_id","subj":"801","obj":"Gene:1636"},{"id":"A802","pred":"tao:has_database_id","subj":"802","obj":"Gene:59272"},{"id":"A803","pred":"tao:has_database_id","subj":"803","obj":"Gene:1636"},{"id":"A804","pred":"tao:has_database_id","subj":"804","obj":"Gene:183"},{"id":"A805","pred":"tao:has_database_id","subj":"805","obj":"Gene:183"},{"id":"A806","pred":"tao:has_database_id","subj":"806","obj":"Gene:185"},{"id":"A807","pred":"tao:has_database_id","subj":"807","obj":"Gene:185"},{"id":"A808","pred":"tao:has_database_id","subj":"808","obj":"Gene:59272"},{"id":"A809","pred":"tao:has_database_id","subj":"809","obj":"Gene:183"},{"id":"A810","pred":"tao:has_database_id","subj":"810","obj":"Gene:183"},{"id":"A811","pred":"tao:has_database_id","subj":"811","obj":"Gene:284"},{"id":"A812","pred":"tao:has_database_id","subj":"812","obj":"Gene:6999"},{"id":"A813","pred":"tao:has_database_id","subj":"813","obj":"Gene:6999"},{"id":"A814","pred":"tao:has_database_id","subj":"814","obj":"Gene:6999"},{"id":"A815","pred":"tao:has_database_id","subj":"815","obj":"Gene:351"},{"id":"A816","pred":"tao:has_database_id","subj":"816","obj":"Gene:351"},{"id":"A817","pred":"tao:has_database_id","subj":"817","obj":"MESH:D007249"},{"id":"A841","pred":"tao:has_database_id","subj":"841","obj":"Gene:59272"},{"id":"A842","pred":"tao:has_database_id","subj":"842","obj":"Gene:1636"},{"id":"A843","pred":"tao:has_database_id","subj":"843","obj":"Gene:183"},{"id":"A844","pred":"tao:has_database_id","subj":"844","obj":"Gene:59272"},{"id":"A845","pred":"tao:has_database_id","subj":"845","obj":"Gene:284"},{"id":"A846","pred":"tao:has_database_id","subj":"846","obj":"Gene:59272"},{"id":"A847","pred":"tao:has_database_id","subj":"847","obj":"Gene:59272"},{"id":"A848","pred":"tao:has_database_id","subj":"848","obj":"Gene:59272"},{"id":"A849","pred":"tao:has_database_id","subj":"849","obj":"Gene:59272"},{"id":"A850","pred":"tao:has_database_id","subj":"850","obj":"Gene:284"},{"id":"A851","pred":"tao:has_database_id","subj":"851","obj":"Gene:183"},{"id":"A852","pred":"tao:has_database_id","subj":"852","obj":"Gene:185"},{"id":"A853","pred":"tao:has_database_id","subj":"853","obj":"Gene:283"},{"id":"A854","pred":"tao:has_database_id","subj":"854","obj":"Gene:6999"},{"id":"A855","pred":"tao:has_database_id","subj":"855","obj":"Gene:6999"},{"id":"A856","pred":"tao:has_database_id","subj":"856","obj":"Gene:6999"},{"id":"A857","pred":"tao:has_database_id","subj":"857","obj":"Gene:6999"},{"id":"A858","pred":"tao:has_database_id","subj":"858","obj":"Gene:6999"},{"id":"A859","pred":"tao:has_database_id","subj":"859","obj":"Tax:2697049"},{"id":"A860","pred":"tao:has_database_id","subj":"860","obj":"Tax:694009"},{"id":"A861","pred":"tao:has_database_id","subj":"861","obj":"Gene:351"},{"id":"A862","pred":"tao:has_database_id","subj":"862","obj":"MESH:D055371"},{"id":"A863","pred":"tao:has_database_id","subj":"863","obj":"MESH:D002543"},{"id":"A875","pred":"tao:has_database_id","subj":"875","obj":"Gene:59272"},{"id":"A876","pred":"tao:has_database_id","subj":"876","obj":"Gene:3827"},{"id":"A877","pred":"tao:has_database_id","subj":"877","obj":"Gene:3827"},{"id":"A878","pred":"tao:has_database_id","subj":"878","obj":"Gene:3827"},{"id":"A879","pred":"tao:has_database_id","subj":"879","obj":"Gene:6999"},{"id":"A880","pred":"tao:has_database_id","subj":"880","obj":"Gene:6999"},{"id":"A881","pred":"tao:has_database_id","subj":"881","obj":"Tax:12814"},{"id":"A882","pred":"tao:has_database_id","subj":"882","obj":"Gene:351"},{"id":"A883","pred":"tao:has_database_id","subj":"883","obj":"MESH:C000657245"},{"id":"A884","pred":"tao:has_database_id","subj":"884","obj":"MESH:D011654"},{"id":"A885","pred":"tao:has_database_id","subj":"885","obj":"MESH:D012131"},{"id":"A891","pred":"tao:has_database_id","subj":"891","obj":"Gene:59272"},{"id":"A892","pred":"tao