Probing the Immune System Dynamics of the COVID-19 Disease for Vaccine Designing and Drug Repurposing Using Bioinformatics Tools
Abstract
:1. Introduction
2. Viral Mutations
3. Coronavirus Adaptations
4. Diagnosis of Coronavirus
- Nucleic acid amplification test (NAAT): The most reliable and accurate methodology for the detection of SARS-CoV-2 is the nucleic acid amplification test (NAAT) [39,40]. The most popular laboratory-based NAAT is the quantitative reverse transcription-polymerase chain reaction [41,42]. The samples that are used for diagnosis include sputum, saliva, nasal, pharyngeal and tracheal swabs, broncho-alveolar lavage, pleural effusion fluid, blood, faeces and sometimes urine and semen [6].According to the World Health Organization (WHO), the detection of a single RNA sequence of coronavirus by RT-PCR is enough for the confirmation of the disease. This test is used for the real-time qualitative detection of nucleic acids from suspected viral pathogens [43]. In case of detection of SARC-CoV-2, the nucleic acid (RNA) isolated from the specific sample is first reverse transcribed into cDNA and then amplified. During the amplification process, the probe anneals to a specific target sequence located between the forward and reverse primers. During the extension phase of the PCR cycle, the 5′ nuclease activity of Taq polymerase degrades the bound probe, causing the reporter dye to separate from the quencher dye, generating a fluorescent signal. Fluorescence intensity is monitored at each PCR cycle [43]. According to the WHO, based on the first sequences of SARS-CoV-2 made available on the GISAID database on 11 January 2020, primers and probes (nCoV_IP2 and nCoV_IP4) were designed to target the RdRp gene spanning nt 12,621–12,727 and 14,010–14,116 [44]. The current test kits may lead to false-negative results because the detection of COVID-19 in the early stages of the infection is challenging due to the improper isolation of RNA or inadequate methods for detection.
- Chest computerized tomography (CT): CT scans are used for the diagnosis and imaging of viral pneumonia. It has been extensively used for the timely diagnosis and treatment of other coronavirus outbreaks caused by SARS-CoV and MERS-CoV. It is a confirmatory scan that is used to detect any false negatives as robust detection of COVID-19 is imperative for avoiding these false negatives because a CT scan can detect the infection even before the manifestation of symptoms resulting in timely treatment [39].
- Serological immunoassays: A plethora of serological immunoassays exists which detect SARS-CoV-2 viral proteins and antibodies against those proteins in the plasma or serum. The most popular biomolecules detected by commercial immunological tests such as rapid lateral flow immunoassay (LFIA) tests, automated chemiluminescence immunoassay (CLIA) and manual ELISA and other formats are IgM and IgG antibodies. The antibodies are released into the bloodstream in the second week of viral infection. IgM and IgG may be detected within 10–30 days and 20 days post-infection, respectively [40]. The IgM antibody unveils a drop in concentration, whereas IgG persists in the systemic circulation for prolonged periods and may play a role in adaptive immunity against SARS-CoV-2 in a possible second encounter. ELISA kits against nucleocapsid (NP) and spike (SP) viral proteins exist in the market but they are mainly used for rsearch and development purposes only [45]. The details of all the diagnostic techniques used for SARS-CoV-2 detection are summarized in the Table 2 below:
4.1. Molecular Targets for Diagnostic Kits
D-Dimer-Based Detection
4.2. Effect of Viral Mutations on the Accuracy of Diagnostic Tests
5. Transmission of Coronavirus
6. Mechanism of Viral Entry into the Host
7. Immunogenic Trigger in Response to Coronavirus
7.1. Hallmarks of the Immune Response to COVID-19
7.2. The Interplay between the Production of Interferons and Inflammatory Cytokines
Mechanism of Action of Interferons
7.3. Role of the Inflammasome in Causing Inflammation
7.3.1. Histopathological Markers of Inflammation
7.3.2. Role of Damage-Associated Molecular Patterns (DAMPs) Inflammation Trigger
7.4. Role of the Adaptive Immune System against COVID-19
7.5. Damage to the T-Lymphocytes Inflicted by COVID-19
7.6. Gender-Based Differences in the Immune Response against COVID-19
7.7. Contribution of Bioinformatics Tools for Designing Theranostics Approaches
7.8. Epitope Designing: The Process
7.9. Approaches for Vaccine Development
- Targeting the cellular immune system: For effective vaccine development against intracellular pathogens, the identification of protective antigens from thousands of candidates is a prerequisite. However, the relevant properties of the antigens which render protection to the endogenous pathogens against the cellular immune system are poorly characterized [138,139], delaying the process of vaccine development. Antigen abundance is an important property that can be exploited for this purpose [138,140]. The antigen expression profile varies from a few to millions of molecules per cell and the antigens which are highly expressed can be selectively tested for their immunogenicity [141,142].In one such study by Rollenhagen et al., the selective recognition of a few highly expressing antigens by CD4+ cells led to the induction of a potent immune response which was shown by the in vivo selection of abundantly expressed antigens. Therefore, the selection of such abundant antigens may facilitate the development of effective vaccines against infectious diseases such as influenza, typhoid fever, COVID-19, etc. This process can be improved by studying the transcriptomic data from viral–host interactions [138].
