Some cases of cutaneous manifestations in adult COVID-19 patients have been reported, although varying incidence among patients has been noted (68, 111, 120). Although much progress has been made in our understanding of the mechanisms underlying SARS-CoV-2 invasion, additional research is needed to delineate exactly how cleavage of the S proteins by TMPRSS2 confers viral particle entry as well as how S-protein cleavage by membrane proteases contributes to viral penetration. WebThe biochemical mechanism of ozone-induced lung injury is due to the reaction of the highly reactive O 3 with biological macromolecules such as protein, lipids, nucleic acids, and They describe settings where transmission of the COVID-19 virus spreads more easily: Crowded places; Close-contact settings, especially where people have Fan Z, Chen L, Li J, Cheng X, Yang J, Tian C, Zhang Y, Huang S, Liu Z, Cheng J. Reduction and functional exhaustion of T cells in patients with Coronavirus Disease 2019 (COVID-19). Liver biochemistries in hospitalized patients with COVID-19. Frontiers | Ginsenosides, potential TMPRSS2 inhibitors, a trade-off 13, 938837. Naunyn-Schmiedeberg's Arch Pharmacol 393, Clerkin KJ, Fried JA, Raikhelkar J, Sayer G, Griffin JM, Masoumi A, Jain SS, Burkhoff D, Kumaraiah D, Rabbani L, Schwartz A, Uriel N. Cole SA, Laviada-Molina HA, Serres-Perales JM, Rodriguez-Ayala E, Bastarrachea RA. COVID-19 Coronavirus origins: genome analysis suggests two viruses may have combined Mar 20, 2020. Localization of endogenous furin in cultured cell lines, COVID-19 illness in native and immunosuppressed states: A clinical-therapeutic staging proposal. In addition to these reports, there is increasing evidence of higher rates of miscarriage and preeclampsia in pregnant women with SARS-CoV-2 infection, suggesting placental involvement (5a). Web..3C and 3CL Proteases of HRV, Picornaviruses, SARS, MERS, COVID-19 and other Nidoviruses share a common catalytic mechanism of action called trypsin like Cystein Pathophysiology of COVID-19: Mechanisms Underlying Disease The receptor binding domain of the viral spike protein is an immunodominant and highly specific target of antibodies in SARS-CoV-2 patients, Role of the spike glycoprotein of human Middle East respiratory syndrome coronavirus (MERS-CoV) in virus entry and syncytia formation. coronavirus Some have suggested this is likely a result of the physiological immune adaptions that occur during pregnancy, preventing escalation to the hyperinflammatory phase of COVID-19 (48). de Wit E, van Doremalen N, Falzarano D, Munster VJ. The first step in COVID-19 pathogenesis is viral invasion via its target host cell receptors. SARS-CoV-2 viral entry has been described in detail elsewhere ( 138 ). Now considered a valuable prognostic indicator for COVID-19 survival, AKI is estimated to affect 2040% of critically ill patients in intensive care, necessitating renal replacement therapy and extracorporeal support therapies such as blood purification (112, 155). Chen IY, Moriyama M, Chang MF, Ichinohe T. Severe acute respiratory syndrome coronavirus viroporin 3a activates the NLRP3 inflammasome. Tay MZ, Poh CM, Rnia L, MacAry PA, Ng LFP. Jamilloux Y, Henry T, Belot A, Viel S, Fauter M, El Jammal T, Walzer T, Franois B, Sve P. Should we stimulate or suppress immune responses in COVID-19? 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). This, however, is unlikely since significant increases in circulating levels of common bile duct injury markers (e.g., serum bilirubin, gamma glutamyltransferase, and alkaline phosphatase) have not been extensively reported (7). Jin JM, Bai P, He W, Wu F, Liu XF, Han DM, Liu S, Yang JK. Received 2020 Jun 23; Revised 2020 Jul 7; Accepted 2020 Jul 7. coagulation, COVID-19, cytokine storm, multisystem organ failure, pathophysiolog. Cheung EW, Zachariah P, Gorelik M, Boneparth A, Kernie SG, Orange JS, Milner JD. Specifically, in a study of 417 COVID-19 patients, 76.3% had abnormal liver tests, and 21.5% had liver injury during hospitalization (14). The reported neurological manifestations of COVID-19 include headache, dizziness, confusion, epilepsy, ataxia (lack of voluntary muscle movement), altered sense of smell (hyposmia/anosmia), loss of taste (ageusia), and Guillain-Barr syndrome, among others (97, 115, 134). Given the homology between these viruses, such direct viral invasion should not be discounted (100, 106). Ellington S, Strid P, Tong VT, Woodworth K, Galang RR, Zambrano LD, Nahabedian J, Anderson K, Gilboa SM. Firstly, deformable convolution is used to extract features in the horizontal and vertical directions, respectively. 