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Source: COVID-19 News  Dec 05, 2020  1 year ago
COVID-19 News: Scientist Identify Antibody nCoV396 That Halts SARS-CoV-2 Nucleocapsid Protein Induced Complement Hyperactivation
COVID-19 News: Scientist Identify Antibody nCoV396 That Halts SARS-CoV-2 Nucleocapsid Protein Induced Complement Hyperactivation
Source: COVID-19 News  Dec 05, 2020  1 year ago
COVID-19 News: Researchers from Sun Yat-Sen University campuses in both Shenzhen and Zhuhai, China have in a new study identified an antibody called nCoV396 that is able to halt the SARS-CoV-2 nucleocapsid protein induced complement hyperactivation that often leads to increased morbidity and mortality in COVID-19 patients.
In the abstract of the study, the researchers said that although human antibodies elicited by the SARS-CoV-2 nucleocapsid (N) protein are profoundly boosted upon infection, little is known about the function of N- reactive antibodies.



In this study, the team led by Professor Dr Sisi Kang from the Molecular Imaging Center, Guangdong Provincial Key Laboratory of Biomedical Imaging, Sun Yat-sen University, Zhuhai-China, isolated and profiled a panel of 32 N protein-specific monoclonal antibodies (mAbs) from a quick recovery COVID-19 convalescent patient who had dominant antibody responses to the SARS-CoV-2 N protein rather than to the SARS- CoV-2 spike (S) protein.
 
The complex structure of the N protein RNA binding domain with the mAb with the highest binding affinity (nCoV396) revealed changes in the epitopes and antigen’s allosteric regulation. Functionally, a virus-free complement hyperactivation analysis demonstrated that nCoV396 specifically compromises the N protein- induced complement hyperactivation, which is a risk factor for the morbidity and mortality of COVID-19 patients, thus laying the foundation for the identification of functional anti-N protein mAbs.
 
The study findings were published on a preprint server and currently being peer-reviewed for publication into the journal: Nature Research. https://www.researchsquare.com/article/rs-106760/v1
 
The fatality rate of critical conditions of COVID-19) patients is exceptionally high (40% - 49%) https://pubmed.ncbi.nlm.nih.gov/32648899/
 
Acute respiratory failure and generalized coagulopathy are significant aspects associated with morbidity and mortality. A subset of severe COVID-19 patients has distinct clinical features compared to classic acute respiratory distress syndrome (ARDS), with delayed onset of respiratory distress and relatively well-preserved lung mechanics despite the severity of hypoxemia. It has been reported that complement-mediated thrombotic microvascular injury in the lung may contribute to atypical ARDS features of COVID-19, accompanied by extensive deposition of the alternative pathway (AP) and lectin pathway (LP) complement components. https://pubmed.ncbi.nlm.nih.gov/32299776/
 
Complement activation is found in multiple organs of severe COVID-19 patients in several other studies, as well as in patients with severe acute respiratory syndrome (SARS). https://pubmed.ncbi.nlm.nih.gov/32417135/
 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246017/
 
A past retrospective observational study of 11,116 patients revealed that complement disorder was associated with the morbidity and mortality of COVID-19.The nucl eocapsid (N) protein of SARS-CoV-2, the etiology agent of COVID-19, is one of the most abundant viral structural proteins with multiple functions inside the viral particles, the host cellular environment, and in ex vivo experiment . https://pubmed.ncbi.nlm.nih.gov/32747830/
 
A recent preprint study found that the SARS-CoV-2 N protein bound to MBL (mannan-binding lectin)-associated serine protease 2 (MASP-2) and resulted in complement hyperactivation and aggravated inflammatory lung injury. https://www.medrxiv.org/content/10.1101/2020.03.29.20041962v3
 
Also the highly pathogenic SARS-CoV N protein was also found to bind with MAP19, an alternative product of MASP-2. https://covid19.elsevierpure.com/da/publications/study-on-interaction-between-sars-cov-n-and-map19
 
Though systemic activation of complement plays a pivotal role in protective immunity against pathogens, hyperactivation of complement may lead to collateral tissue injury. Thus, how to precisely regulate virus-induced dysfunctional complement activation in COVID-19 patients remains to be elucidated. The SARS-CoV-2 N protein is a highly immunopathogenic viral protein that elicits high titers of binding antibodies in humoral immune responses. https://pubmed.ncbi.nlm.nih.gov/32571838/

Numerous studies have reported the isolation of human monoclonal antibodies (mAbs) targeting the SARS-CoV-2 spike (S) protein, helping explain the possible developing therapeutic interventions for COVID-1 . However, little is known about the potential therapeutic applications of N protein-targeting mAbs in the convalescent B cell repertoire.
 