- Pooling of highly immunogenic epitopes: The human serum consists of a range of polyclonal antibodies that may or may not correspond to immunogenic antigens. This is because a pathogen consists of several antigenic particles/epitopes which have originated from regions of the pathogens that were genetically evolved to be less immunogenic This deceives the immune system into recognizing the non-immunogenic epitopes which undergo constant mutations. Even after having a memory of the antigens, the immune system fails on a second encounter because of the accumulation of mutations in the epitopes. Selecting such antigens will ensure that the immune system can induce the production of antibodies specific to the pathogen Therefore, pooling out the highly conserved epitopes of the virus which are seemingly non-immunogenic, and raising an antibody response against them in absence of the whole virus would enhance their immunogenicity and promise a robust immune response against the virus [90,143].
- Computational Docking: Designing vaccines can also be done by docking studies. The first step in the process of vaccine designing is the generation of crystal structures of the antigens and their respective antibodies. Once this task is accomplished, the next step is the in silico docking of both the structures in a bid to discover useful epitopes which are immunogenic.This approach was attempted by Kuntz et al. in 1982 [144]. In their study, they analyzed the binding geometries of different ligands and their respective receptors for steric overlapping by devising a docking program DOCK. This aided in identifying binding sites on the macromolecular surface. They studied the binding interactions between heme-myoglobin and thyroid hormone and pre-albumin. Since then, this field has had major reformations and is still flourishing at a rapid rate [144,145]. Some of the studies also involved the utilization of Ayurvedic plants Piper longum and Ocimum sanctum for the treatment of coronavirus by targeting ACE2 and TMPRSS2 receptor proteins [146].
- Multi-subunit-based vaccines:In a study by Dar et al., in silico studies were conducted on the spike protein of COVID-19 and multiple epitopes were identified for their ability to elicit a strong immune response. All of these epitopes were then combined via flexible GPGPG linkers along with a cholera toxin β subunit (CTB) sequence at the N-terminal joined by an EAAAK linker, as an adjuvant to form a multi-subunit vaccine candidate. This vaccine was then subjected to molecular docking studies with toll-like receptors to understand their interaction dynamics and to check for the immunogenicity of the multi-subunit vaccine against COVID-19. Quality assessment by the proSA web server showed a good match with experimentally resolved similar PDB structures. Ramachandran plot results revealed that 95% of residues were in favourable regions. Discotope and Ellipro servers revealed the competency of the vaccine in terms of possessing 27% and 52% epitopes recognized by the B-cells. The HADDOCK server showed that the binding between the protein clusters exhibited good stability and flexibility. However, there was an improvement in the HADDOCK scores when molecular refinements were applied to the docked protein complex. Moreover, the interactions between the protein clusters were also energetically favourable. Hence, in vitro studies must be performed to validate the docking results to further prove the effectiveness of the vaccine against COVID-19 [147].
8. Drug Repurposing
Targeting Viral Replication Proteins for Drug Repurposing
- (a)
- Enriching the drug candidates using glide software;
- (b)
- Evaluation of the docking hits using the MM-PBSA-WSAS method;
- (c)
- Selection of the drug candidates based on their binding energies.
9. Phage Display Techniques for Understanding the Molecular Dynamics of Viral Pathogenesis
10. Artificial Intelligence (AI) Based Vaccine Designing and Drug Repurposing against SARS-CoV-2 Virus
- Machine learning (ML): ML allows for the generation of models which analyze and learn from the available data to identify patterns and derive inferences from previously unseen data [203]. Some of the popular ML algorithms include support vector machines, random forest classifiers, k-means, hierarchical clustering, etc., and recently artificial neural networks (ANN) [204].
11. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Type of Variant | Region of Viral Mutations | Types of Mutations | References |
---|---|---|---|
α-variant | Spike protein | 60–70 del, 145 del, N501Y, A570D, D614G, P681H, T7161, S982A, D1118H | [27] |
β-variant | Spike protein | K417N, E484K and N501Y | [28] |
Epsilon variant | Spike protein | S13I, W152C and L452R | [29] |
γ-variant | Spike protein | K417T, E484K, N501Y | [30] |
Eta-variant | Spike protein | E484K ΔH69/ΔV70 deletion | [31] |
Cluster 5 | Spike protein | ΔH69/ΔV70 deletion | [32] |
S. No. | Diagnostic Method | Principle of Method | Sample | Time Duration | Detected Component | References |
---|---|---|---|---|---|---|
1. | RT-PCR | Polymerase chain reaction | Sputum, saliva, nasal, phalangeal and tracheal swabs, broncho-alveolar lavage, pleural effusion fluid, blood, faeces, urine and semen | 6–8 h | Viral RNA | [6,46,47] |
2. | PCR with fluorescently labelled probes | Polymerase chain reaction | RNA | 6–8 h | Viral RNA | [41] |
3. | Chest computerized tomography (CT) | X-ray | Chest X-ray | 30–60 min | Small nodules in the chest | [48,49,50] |
4. | Rapid lateral Flow Immunoassay (LFIA) | A liquid sample consisting of analyte transports without the help of capillary action through 3 zones of polymeric strips, upon which molecules that can interact with the analyte are attached | Throat swab or sputum | IgG | [51] | |
5. | Automated chemiluminescence immunoassay (CLIA) | Chemiluminescent methods utilizing luminophore markers | serum | IgM and IgG antibodies | [52] | |
6. | Manual ELISA | Specific antibody-antigen interactions | Saliva, serum, plasma | 5–6 h | IgG antibodies | [53,54] |
7. | Rapid antigen test | Rapid membrane-based lateral flow immunoassay | Saliva | 15–30 min | nucleocapsid protein antigen of the coronavirus SARS-CoV-2 | [55] |
8. | Detection of D-dimer levels | Coagulation | Blood | 1–2 days | D-dimer concentrations | [56] |
9. | Microbial culture test | NAAT (nucleic acid amplification test) | Nucleic acids | 2–3 days | Viral growth | [57] |
10. | Lateral flow antigen test | Immunochromatographic assay | Throat swab or sputum | 30–60 min | Nucleocapsid protein antigen | [58] |
11. | Neutralizing antibody test | Rapid membrane-based lateral flow immunoassay | Serum, throat swab or sputum | 30–60 min | Neutralizing antibodies | [59] |
Diagnostic Technique | Advantages | Disadvantages | References |
---|---|---|---|
NAAT |
|
| [68,69] |
CT scan |
|
| [70,71] |
Serological immunoassays |
|
| [72] |
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Yadav, D.; Agarwal, S.; Pancham, P.; Jindal, D.; Agarwal, V.; Dubey, P.K.; Jha, S.K.; Mani, S.; Rachana; Dey, A.; et al. Probing the Immune System Dynamics of the COVID-19 Disease for Vaccine Designing and Drug Repurposing Using Bioinformatics Tools. Immuno 2022, 2, 344-371. https://doi.org/10.3390/immuno2020022
Yadav D, Agarwal S, Pancham P, Jindal D, Agarwal V, Dubey PK, Jha SK, Mani S, Rachana, Dey A, et al. Probing the Immune System Dynamics of the COVID-19 Disease for Vaccine Designing and Drug Repurposing Using Bioinformatics Tools. Immuno. 2022; 2(2):344-371. https://doi.org/10.3390/immuno2020022
Chicago/Turabian StyleYadav, Deepshikha, Shriya Agarwal, Pranav Pancham, Divya Jindal, Vinayak Agarwal, Premshankar Kumar Dubey, Saurabh K. Jha, Shalini Mani, Rachana, Abhijit Dey, and et al. 2022. "Probing the Immune System Dynamics of the COVID-19 Disease for Vaccine Designing and Drug Repurposing Using Bioinformatics Tools" Immuno 2, no. 2: 344-371. https://doi.org/10.3390/immuno2020022