The consistent observation of high IL-6 levels in CSS patients suggests that this cytokine is a key mediator of CSS, although the mechanisms of such action have not yet been fully elucidated [112]. IL-6 is known to be essential for the adaptive immune response in which T cells and B cells are recruited to the infected site. There are two main pathways of IL-6 signaling transduction, referred to as classic cis or trans signaling. In classic cis signaling, IL-6 and gp130 form a complex with membrane-bound IL-6 receptor (mIL-6R), while in the trans pathway, they bind to the soluble form of IL-6 receptor (sIL-6R). In either case, the IL-6 receptor (IL-6R) signaling complex activates intercellular signaling involved in a wide range of biological functions, such as immune regulation through downstream JAK-STAT3 signaling [113]. Importantly, elevated IL-6 level has been tightly associated with ARDS and high mortality of COVID-19 patients; therefore, IL-6 is thought to be a promising therapeutic target to reduce hyper inflammation and prevent the high mortalities of COVID-19 [112, 114,115,116]. According to the key role of IL-6 in CSS, several mAb drugs have been considered for the treatment of severe COVID-19, including sarilumab (Kevzara), tocilizumab (Actemra) and levilimab, which target IL-6R, as well as clazakizumab, siltuximab and olokizumab, which target IL-6 [19, 20, 117, 118].
Cb Sachdeva Class 12 Pdf 60
Download Zip: https://cinurl.com/2vCZ3k
In addition to GM-CSF, the complement system may be a valuable target for COVID-19 therapy, as it is an integral component of the innate immune response to virus infection. Complement signaling comprises three known axes, including the classical complement, alternative complement, and lectin pathways. All three pathways converge on the main component C3 of the complement pathway and result in the production of proinflammatory anaphylatoxins, C3a and C5a, and the formation of the terminal membrane attack complex (MAC) [142]. Patients with severe COVID-19 showed complement activation and high concentrations of C5a and MAC, suggesting that dysregulation of the complement pathway may participate in CSS and severe COVID-19 complications [143,144,145,146,147]. Notably, mechanistic studies showed the S or nucleocapsid protein of SARS-CoV-2 can activate the complement pathway [148, 149]. Based on the apparent involvement of complement in COVID-19, clinical studies have been initiated for several Abs, including avdoralimab, eculizumab, and vilobelimab (Table 3). Eculizumab is a humanized mAb with a high affinity to C5 that inhibits the generation of C5a and C5b proteins and prevents the formation of the inflammatory anaphylatoxin and the MAC [150]. In addition, avdoralimab and vilobelimab are mAbs targeting C5aR or C5a that prevent binding of C5a to C5aR and block the formation of the inflammatory anaphylatoxin associated with pulmonary pathology of ARDS in COVID-19 [145, 151]. Conceivably, these therapeutic antibodies could be effective treatments for severe COVID-19 with CSS.
Using our classification system, the third group of nAbs may be effectively used in therapeutic combinations with Abs from the first or second groups. However, structural analyses predicting whether nAbs have overlapping epitopes showed that S protein has a dynamic nature, with movement of the NTD, RBD, S2 domain, and the stalk domain in different conformations. Thus, it may be insufficient to only examine Ab-RBD structures or even static images of the S trimer; one must also consider and test for possible simultaneous engagement of nAbs on S proteins with different combinations of up and down RBDs [184, 197]. With these data, researchers may sufficiently understand the SARS-CoV-2 S protein-Ab complexes and proceed to develop novel therapeutic measures against SARS-CoV-2.
SARS-CoV-2 spike mutations. a Top 200 identified SARS-CoV-2 spike mutations. Each dot indicates an amino acid mutation in the S protein. The colors indicate different domains of the SARS-CoV-2 spike protein; NTD N-terminal domain, RBD receptor-binding domain, RBM receptor-binding motif, CTD C-terminal domain, S2 subdomain 2, FP fusion peptide, TM transmembrane region. The altered amino acids of the top 20 SARS-CoV-2 spike mutations are shown as indicated. The data from 4,450,473 sequences were collected from GISAID and COVID CG (updated to 2021-11-22). b Nonsynonymous mutation positions in spike protein of newly emerged SARS-CoV-2 variants. The B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), B.1.617.2 (Delta) and B.1.1.529 (Omicron) variants are classified as variants of concern by WHO. The percentage of India B.1.617.2 (Delta) variant includes B.1.617.2 and its all AY sub-lineages. c Confirmed COVID-19 cases comprising SARS-CoV-2 variants. The data from 4,337,516 sequences were collected from GISAID and COVID CG (from 2020-12-01 to 2021-11-30) and grouped by lineage
2ff7e9595c
Comments