Using biochemical and pseudovirus entry assays and SARS-CoV as a comparison, we have identified key cell entry mechanisms of SARS-CoV-2 that potentially Before Cheung CY, Poon LLM, Ng IHY, Luk W, Sia S-F, Wu MHS, Chan K-H, Yuen K-Y, Gordon S, Guan Y, Peiris JSM. WC,, Benoit Toscano G, Palmerini F, Ravaglia S, Ruiz L, Invernizzi P, Cuzzoni MG, Franciotta D, Baldanti F, Daturi R, Postorino P, Cavallini A, Micieli G. Guillain-Barr Syndrome associated with SARS-CoV-2. WebTo further elucidate the mechanism of COVID-19 severity, we conducted differential expression analysis between moderate disease versus severe disease group in ncMono. For example, Toll-like receptors (TLRs) recognize PAMPs in mostly the extracellular space, triggering induction of proinflammatory cytokine transcription factors such as NF-, as well as activating interferon regulatory factors that mediate the type I interferon-dependent antiviral response (122, 125). Complement-mediated pulmonary tissue damage and microvascular injury have been observed in small cohorts with severe COVID-19 (85). Lipase elevation in patients with COVID-19. Laboratory abnormalities in children with mild and severe coronavirus disease 2019 (COVID-19): A pooled analysis and review. In a case study series of >2,000 children with suspected or confirmed COVID-19 in China, 5% of symptomatic children had dyspnea or hypoxemia, and only 0.6% progressed to ARDS or MOF (36). Online ahead of print. A team of Russian researchers has uncovered the mechanisms behind the emergence of new and dangerous coronavirus variants, such as Alpha, Delta, Omicron, and others. Gastrointestinal manifestations of SARS-CoV-2 infection and virus load in fecal samples from the Hong Kong cohort and systematic review and meta-analysis. Interestingly, SARS-CoV-2 has developed a unique S1/S2 cleavage site in its S protein, characterized by a four-amino acid insertion, which seems to be absent in all other coronaviruses (4). Nevertheless, the exact contribution of direct viral immune cell infection is unknown and highly debated (155). Potential mechanisms include 1) viral entry via ACE2 receptors into the endothelia that line the blood capillaries and subsequent neuro-invasion, 2) neurological edema and brain stem compression as a result of breached blood-brain barrier, 3) neurological edema and hypercoagulability as a result of cytokine storm syndrome, and 4) propagation via mechanoreceptors and chemoreceptors in the lung and lower respiratory airways (65). This is surprising since lymphopenia has been estimated to be one of the most consistent laboratory abnormalities in adult patients with severe COVID-19 illness (57). Ranucci M, Ballotta A, Di Dedda U, Bayshnikova E, Dei Poli M, Resta M, Falco M, Albano G, Menicanti L. The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome, Cutaneous manifestations in COVID-19: a first perspective. Cai Q, Huang D, Yu H, Zhu Z, Xia Z, Su Y, Li Z, Zhou G, Gou J, Qu J, Sun Y, Liu Y, He Q, Chen J, Liu L, Xu L. Carsana L, Sonzogni A, Nasr A, Rossi RS, Pellegrinelli A, Zerbi P, Rech R, Colombo R, Antinori S, Corbellino M, Galli M, Catena E, Tosoni A, Gianatti A, Nebuloni M. Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study, Centers for Disease Control and Prevention, Coronavirus disease 2019 in childrenUnited States, February 12April 2, 2020, Gastrointestinal and hepatic manifestations of COVID-19: A comprehensive review. A more plausible mechanism behind liver dysfunction in COVID-19 is the observed systemic inflammatory response, as described previously, leading to cytotoxic T-cell-mediated necrosis and MOF. coronavirus Although these reports indicate a milder COVID-19 profile in pediatric patients compared with adults (159), reports from China and the CDC indicate that the documented hospitalization and mortality rates in pediatric cases are concerning and emphasize the importance of comprehensive studies to examine the clinical picture of