Exploring the Immunomodulatory Aspect of Mesenchymal Stem Cells for Treatment of Severe Coronavirus Disease 19.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is an enveloped, positive sense, single stranded RNA (+ssRNA) virus, belonging to the genus Betacoronavirus and family Coronaviridae. It is primarily transmitted from infected persons to healthy ones through inhalation of virus-laden respiratory droplets. After an average incubation period of 2-14 days, the majority of infected individuals remain asymptomatic and/or mildly symptomatic, whereas the remaining individuals manifest a myriad of clinical symptoms, including fever, sore throat, dry cough, fatigue, chest pain, and breathlessness. SARS-CoV-2 exploits the angiotensin converting enzyme 2 (ACE-2) receptor for cellular invasion, and lungs are amongst the most adversely affected organs in the body. Thereupon, immune responses are elicited, which may devolve into a cytokine storm characterized by enhanced secretion of multitude of inflammatory cytokines/chemokines and growth factors, such as interleukin (IL)-2, IL-6, IL-7, IL-8, IL-9, tumor necrosis factor alpha (TNF-α), granulocyte colony-stimulating factor (GCSF), basic fibroblast growth factor 2 (bFGF2), monocyte chemotactic protein-1 (MCP1), interferon-inducible protein 10 (IP10), macrophage inflammatory protein 1A (MIP1A), platelet-derived growth factor subunit B (PDGFB), and vascular endothelial factor (VEGF)-A. The systemic persistence of inflammatory molecules causes widespread histological injury, leading to functional deterioration of the infected organ(s). Although multiple treatment modalities with varying effectiveness are being employed, nevertheless, there is no curative COVID-19 therapy available to date. In this regard, one plausible supportive therapeutic modality may involve administration of mesenchymal stem cells (MSCs) and/or MSC-derived bioactive factors-based secretome to critically ill COVID-19 patients with the intention of accomplishing better clinical outcome owing to their empirically established beneficial effects. MSCs are well established adult stem cells (ASCs) with respect to their immunomodulatory, anti-inflammatory, anti-oxidative, anti-apoptotic, pro-angiogenic, and pro-regenerative properties. The immunomodulatory capabilities of MSCs are not constitutive but rather are highly dependent on a holistic niche. Following intravenous infusion, MSCs are known to undergo considerable histological trapping in the lungs and, therefore, become well positioned to directly engage with lung infiltrating immune cells, and thereby mitigate excessive inflammation and reverse/regenerate damaged alveolar epithelial cells and associated tissue post SARS-CoV-2 infection. Considering the myriad of abovementioned biologically beneficial properties and emerging translational insights, MSCs may be used as potential supportive therapy to counteract cytokine storms and reduce disease severity, thereby facilitating speedy recovery and health restoration.

Insights into COVID-19 Vaccine Development Based on Immunogenic Structural Proteins of SARS-CoV-2, Host Immune Responses, and Herd Immunity.

The first quarter of the 21st century has remarkably been characterized by a multitude of challenges confronting human society as a whole in terms of several outbreaks of infectious viral diseases, such as the 2003 severe acute respiratory syndrome (SARS), China; the 2009 influenza H1N1, Mexico; the 2012 Middle East respiratory syndrome (MERS), Saudi Arabia; and the ongoing coronavirus disease 19 (COVID-19), China. COVID-19, caused by SARS-CoV-2, reportedly broke out in December 2019, Wuhan, the capital of China's Hubei province, and continues unabated, leading to considerable devastation and death worldwide. The most common target organ of SARS-CoV-2 is the lungs, especially the bronchial and alveolar epithelial cells, culminating in acute respiratory distress syndrome (ARDS) in severe patients. Nevertheless, other tissues and organs are also known to be critically affected following infection, thereby complicating the overall aetiology and prognosis. Excluding H1N1, the SARS-CoV (also referred as SARS-CoV-1), MERS, and SARS-CoV-2 are collectively referred to as coronaviruses, and taxonomically placed under the realm Riboviria, order Nidovirales, suborder Cornidovirineae, family Coronaviridae, subfamily Orthocoronavirinae, genus Betacoronavirus, and subgenus Sarbecovirus. As of 23 September 2021, the ongoing SARS-CoV-2 pandemic has globally resulted in around 229 million and 4.7 million reported infections and deaths, respectively, apart from causing huge psychosomatic debilitation, academic loss, and deep economic recession. Such an unprecedented pandemic has compelled researchers, especially epidemiologists and immunologists, to search for SARS-CoV-2-associated potential immunogenic molecules to develop a vaccine as an immediate prophylactic measure. Amongst multiple structural and non-structural proteins, the homotrimeric spike (S) glycoprotein has been empirically found as the most suitable candidate for vaccine development owing to its immense immunogenic potential, which makes it capable of eliciting both humoral and cell-mediated immune responses. As a consequence, it has become possible to design appropriate, safe, and effective vaccines, apart from related therapeutic agents, to reduce both morbidity and mortality. As of 23 September 2021, four vaccines, namely, Comirnaty, COVID-19 vaccine Janssen, Spikevax, and Vaxzevria, have received the European Medicines Agency's (EMA) approval, and around thirty are under the phase three clinical trial with emergency authorization by the vaccine-developing country-specific National Regulatory Authority (NRA). In addition, 100-150 vaccines are under various phases of pre-clinical and clinical trials. The mainstay of global vaccination is to introduce herd immunity, which would protect the majority of the population, including immunocompromised individuals, from infection and disease. Here, we primarily discuss category-wise vaccine development, their respective advantages and disadvantages, associated efficiency and potential safety aspects, antigenicity of SARS-CoV-2 structural proteins and immune responses to them along with the emergence of SARS-CoV-2 VOC, and the urgent need of achieving herd immunity to contain the pandemic.

Host Cell and SARS-CoV-2-Associated Molecular Structures and Factors as Potential Therapeutic Targets.

Coronavirus disease 19 (COVID-19) is caused by an enveloped, positive-sense, single-stranded RNA virus, referred to as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which belongs to the realm Riboviria, order Nidovirales, family Coronaviridae, genus Betacoronavirus and the species Severe acute respiratory syndrome-related coronavirus. This viral disease is characterized by a myriad of varying symptoms, such as pyrexia, cough, hemoptysis, dyspnoea, diarrhea, muscle soreness, dysosmia, lymphopenia and dysgeusia amongst others. The virus mainly infects humans, various other mammals, avian species and some other companion livestock. SARS-CoV-2 cellular entry is primarily accomplished by molecular interaction between the virus's spike (S) protein and the host cell surface receptor, angiotensin-converting enzyme 2 (ACE2), although other host cell-associated receptors/factors, such as neuropilin 1 (NRP-1) and neuropilin 2 (NRP-2), C-type lectin receptors (CLRs), as well as proteases such as TMPRSS2 (transmembrane serine protease 2) and furin, might also play a crucial role in infection, tropism, pathogenesis and clinical outcome. Furthermore, several structural and non-structural proteins of the virus themselves are very critical in determining the clinical outcome following infection. Considering such critical role(s) of the abovementioned host cell receptors, associated proteases/factors and virus structural/non-structural proteins (NSPs), it may be quite prudent to therapeutically target them through a multipronged clinical regimen to combat the disease.