:has_database_id","subj":"892","obj":"Gene:7113"},{"id":"A893","pred":"tao:has_database_id","subj":"893","obj":"Gene:6999"},{"id":"A894","pred":"tao:has_database_id","subj":"894","obj":"Tax:9606"},{"id":"A895","pred":"tao:has_database_id","subj":"895","obj":"MESH:D007239"},{"id":"A901","pred":"tao:has_database_id","subj":"901","obj":"Gene:59272"},{"id":"A902","pred":"tao:has_database_id","subj":"902","obj":"Gene:7113"},{"id":"A903","pred":"tao:has_database_id","subj":"903","obj":"Gene:1514"},{"id":"A904","pred":"tao:has_database_id","subj":"904","obj":"Tax:2697049"},{"id":"A905","pred":"tao:has_database_id","subj":"905","obj":"MESH:D007674"},{"id":"A915","pred":"tao:has_database_id","subj":"915","obj":"Gene:59272"},{"id":"A916","pred":"tao:has_database_id","subj":"916","obj":"Gene:7113"},{"id":"A917","pred":"tao:has_database_id","subj":"917","obj":"Gene:6999"},{"id":"A918","pred":"tao:has_database_id","subj":"918","obj":"Tax:2697049"},{"id":"A919","pred":"tao:has_database_id","subj":"919","obj":"Tax:9606"},{"id":"A920","pred":"tao:has_database_id","subj":"920","obj":"Gene:351"},{"id":"A921","pred":"tao:has_database_id","subj":"921","obj":"Gene:351"},{"id":"A923","pred":"tao:has_database_id","subj":"923","obj":"MESH:C000657245"},{"id":"A936","pred":"tao:has_database_id","subj":"936","obj":"Gene:6999"},{"id":"A937","pred":"tao:has_database_id","subj":"937","obj":"Gene:6999"},{"id":"A938","pred":"tao:has_database_id","subj":"938","obj":"Gene:6999"},{"id":"A939","pred":"tao:has_database_id","subj":"939","obj":"Gene:6999"},{"id":"A940","pred":"tao:has_database_id","subj":"940","obj":"Tax:9606"},{"id":"A941","pred":"tao:has_database_id","subj":"941","obj":"Gene:351"},{"id":"A942","pred":"tao:has_database_id","subj":"942","obj":"MESH:D007239"},{"id":"A943","pred":"tao:has_database_id","subj":"943","obj":"MESH:D007239"},{"id":"A944","pred":"tao:has_database_id","subj":"944","obj":"MESH:D006973"},{"id":"A945","pred":"tao:has_database_id","subj":"945","obj":"MESH:D003920"},{"id":"A946","pred":"tao:has_database_id","subj":"946","obj":"MESH:D029424"},{"id":"A947","pred":"tao:has_database_id","subj":"947","obj":"MESH:D029424"},{"id":"A960","pred":"tao:has_database_id","subj":"960","obj":"Gene:59272"},{"id":"A961","pred":"tao:has_database_id","subj":"961","obj":"Gene:1636"},{"id":"A962","pred":"tao:has_database_id","subj":"962","obj":"Gene:6999"},{"id":"A963","pred":"tao:has_database_id","subj":"963","obj":"Gene:6999"},{"id":"A964","pred":"tao:has_database_id","subj":"964","obj":"Tax:9606"},{"id":"A965","pred":"tao:has_database_id","subj":"965","obj":"Tax:9606"},{"id":"A966","pred":"tao:has_database_id","subj":"966","obj":"Gene:351"},{"id":"A967","pred":"tao:has_database_id","subj":"967","obj":"Gene:351"},{"id":"A968","pred":"tao:has_database_id","subj":"968","obj":"MESH:D006973"},{"id":"A969","pred":"tao:has_database_id","subj":"969","obj":"MESH:C000657245"},{"id":"A970","pred":"tao:has_database_id","subj":"970","obj":"MESH:C000657245"},{"id":"A971","pred":"tao:has_database_id","subj":"971","obj":"MESH:C000657245"},{"id":"A996","pred":"tao:has_database_id","subj":"996","obj":"Gene:59272"},{"id":"A997","pred":"tao:has_database_id","subj":"997","obj":"Gene:6999"},{"id":"A998","pred":"tao:has_database_id","subj":"998","obj":"Gene:6999"},{"id":"A999","pred":"tao:has_database_id","subj":"999","obj":"Gene:6999"},{"id":"A1000","pred":"tao:has_database_id","subj":"1000","obj":"Gene:6999"},{"id":"A1001","pred":"tao:has_database_id","subj":"1001","obj":"Gene:6999"},{"id":"A1002","pred":"tao:has_database_id","subj":"1002","obj":"Gene:6999"},{"id":"A1003","pred":"tao:has_database_id","subj":"1003","obj":"Tax:9606"},{"id":"A1004","pred":"tao:has_database_id","subj":"1004","obj":"Tax:9606"},{"id":"A1005","pred":"tao:has_database_id","subj":"1005","obj":"Gene:351"},{"id":"A1006","pred":"tao:has_database_id","