pediatric disease (15a, 36). The urgent need to appropriately identify these patients has led the World Health Organization (WHO) and other regulatory bodies to develop a preliminary case definition known as Multisystem Inflammatory Disorder in Children and adolescents (MIS-C) (142a). de Wit E, van Doremalen N, Falzarano D, Munster VJ. MHS,, Hsieh SW, de Oliveira Multiple organ infection and the pathogenesis of SARS. Increases in TNF- were not observed in contrast to adult patients (24). Before this, TMPRSS2 has presented biological functions in cancer, but the roles remain controversial and the mechanism remains unelucidated. Cheng Y, Luo R, Wang K, Zhang M, Wang Z, Dong L, Li J, Yao Y, Ge S, Xu G. Kidney disease is associated with in-hospital death of patients with COVID-19. Autopsy findings in SARS-CoV infections have shown strong evidence of neuro-invasion, with demonstrated viral presence in the cerebrospinal fluid (6, 95). Wong SF, Chow KM, Leung TN, Ng WF, Ng TK, Shek CC, Ng PC, Lam PWY, Ho LC, To WWK, Lai ST, Yan WW, Tan PYH. An understanding of the complex and likely multifactorial pathophysiological mechanisms behind kidney failure in COVID-19 is thus needed for early recognition and appropriate treatment selection. mechanism SARS and MERS: recent insights into emerging coronaviruses. However, whether furin-like protease-mediated cleavage is required for SARS-CoV-2 host entry has yet to be determined. COVID-19 coronavirus This not only suggests the importance of defining the timing of antibody response through serological testing in multiple age groups but also points toward the increasing complexity of COVID-19. and K.A. Bohn MK, Lippi G, Horvath A, Sethi S, Koch D, Ferrari M, Wang C-B, Mancini N, Steele S, Adeli K. Molecular, serological, and biochemical diagnosis and monitoring of COVID-19: IFCC taskforce evaluation of the latest evidence. Many groups have suggested extrapulmonary involvement in COVID-19 is a direct result of unrestrained inflammation. Recent autopsy data from Italy also observed fibrin thrombi in pulmonary small arterial vessels in 87% of fatal cases examined, suggesting the contribution of coagulation in diffuse alveolar and endothelial damage (15). SARS-CoV-2, the virus which causes COVID-19, tends to change more slowly than others such as HIV or influenza viruses. Klok FA, Kruip MJHA, van der Meer NJM, Arbous MS, Gommers DAMPJ, Kant KM, Kaptein FHJ, van Paassen J, Stals MAM, Huisman MV, Endeman H. Incidence of thrombotic complications in critically ill ICU patients with COVID-19, Role of cytokines in cardiovascular diseases: a focus on endothelial responses to inflammation. Some have suggested MIS-C is mainly resultant from post-infectious IgG-mediated enhancement, whereas others have proposed it is due to blockage of type I and III interferon responses, leading to uncontrolled viral replication and high viral load (119). Interestingly, current evidence suggests that the laboratory profile observed in pediatric COVID-19 patients is different from that of adults. Okba NMA, Mller MA, Li W, Wang C, GeurtsvanKessel CH, Corman VM, Lamers MM, Sikkema RS, de Bruin E, Chandler FD, Yazdanpanah Y, Le Hingrat Q, Descamps D, Houhou-Fidouh N, Reusken CBEM, Bosch BJ, Drosten C, Koopmans MPG, Haagmans BL. RA,, Plebani M,, Lippi Advanced polymer hydrogels that promote diabetic ulcer healing The COVID-19 outbreak has been a serious public health threat worldwide and the basic reproduction number is estimated to be 1.54 with contact tracing, quarantine However, traditional dressings with a simple structure and a single function cannot meet clinical requirements. Drugdrug interaction between Nitazoxanide and Azithromycin is The condition is typically treated with either an infusion of antibodies, known as immunoglobulin therapy, or plasma exchange, in which a patients blood plasma is removed and replaced. 