In this study the team reports that human mAb derived from the COVID-19 convalescent patient that specifically targets the SARS-CoV-2 N protein and functionally compromises complement hyperactivation ex vivo.
 
The study team isolated 32 mAbs specifically targeting the SARS-CoV-2 N protein from a quickly recovered COVID-19 patient. The binding affinity of mAbs ranged from 1 nM to 25 nM, which is comparable with the binding affinity of mature S protein reactive antibodies and the other mature antibodies identified during acute infections.
 
The key characteristics of the isolated N-reactive mAbs are different from those of the isolated S-reactive mAbs in COVID-19 patients during the early recovery phase, suggesting that sampling time is pivotal for identifying differential immune responses to different SARS-CoV-2 viral proteins. The crystal structure of nCoV396 bound to SARS-CoV-2 N-NTD elucidates the interaction mechanism of the complex between the first reported N protein- reactive human mAb and its targeted N protein.
 
Importantly three conserved amino acids (Q163, L167, and K169) in the N protein are responsible for nCoV396 recognition, which provides evidence of cross-reactivity of nCoV396 to the N protein of SARS-CoV or MERS-CoV.
 
Interestingly, the nCoV396 binding of SARS-CoV-2 N-NTD undergoes several conformational changes, resulting in an enlargement of the N-NTD RNA binding pocket enlargement and partial unfolding of the basic palm region.
 
More significantly, this conformational change occurs in the CT tail of the N-NTD, which may alter the positioning of individual domains in the context of the full-length protein and lead to a potential allosteric effect for protein functions. Complement is one of the first lines of defense in innate immunity and is essential for cellular integrity and tissue homeostasis and for modifying the adaptive immune response. https://pubmed.ncbi.nlm.nih.gov/19730437/
 
Emerging evidence suggests that the complement system plays a vital role in a subset of critical COVID-19 patients, with features of atypical acute respiratory distress syndrome, disseminated intravascular coagulation, and multiple organ failure. https://pubmed.ncbi.nlm.nih.gov/32699160/
 
A few pieces of evidence show that the N protein of highly pathogenic coronaviruses (SARS-CoV-2 and SARS-CoV) is involved in the initiation of MASP-2-dependent complement activation. Encouragingly, critical COVID-19 patients treated with complement inhibitors, including small molecules to the complement component C3 and an antibody targeting the complement component C5, show remarkable therapeutic outcome. https://www.medrxiv.org/content/10.1101/2020.03.29.20041962v3
 
Presently, there are 11 clinical trials related to targeting the complement pathway. To avoid adverse effects of human complement component-targeting therapy, a viral protein-specific approach is warranted. The antibody nCoV396 isolated from COVID-19 convalescent patients is an excellent potential candidate with a high binding affinity to the N protein and high potency to inhibit complement hyperactivation. As revealed by atomic structural information, the binding may allosterically change the full-length N protein conformation.
 
In order to determine the role of nCoV396 318 in the suppression of complement hyperactivation, the study team monitored MASP-2 protease activity based on its specific fluorescence-quenched C2 substrate in sera from autoimmune disease patients. The complete complement components in the sera of patients with autoimmune disorders allow the researchers to monitor the activating effects of the SARS-CoV-2 N protein and its specific mAbs.
 
Though the team cannot calculate the other steady-state enzymatic reaction constants as the precise concentration of MASP-2 in serum is unknown, they identified the Vmax of the specific C2 substrate for the enzymatic reaction.
 
The study team demonstrated that the SARS-CoV-2 N protein elevated the Vmax of the reaction, up to 40-fold, in the sera of all 7 individuals tested, while nCoV396 effectively suppressed the Vmax of the reaction mixtures.
 
The study findings indicated that serum-based complement activation analysis of autoimmune disease patients is a virus-free and an effective method for examining complement activation mediated by the SARS-CoV-2 N protein.
 
Despite the precise interaction of the SARS-CoV-2 N protein with MASP-2remains to be elucidated, the study defined the region on the SARS-CoV-2 N protein recognized by the mAb nCoV396 that plays an important role in complement hyperactivation and indicates that human mAbs from convalescents could be a promising potential therapeutic candidate for the treatment of COVID- 19 but further research is warranted.
 
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