subj":"1006","obj":"Gene:351"},{"id":"A1007","pred":"tao:has_database_id","subj":"1007","obj":"Gene:351"},{"id":"A1008","pred":"tao:has_database_id","subj":"1008","obj":"MESH:D012140"},{"id":"A1009","pred":"tao:has_database_id","subj":"1009","obj":"MESH:D029424"},{"id":"A1010","pred":"tao:has_database_id","subj":"1010","obj":"MESH:D001249"},{"id":"A1011","pred":"tao:has_database_id","subj":"1011","obj":"MESH:D011014"},{"id":"A1012","pred":"tao:has_database_id","subj":"1012","obj":"MESH:C000657245"},{"id":"A1013","pred":"tao:has_database_id","subj":"1013","obj":"MESH:D029424"},{"id":"A1014","pred":"tao:has_database_id","subj":"1014","obj":"MESH:D011014"},{"id":"A1015","pred":"tao:has_database_id","subj":"1015","obj":"MESH:D008171"},{"id":"A1016","pred":"tao:has_database_id","subj":"1016","obj":"MESH:C000657245"},{"id":"A1017","pred":"tao:has_database_id","subj":"1017","obj":"MESH:D029424"},{"id":"A1018","pred":"tao:has_database_id","subj":"1018","obj":"MESH:D012141"},{"id":"A1019","pred":"tao:has_database_id","subj":"1019","obj":"MESH:D007239"}],"namespaces":[{"prefix":"Tax","uri":"https://www.ncbi.nlm.nih.gov/taxonomy/"},{"prefix":"MESH","uri":"https://id.nlm.nih.gov/mesh/"},{"prefix":"Gene","uri":"https://www.ncbi.nlm.nih.gov/gene/"},{"prefix":"CVCL","uri":"https://web.expasy.org/cellosaurus/CVCL_"}],"text":"Pathogenic Mechanisms\nConsidering the similarity between SARS-CoV-1 and SARS-CoV-2, it is likely that their biochemical interactions and pathogenesis are also similar (80, 81). Once SARS-CoV-2 was reported to use ACE2 to enter host cells, it is suggested that the virus may target a cell spectrum similar to SARS-CoV-1 (38, 82, 83). SARS-CoV-1 is known to mainly infect macrophages and pneumocytes in the lungs, as well as other extrapulmonary tissues that express ACE2, which can also be expected for SARS-CoV-2 (82–84). However, the affinity of SARS-CoV-2 to ACE2 is 10–20-fold higher than that of SARS-CoV-1, which could explain its higher transmissibility and demonstrate that it can bind more efficiently to host cells, having a robust infection in ACE2+ cells in the upper respiratory tract (7).\nACE2 is an enzyme belonging to the renin-angiotensin system, located on the cell surface of type II alveolar epithelial cells in the lungs and cells of other tissues, and plays a crucial role in controlling vasoactive effects in the body. Despite their similarities, ACE and ACE2 have different substrate specificities with distinct functionalities that perform opposite actions in the body. In brief, ACE cleaves angiotensin I to generate angiotensin II, the peptide that binds and activates angiotensin type 1 receptor (AT1R) to constrict blood vessels, thereby raising blood pressure. In contrast, ACE2 inactivates angiotensin II (Ang-II) while generating angiotensin 1-7 (Ang-1-7), a potent heptapeptide that acts in vasodilation and attenuation of inflammation (85).\nTherefore, considering that SARS-CoV-2 uses ACE2 to enter cells, the main hypothesis of pulmonary pathology is that the increased activity of ACE (Ang-II) over ACE2 (Ang-1-7) may cause acute lung injury since the binding of the S protein to ACE2 leads to its blockage. Thus, the suppression of ACE2 occurs due to the increased internalization and release of ACE2 from the cell surface, which leads to a decrease in tissue ACE2 and the generation of Ang-1-7, and consequently higher Ang-II levels. Because of this, as shown in an experimental SARS-CoV-1 model, this process can drive an Ang II-AT1R-mediated inflammatory response in the lungs and potentially induce direct parenchymal injury (67, 80, 86, 87).