1) Potential mechanisms of COVID-pain (SARS-CoV-2/COVID-19-induced pain) (A) ACE2/RAS pathway and the direct virus-induced damage. Interestingly, although the S proteins of SARS-CoV-2 and SARS-CoV share 72% homology in amino acid sequences, SARS-CoV-2 has been reported to have a higher affinity for the ACE2 receptor (18, 21, 143). Procoagulant response is also associated with the inflammatory effects of cytokines in the vascular endothelium, including increased vascular permeability and damage as a result of immune-cell infiltration (62). 13, 938837. WebThe coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is a highly contagious enveloped positive-strand RNA virus that causes respiratory diseases, fever, and severe pneumonia in humans (13). mechanisms of COVID More comprehensive studies based on larger sample sizes are needed to better characterize the laboratory and clinical profile of mild versus severe pediatric COVID-19 and to help develop our understanding of immune pathogenesis. Pulmonary pathology of early-phase 2019 novel Coronavirus (COVID-19) pneumonia in two patients with lung cancer, Review article: gastrointestinal features in COVID-19 and the possibility of faecal transmission. The .gov means its official. It is unclear whether increased antibody prevalence in severe COVID-19 patients suggests potential antibody-dependent enhancement (ADE) or is simply a result of higher viral antigen exposure. TWC India. Although prominent changes in blood coagulation may be a contributing mechanism to COVID-19 mortality, its pathogenesis is estimated to be tightly linked to inflammation and cytokine release. (B) Macrophage activation. M.K.B. ACE2 is expressed in the kidney, and although previous studies suggested absence of viral particles in postmortem renal specimens from SARS patients (27), electron microscopic examination of 26 postmortem COVID-19 patients demonstrated direct virulence in tubular epithelium and podocytes (126). Eroshenko N, Gill T, Keaveney MK, Church GM, Trevejo JM, Rajaniemi H. Implications of antibody-dependent enhancement of infection for SARS-CoV-2 countermeasures. Background Micronutrients have been associated with disease severity and poorer clinical outcomes in patients with COVID-19. Indeed, Hoffman and colleagues demonstrated that S-protein priming by transmembrane serine protease 2 (TMPRSS2), which may be substituted by cathepsin B/L, is required to facilitate SARS-CoV-2 entry into host cells (58). Tersalvi G, Vicenzi M, Calabretta D, Biasco L, Pedrazzini G, Winterton D. Elevated troponin in patients with Coronavirus Disease 2019: possible mechanisms. Naunyn-Schmiedeberg's Arch Pharmacol 393, 11531156 (2020). These factors need to be observed more thoroughly to complete our clinical understanding of COVID-19. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li Y, Wang X, Peng Z. Cheung EW, Zachariah P, Gorelik M, Boneparth A, Kernie SG, Orange JS, Milner JD. J,, Ballout The underlying pathophysiology of the loss of these olfactory and gustatory perceptions have been postulated to be related to direct damage of the supporting cells of the olfactory epithelium, olfactory bulb and altered function of the olfactory neurons, altered ACE2 signal transmission, and accelerated gustatory particle degradation by sialic acid (87, 137). Khalil A, Kalafat E, Benlioglu C, OBrien P, Morris E, Draycott T, Thangaratinam S, Le Doare K, Heath P, Ladhani S, von Dadelszen P, Magee LA. However, as has been reported extensively, viral infection can progress to severe disease due to dysregulated immune response. Can COVID-19 in pregnancy cause preeclampsia? conceived and designed research; M.K.B., A.H., L.S., and K.A. In t Wang Y, Liu S, Liu H, Li W, Lin F, Jiang L, Li X, Xu P, Zhang L, Zhao L, Cao Y, Kang J, Yang J, Li L, Liu X, Li Y, Nie R, Mu J, Lu F, Zhao S, Lu J, Zhao J. SARS-CoV-2 infection of the liver directly contributes to hepatic impairment in patients with COVID-19. Naunyn-Schmiedeberg's Arch Pharmacol 393, Severe acute respiratory syndrome Coronavirus 2-specific antibody responses in Coronavirus Disease 2019 patients. 