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). Human leukocyte antigen susceptibility map for severe acute respiratory syndrome Coronavirus 2, The neurological manifestations of COVID-19: a review article. It is important to note that the heterogeneous standards used to interpret laboratory tests in pediatrics could contribute to the variation observed in study findings. Interestingly, most studies report similar clinical characteristics and mortality rates in pregnant women with COVID-19 compared with nonpregnant women of reproductive age (48). Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. This disproportionate clinical epidemiology may be explained by sex-specific regulation of ACE2, increased incidence of preexisting comorbidities in males (i.e., hypertension, diabetes, cardiovascular disease), as well as sex-specific differences in viral immune response, as described elsewhere (47, 109). SARS and MERS: recent insights into emerging coronaviruses. Genetic predispositions have also been proposed, including polymorphisms in ACE2 and genetic variability in histocompatibility complex (MHC) class I genes (96). While primer extension inhibition is weak, variable, and Specifically, immunothrombosis is a phenomenon known to occur as a result of host defense against various pathogens, including viral infection (30). The pathophysiological mechanisms behind key events in the progression from mild to severe disease remain unclear, warranting further investigation to inform therapeutic decisions. Laboratory/clinical profile and key potential mechanisms underlying extrapulmonary manifestations observed in severe COVID-19 patients. The global epidemiology of coronavirus disease 2019 (COVID-19) suggests a wide spectrum of clinical severity, ranging from asymptomatic to fatal. Biochemical Mechanisms - an overview | ScienceDirect Topics 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). The nuances of age-related immune response appear to play a role, with increasing disease severity observed in older populations (82). In brief, SARS-CoV-2 consists of four main structural glycoproteins: spike (S), membrane (M), envelope (E), and nucleocapsid (N). Although direct damage of pancreatic -cells has been proposed as a plausible mechanism behind this phenotype, immune destruction of -cells has also been suggested in addition to bystander death due to exocrine infection (101). The trinity of COVID-19: immunity, inflammation and intervention. Clinical characteristics of 138 hospitalized patients with 2019 novel Coronavirus-infected pneumonia in Wuhan, China. Direct viral infection of macrophages and/or dendritic cells is estimated to propagate further cytokine and chemokine release, subsequently activating late-phase immune-cell recruitment of antigen-specific T cells to destroy virally infected alveolar cells (61, 130, 132, 149). Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation, Characteristics of and important lessons from the Coronavirus Disease 2019 (COVID-19) outbreak in China: summary of a report of 72,314 cases From the Chinese Center for Disease Control and Prevention. RA,, Plebani Electronic address: https://www.lancovid.org . Inside the new mRNA vaccines for COVID-19 Notably, increasing cardiac troponin levels have been correlated to other inflammatory markers, such as CRP, ferritin, and IL-6, suggesting inflammatory damage as opposed to primary myocardial injury (28). Physiological host immune response to SARS-CoV-2 infection. 