\nAnother hypothesis states that SARS-CoV-2 infection blocks ACE2 function when binding to host cells, inhibiting its role of cleaving bradykinin and, as a consequence, bradykinin accumulates in the lung, promoting pulmonary edemas due to vasodilator activity and consequent respiratory failure. The increased bradykinin activation in the pulmonary endothelium can also induce neutrophil migration, enhancing tissue damage caused by the respiratory burst of these cells (88).\nACE2 is also highly expressed and co-expressed with TMPRSS2 in nasal epithelial cells, chalices, and hair cells (89). This finding is in accordance with the high detection of viral RNA in the upper airways present in nasal swabs and throats of both symptomatic and asymptomatic patients, demonstrating that the nasal epithelium is an important site for the infection to initiate and can represent an essential reservoir for viral dissemination and transmission (38).\nAlthough the virus mainly affects the lungs, there are reports that SARS-CoV-2 also has organotropism, accompanied by dysfunction, in multiple organs, including the kidneys, liver, heart, and brain, which can influence the course of the disease and possibly worsen pre-existing conditions. It has been reported that ACE2, TMPRSS2, and cathepsin L can be expressed on glial cells and neurons, cardiomyocytes, liver cells, bile duct cells, and renal tubular cells (90, 91).\nEvidence indicates that SARS-CoV-2 “neuroinvasion” can establish a direct entry along the olfactory nerve, mainly through the nasal olfactory epithelium, which expresses ACE2 and TMPRSS2, allowing access to the central nervous system (CNS). The spread of the virus through the hematogenous or transsynaptic pathway has also been widely discussed, however, it is known that the different levels of neurotropism and neurovirulence in patients with COVID-19 can be explained by a combination of viral factors and their interaction with the host (41, 92, 93).\nRegarding the evolution of infected individuals, aging, comorbidities, and weakening of the immune system are factors that generally cause the infection to intensify at the acute phase, leading to the manifestation of more severe conditions (6). Thus, according to epidemiological studies, it is known that patients with chronic conditions, such as hypertension, diabetes, and chronic obstructive pulmonary disease (COPD), are more likely to develop a critical form of the disease (94–96).\nThe risk of applying medication commonly used in hypertension treatments to COVID-19 patients (97, 98) has raised different hypotheses over the issue of invoking a higher expression of ACE2 (99–101). A systematic review assessing the clinical outcomes for SARS-CoV-2-infected individuals regarding treatment using angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) concluded that these types of drugs have no deleterious effects and should continue to be used in COVID-19 patients (102), reinforcing the recommendations of several medical societies, including the American Heart Association (103) and European Society of Cardiology (104).\nRespiratory diseases, such as COPD and asthma, cause a reduced lung function and greater susceptibility to lung inflammation, and are expected to show a potentially critical course of COVID-19. COPD patients are already considered more susceptible to the development of pneumonia based on the clinical characteristics exhibited, such as lung structural damage, alterations in local/systemic inflammatory response, impaired host immunity, microbiome imbalance, persistent mucus production, and the presence of potentially pathogenic bacteria in the airways (105). Additionally, in the scenario of COVID-19, smokers and individuals with COPD have shown to have increased airway expressions of ACE-2 (106). It is still worth mentioning that patients who have this type of disorder often use corticosteroid immune-suppressing drugs, whose effect of reducing the immunity to respiratory infections may represent another contributing factor to a higher risk of infection (107)."}