1: SARS-CoV-2 enters alveolar epithelial cells by binding to angiotensin converting enzyme 2 (ACE2) through surface spike (S) protein mediated by transmembrane serine protease 2 (TMPRSS2). Xu X, Chen P, Wang J, Feng J, Zhou H, Li X, Zhong W, Hao P. Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission. Zuo Y, Yalavarthi S, Shi H, Gockman K, Zuo M, Madison JA, Blair C, Weber A, Barnes BJ, Egeblad M, Woods RJ, Kanthi Y, Knight JS. A multicenter European study of children with PCR-confirmed SARS-CoV-2 infection also reported that 8% of pediatric patients required ICU admission, 4% required mechanical ventilation, 3% required inotropic support, and <1% required extracorporeal membrane oxygenation (49). Coutard B, Valle C, de Lamballerie X, Canard B, Seidah NG, Decroly E. The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade. COVID and Coagulation: Bleeding and Thrombotic Manifestations of SARS-CoV2 Infection. Here, we review the current literature and summarize key proposed mechanisms of COVID-19 pathophysiological progression (FIGURE 1). Several cohort studies have observed markedly elevated levels of circulating proinflammatory cytokines and chemokines, significantly correlating to disease severity and mortality. Advanced polymer hydrogels that promote diabetic ulcer healing Collapsing glomerulopathy in a patient with Coronavirus Disease 2019 (COVID-19). Most studies have reported no evidence of detectable SARS-CoV-2 RNA in the placenta. Traditional Chinese medicine theory-driven natural drug research and development (TCMT-NDRD) is a feasible method to address this issue as the traditional Chinese medicine formulae have been shown COVID-19 JCM | Free Full-Text | Long-Term Effects of SARS-CoV-2 in the The association of GI manifestations with disease severity is not well described, with many conflicting results reported (25, 139, 154). NSF Award Search: Award # 2113736 - SenSE:Wearable hybrid However, it is important to note that a handful of studies have described patients presenting with primary cardiac symptoms, suggesting myocarditis and stress-related cardiomyopathy due to respiratory failure and hypoxemia (60, 63, 152). Importantly, COVID-19 appears to enhance complications in patients with diabetes, likely due to viral-induced pancreatic dysfunction as well as associated immune dysregulation, vasculopathy, and coagulopathy (29, 37). The mechanisms behind progressive lymphopenia in severe COVID-19 remain unclear, although T-cell redistribution via pulmonary recruitment, exhaustion, as well as depletion through TNF--mediated apoptosis or even direct cytopathic injury have been suggested (35, 147). Here, we review the current literature and summarize key proposed mechanisms of COVID-19 pathophysiological progression (FIGURE 1). DeBiasi RL, Song X, Delaney M, Bell M, Smith K, Pershad J, Ansusinha E, Hahn A, Hamdy R, Harik N, Hanisch B, Jantausch B, Koay A, Steinhorn R, Newman K, Wessel D. Severe COVID-19 in children and young adults in the Washington, DC metropolitan region. Recent studies indicate that like other coronaviruses, SARS-CoV-2 also hijacks or The pathophysiological mechanisms behind the neurological manifestations of COVID-19 have not been well elucidated. Severe Coronavirus infections in pregnancy: a systematic review. Once the nucleocapsid is deposited into the cytoplasm of the host cell, the RNA genome is replicated and translated into structural and accessory proteins. Molecular mechanism of interaction between SARS-CoV-2 and As of June 15, 2020, the number of global confirmed cases has surpassed 8 million, with over 400,000 reported mortalities. Qin L, Li X, Shi J, Yu M, Wang K, Tao Y, Zhou Y, Zhou M, Xu S, Wu B, Yang Z, Zhang C, Yue J, Cheng C, Liu X, Xie M. Gendered effects on inflammation reaction and outcome of COVID19 patients in Wuhan. Virus-induced breath biomarkers: A new