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). Kathryn Tewson on Twitter Gastrointestinal manifestations of SARS-CoV-2 infection and virus load in fecal samples from the Hong Kong cohort and systematic review and meta-analysis. Henry BM, De Oliveira MHS, Benoit S, Plebani M, Lippi G. Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): A meta-analysis. Cytokine and anti-cytokine interventions. TWC India. HHS Vulnerability Disclosure, Help Direct renal infection and damage presents one potential contributing mechanism. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. Zhu L, She ZG, Cheng X, Qin JJ, Zhang XJ, Cai J, Lei F, Wang H, Xie J, Wang W, Li H, Zhang P, Song X, Chen X, Xiang M, Zhang C, Bai L, Xiang D, Chen MM, Liu Y, Yan Y, Liu M, Mao W, Zou J, Liu L, Chen G, Luo P, Xiao B, Zhang C, Zhang Z, Lu Z, Wang J, Lu H, Xia X, Wang D, Liao X, Peng G, Ye P, Yang J, Yuan Y, Huang X, Guo J, Zhang BH, Li H. Association of blood glucose control and outcomes in patients with COVID-19 and pre-existing Type 2 diabetes, Coronavirus infections in children including COVID-19: An overview of the epidemiology, clinical features, diagnosis, treatment and prevention options in children, Dissecting antibody-mediated protection against SARS-CoV-2. COVID-19 and myocarditis: What do we know so far? Biological WebIn fact, in this mechanism, all three phases of clinical trials that are conducted in the routine process of evaluating medical biotechnology products are performed, but for example, to receive it from The United States Food and Drug Administration (FDA), at least 3,000 people must participate in phase III and be followed for a median two months However, a recent case report showed evidence of SARS-CoV-2 in the syncytiotrophoblast cells of a pregnant COVID-19 patient in the second trimester of gestation with preeclampsia (59). Some authors have proposed this is due to direct exocrine damage, whereas others suggest it is likely resultant from the gastrointestinal symptoms observed in many COVID-19 patients (32). Firstly, deformable convolution is used to extract features in the horizontal and vertical directions, respectively. Preliminary reports from the Chinese Center for Disease Control and Prevention have estimated that the large majority of confirmed SARS-CoV-2 cases are mild (81%), with ~14% progressing to severe pneumonia and 5% developing acute respiratory distress syndrome (ARDS), sepsis, and/or multisystem organ failure (MOF) (144). Chiotos K, Bassiri H, Behrens EM, Blatz AM, Chang J, Diorio C, Fitzgerald JC, Topjian A, John ARO. 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. Biological ORNL-led team designs molecule to disrupt SARS-CoV-2 infection Like, check this out -- Rizzo, E. Ivermectin, antiviral properties and COVID-19: a possible new mechanism of action. Although the clinical and laboratory characteristics of COVID-19 patients have been well characterized, the pathophysiological mechanisms underlying disease severity and progression remain unclear. It is thus hypothesized that the GI manifestations observed in COVID-19 are a result of SARS-CoV-2 infection of intestinal enterocytes and subsequent dysfunction in the ileum and colon (16). Following host cell binding, viral and cell membranes fuse, enabling the virus to enter into the cell (89). 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 In addition to cytokine release and immune cell recruitment, another potential mechanism that could contribute to successful viral clearance is antibody neutralization. Complement-mediated pulmonary tissue damage and microvascular injury have been observed in small cohorts with severe COVID-19 (85). Immune dysregulation, auto-immunity, endothelial dysfunction, occult viral persistence, as well as coagulation activation are the main underlying pathophysiological mechanisms so far. Conclusion Evidence on why persistent symptoms occur is still limited, and available studies are heterogeneous. In addition to the coagulopathy observed in COVID-19, severe bleeding in patients is rare in comparison to other RNA-type viruses with hemorrhagic manifestations (30). This work was supported by a Foundation Grant from the Canadian Institutes of Health Research (CIHR) (grant no. Su H, Yang M, Wan C, Yi LX, Tang F, Zhu HY, Yi F, Yang HC, Fogo AB, Nie X, Zhang C. Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Notably, the cytokine concentrations observed in hospitalized COVID-19 patients are rarely elevated to the same extent as in secondary hemophagocytic lymphohistiocytosis and cytokine release syndrome following CAR-T cell treatment (64). In terms of exocrine-related damage, a study by Wang et al. Since a hyperinflammatory profile consistent with cytokine storm has been robustly associated with COVID-19 severity and suggested as the predominant cause of patient mortality, most initial literature has focused on the dysregulation of immune response in COVID-19 patients and the potential value of immune modulating treatments. FIGURE 3. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Eroshenko N, Gill T, Keaveney MK, Church GM, Trevejo JM, Rajaniemi H. Implications of antibody-dependent enhancement of infection for SARS-CoV-2 countermeasures. Due to the paucity of data in this area, further research is required to elucidate what mechanisms confer protection from COVID-19 in most pediatric patients as well as what factors predispose children to progress to MIS-C. 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. As new therapeutic paradigms emerge, our understanding of disease pathophysiology will undoubtedly advance and not only inform current clinical practice for COVID-19 but fundamentally shape our understanding of immune involvement in systemic disease. Pathological findings of COVID-19 associated with acute respiratory distress syndrome, Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes, The pathogenesis and treatment of the cytokine storm in COVID-19. Similar to SARS-CoV, several researchers have identified human angiotensin converting enzyme 2 (ACE2) as an entry receptor for SARS-CoV-2 (75, 99, 148, 156). 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. As such, the neutrophil-to-lymphocyte ratio appears to be a useful indicator of disease prognostication and management (83). 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). Bioactive compounds from Huashi Baidu decoction possess both Nevertheless, the exact contribution of direct viral immune cell infection is unknown and highly debated (155). The unparalleled pathogenicity and global impact of this pandemic has rapidly engaged the scientific community in urgently needed research. WebThe coronavirus disease 2019 (COVID-19) pandemic is an ongoing global health concern, and effective antiviral reagents are urgently needed. 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. This paper proposes a model algorithm based on convolutional neural network combined with attention mechanism to realize fast and accurate identification of biological image. Jones VG, Mills M, Suarez D, Hogan CA, Yeh D, Segal JB, Nguyen EL, Barsh GR, Maskatia S, Mathew R. COVID-19 and Kawasaki Disease: novel virus and novel case, COVID-19 can present with a rash and be mistaken for dengue. Bertram S, Glowacka I, Mller MA, Lavender H, Gnirss K, Nehlmeier I, Niemeyer D, He Y, Simmons G, Drosten C, Soilleux EJ, Jahn O, Steffen I, Phlmann S. Cleavage and activation of the severe acute respiratory syndrome coronavirus spike protein by human airway trypsin-like protease. COVID-19 coronavirus COVID Can COVID-19 in pregnancy cause preeclampsia? Similar to renal COVID-19 involvement, there is evidence of direct SARS-CoV-2 GI infection through isolation of viral RNA from GI epithelial cells (146). A timely, localized, and well-coordinated immune response presents the first line of physiological defense against SARS-CoV-2 infection (FIGURE 2). This review presents various potential pathophysiological mechanisms behind SARS-CoV-2 infection. Hadi A, Werge M, Kristiansen KT, Pedersen UG, Karstensen JG, Novovic S, Gluud LL. In total, these processes foster an increased secretion of proinflammatory cytokines and chemokines, such as IL-6, type II interferon (IFN), monocyte chemoattractant protein 1 (MCP1), and interferon gamma-induced protein 10 (IP-10), as well as subsequent pulmonary recruitment of immune cells, including macrophages and dendritic cells. Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW, Barnaby DP, Becker LB, Chelico JD, Cohen SL, Cookingham J, Coppa K, Diefenbach MA, Dominello AJ, Duer-Hefele J, Falzon L, Gitlin J, Hajizadeh N, Harvin TG, Hirschwerk DA, Kim EJ, Kozel ZM, Marrast LM, Mogavero JN, Osorio GA, Qiu M, Zanos TP; the Northwell COVID-19 Research Consortium . The association of GI manifestations with disease severity is not well described, with many conflicting results reported (25, 139, 154). Further studies are needed to evaluate the contribution of antibodies to both physiological and pathogenic host response (39, 160). Henry BM, Benoit. Escher F, Pietsch H, Aleshcheva G, Bock T, Baumeier C, Elsaesser A, Wenzel P, Hamm C, Westenfeld R, Schultheiss M, Gross U, Morawietz L, Schultheiss H. Detection of viral SARSCoV2 genomes and histopathological changes in endomyocardial biopsies, Severe COVID-19 infection associated with endothelial activation. It is also important to note that immune-cell infiltration can lead to the excessive secretion of proteases and reactive oxygen species, fostering further damage and hyperinflammation (130). Anand P, Puranik A, Aravamudan M, Venkatakrishnan AJ, Soundararajan V. SARS-CoV-2 strategically mimics proteolytic activation of human ENaC, Elevated interleukin-6 and severe COVID-19: A meta-analysis, Evidence of the COVID-19 virus targeting the CNS: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms, COVID-19 and the liver: little cause for concern. TWC India. Xu H, Zhong L, Deng J, Peng J, Dan H, Zeng X, Li T, Chen Q. For many coronaviruses, including SARS-CoV, host cell binding alone is insufficient to facilitate membrane fusion, requiring S-protein priming or cleavage by host cell proteases or transmembrane serine proteases (9, 10, 90, 94, 108). JCM | Free Full-Text | Long-Term Effects of SARS-CoV-2 in the In addition to GI manifestations, several studies have reported elevated liver enzymes and higher rates of liver injury in patients with severe COVID-19. Lechien JR, Chiesa-Estomba CM, De Siati DR, Horoi M, Le Bon SD, Rodriguez A, Dequanter D, Blecic S, El Afia F, Distinguin L, Chekkoury-Idrissi Y, Hans S, Delgado IL, Calvo-Henriquez C, Lavigne P, Falanga C, Barillari MR, Cammaroto G, Khalife M, Leich P, Souchay C, Rossi C, Journe F, Hsieh J, Edjlali M, Carlier R, Ris L, Lovato A, De Filippis C, Coppee F, Fakhry N, Ayad T, Saussez S. Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study. (B) Macrophage activation. Although hepatocytes have not been shown to exhibit high ACE2 expression, previous studies have demonstrated a high level of ACE2 expression in cholangiocytes, suggesting direct bile duct infection/damage as a potential cause of abnormal liver enzymes (17). However, there is a paucity of studies Clinical features of COVID-19-related liver damage, The laboratorys role in combating COVID-19. Subramaniam S, Jurk K, Hobohm L, Jckel S, Saffarzadeh M, Schwierczek K, Wenzel P, Langer F, Reinhardt C, Ruf W. Distinct contributions of complement factors to platelet activation and fibrin formation in venous thrombus development, Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. A new variant of COVID-19 starting to spread around the United States could be responsible for a new symptom that is unlike any weve seen with the virus so far. 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. Zeng JH, Liu YX, Yuan J, Wang FX, Wu WB, Li JX, Wang LF, Gao H, Wang Y, Dong CF, Li YJ, Xie XJ, Feng C, Liu L. First case of COVID-19 complicated with fulminant myocarditis: a case report and insights. Diao B, Wang C, Tan Y, Chen X, Liu Y, Ning L, Chen L, Li M, Liu Y, Wang G, Yuan Z, Feng Z, Zhang Y, Wu Y, Chen Y. 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. 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. Researchers Discover Mechanisms Behind Emergence of COVID Several cohort studies have observed markedly elevated levels of circulating proinflammatory cytokines and chemokines, significantly correlating to disease severity and mortality. Effect of gastrointestinal symptoms on patients infected with COVID-19. Elevations in troponin and brain natriuretic peptide were also observed in the majority of patients (44). These factors need to be observed more thoroughly to complete our clinical understanding of COVID-19. In addition to prolonged prothrombin time, studies in other cohorts have reported high prevalence of lupus anticoagulant in the circulation (13). 8600 Rockville Pike Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Theres a New Symptom the Arcturus COVID Variant May be Oudit GY, Kassiri Z, Jiang C, Liu PP, Poutanen SM, Penninger JM, Butany J. SARS-coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS, COVID-19 and the endocrine system: exploring the unexplored, Nephrotoxicity of cancer immunotherapies: past, present and future. 1) Potential mechanisms of COVID-pain (SARS-CoV-2/COVID-19-induced pain) (A) ACE2/RAS pathway and the direct virus-induced damage. Frontiers | Ginsenosides, potential TMPRSS2 inhibitors, a trade-off Kidney involvement in COVID-19 and rationale for extracorporeal therapies, Management of acute kidney injury in patients with COVID-19, Understanding SARS-CoV-2-related multisystem inflammatory syndrome in children. 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. However, whether furin-like protease-mediated cleavage is required for SARS-CoV-2 host entry has yet to be determined. SARS-CoV-2 is mostly transmissible through large respiratory droplets, directly infecting cells of the upper and lower respiratory tract, especially nasal ciliated and alveolar epithelial cells (161). Before this, TMPRSS2 has presented biological functions in cancer, but the roles remain controversial and the mechanism remains unelucidated. Diabetic ulcers (DUs) are one of the most serious complications of diabetes mellitus. Kathryn Tewson on Twitter WC,, Benoit In an endeavor to understand the pathogenic mechanisms, extensive experimental studies have been conducted across the globe involving cell culture-based Similar to other cytopathic viruses, SARS-CoV-2 infection induces cellular death and injury in airway epithelial cells through diverse processes such as pyroptosis (19, 153). Mechanisms In a case study series of 214 patients diagnosed with COVID-19, neurological symptoms were observed in 36.4% of patients, and this percentage increased to 45.5% when examining patients with severe infection (86). Both these mechanisms combine to enhance inhibition of RNA synthesis for SARS-CoV-2 more than for HCV. Direct SARS-CoV-2 infection of the renal epithelium is estimated to result in mitochondrial dysfunction, acute tubular necrosis, and protein leakage (72, 118). Impact of sex and gender on COVID-19 outcomes in Europe, Maternal and neonatal response to COVID-19. Bioinformatics analysis of potential common pathogenic mechanisms for COVID-19 infection and primary Sjogrens syndrome. Gebhard C, Regitz-Zagrosek V, Neuhauser HK, Morgan R, Klein SL. Pregnancy and perinatal outcomes of women with severe acute respiratory syndrome, Multisystem inflammatory syndrome in children and adolescents temporally related to COVID-19. For example, the activation of complement pathways can lead to initiation of the coagulation cascade (30, 127). Zhou Z, Zhao N, Shu Y, Han S, Chen B, Shu X. Previous data from the SARS epidemic suggests 35% of heart specimens showed presence of viral RNA in the myocardium. Barnes BJ, Adrover JM, Baxter-Stoltzfus A, Borczuk A, Cools-Lartigue J, Crawford JM, Daler-Plenker J, Guerci P, Huynh C, Knight JS, Loda M, Looney MR, McAllister F, Rayes R, Renaud S, Rousseau S, Salvatore S, Schwartz RE, Spicer JD, Yost CC, Weber A, Zuo Y, Egeblad M. Targeting potential drivers of COVID-19: neutrophil extracellular traps, Activation of the SARS coronavirus spike protein via sequential proteolytic cleavage at two distinct sites. 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). Frontiers From our preliminary understanding, immunomodulatory therapies are likely to be equally or more effective than solely targeting viral host cell entry. SARS-CoV-2 infection in pregnancy: a systematic review and meta-analysis of clinical features and pregnancy outcomes.