perspective to study the The pleiotropic hepatic effects of IL-6 could play a particularly important role, inducing expression of serum amyloid A, fibrinogen, and CRP (121). A recent meta-analysis suggested serum IL-6 cut-offs of >55 pg/ml and >80 pg/ml to identify patients at high risk for severe COVID-19 and mortality, respectively (5). Multisystem inflammatory syndrome related to COVID-19 in previously healthy children and adolescents in New York City. COVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study. SARS-CoV-2 infection in pregnancy: a systematic review and meta-analysis of clinical features and pregnancy outcomes. 353989). HHS Vulnerability Disclosure, Help Kathryn Tewson on Twitter In addition, direct viral infection of immune cells such as monocytes and macrophages have been proposed to contribute to dysregulated immune response, as has been observed in SARS (23, 52, 136). That Kathryn Tewson on Twitter Conclusion Evidence on why persistent symptoms occur is still limited, and available studies are heterogeneous. prepared figures; M.K.B., A.H., L.S., B.J., and K.A. Scientists have been trying to understand the origin of COVID-19 and the virus that causes it: SARS-CoV-2. Cheung KS, Hung IF, Chan PP, Lung KC, Tso E, Liu R, Ng YY, Chu MY, Chung TW, Tam AR, Yip CC, Leung K-H, Yim-Fong Fung A, Zhang RR, Lin Y, Cheng HM, Zhang AJ, To KK, Chan K-H, Yuen K-Y, Leung WK. JCM | Free Full-Text | Long-Term Effects of SARS-CoV-2 in the In addition to understanding relevant risk factors, there is increasing suspicion of delayed but severe COVID-19 presentation, particularly in children, even after viral clearance (113). Considering this, it is still unclear what factors influence the transition from normal physiological to pathogenic hyperinflammatory response. Nitazoxanide and Azithromycin are widely used for the early treatment of COVID-19. The trinity of COVID-19: immunity, inflammation and intervention. The first step in COVID-19 pathogenesis is viral invasion via its target host cell receptors. COVID-19 and myocarditis: What do we know so far? WebThe coronavirus disease 2019 (COVID-19) pandemic is an ongoing global health concern, and effective antiviral reagents are urgently needed. Biochemical Mechanisms - an overview | ScienceDirect Topics The pyrin inflammasome in health and disease. Individuals with Alzheimers disease (AD) and related dementia, as well as persons with Down syndrome (DS), are especially vulnerable to COVID-19, but the Neutrophil extracellular traps in COVID-19, https://www.cdc.gov/coronavirus/2019-ncov/downloads/pui-form.pdf, https://www.who.int/news-room/commentaries/detail/multisystem-inflammatory-syndrome-in-children-and-adolescents-with-covid-19. However, other contributing mechanisms have been proposed and are explored below (FIGURE 3). March 28, 2023 A team of scientists led by the Department of Energys Oak Ridge National Laboratory designed a molecule that disrupts the infection mechanism of the SARS-CoV-2 coronavirus and could be used to develop new treatments for COVID-19 and other viral diseases. In addition to direct infection, uncontrolled cytokine release, thrombosis, and ischemia can also result in further kidney dysfunction, characterized by intrarenal inflammation, increased vascular permeability, and volume depletion (88). Chiotos K, Bassiri H, Behrens EM, Blatz AM, Chang J, Diorio C, Fitzgerald JC, Topjian A, John ARO. Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Si HR, Zhu Y, Li B, Huang CL, Chen HD, Chen J, Luo Y, Guo H, Jiang RD, Liu MQ, Chen Y, Shen XR, Wang X, Zheng XS, Zhao K, Chen QJ, Deng F, Liu LL, Yan B, Zhan FX, Wang YY, Xiao GF, Shi ZL. Zhang H, Zhou P, Wei Y, Yue H, Wang Y, Hu M, Zhang S, Cao T, Yang C, Li M, Guo G, Chen X, Chen Y, Lei M, Liu H, Zhao J, Peng P, Wang CY, Du R. Histopathologic changes and SARS-COV-2 immunostaining in the lung of a patient with COVID-19. Researchers Discover Mechanisms Behind Emergence of COVID