Innate immune responses to SARS-CoV-2.

This chapter provides an overview of the innate immune response to SARS-CoV-2, focusing on the recognition, activation, and evasion strategies employed by the virus. The innate immune system plays a crucial role in the early defense against viral infections, and understanding its response to SARS-CoV-2 is essential for developing effective therapeutic approaches. The chapter begins by explaining the basics of the innate immune system, including its components and salient features. It discusses the various pattern recognition receptors involved in recognizing SARS-CoV-2, such as toll-like receptors, RIG-I-like receptors, NOD-like receptors, and other cytosolic sensors. The binding and entry of the virus into host cells and subsequent activation of innate immune cells, including neutrophils, monocytes, macrophages, dendritic cells, NK cells, and ILCs, are explored. Furthermore, the secretion of key cytokines and chemokines, including type I interferons, IL-6, IL-17, and TNF-alpha, is discussed as part of the innate immune response. The concept of PANoptosis, involving programmed cell death mechanisms, is introduced as a significant aspect of the response to SARS-CoV-2. The chapter also addresses the innate immune evasion strategies employed by SARS-CoV-2, which allow the virus to evade or subvert the host immune response, contributing to viral persistence. Understanding these strategies is crucial for developing targeted therapies against the virus.

SARS-CoV-2-Virus structure and life cycle.

This book chapter presents a concise overview of SARS-CoV-2, the virus responsible for the COVID-19 pandemic. It explores viral classification based on morphology and nucleic acid composition with a focus on DNA and RNA viruses, the SARS-CoV-2 structure including the structural as well as nonstructural proteins in detail, and the viral replication mechanisms. The chapter then delves into the characteristics and diversity of coronaviruses, particularly SARS-CoV-2, highlighting its similarities with other beta-coronaviruses. The replication and transcription complex, RNA elongation, and capping, as well as the role of accessory proteins in viral replication and modulation of the host immune response is discussed extensively.

Long Covid.

Long COVID, also known as post-acute sequelae of SARS-CoV-2 infection (PASC), refers to a constellation of persistent symptoms and health issues that continue beyond the acute phase of COVID-19. This chapter provides an overview of the pathogenesis, risk factors, manifestations, major findings, and diagnosis and treatment strategies associated with Long COVID. Hypotheses regarding the pathogenesis of Long COVID are discussed, encompassing various factors such as persistent viral reservoirs, immune dysregulation with or without reactivation of herpesviruses (e.g., Epstein-Barr Virus and human herpesvirus), dysbiosis, autoimmunity triggered by infection, endothelial dysfunction, microvessel blood clotting, and dysfunctional brainstem and/or vagal signaling. The chapter also highlights the risk factors associated with Long COVID and its occurrence in children. The major findings of Long COVID, including immune dysregulation, vessel and tissue damage, neurological and cognitive pathology, eye symptoms, endocrinal issues, myalgic encephalomyelitis and chronic fatigue syndrome, reproductive system involvement, respiratory and gastrointestinal symptoms, and the chronology of symptoms, are thoroughly explored. Lastly, the chapter discusses the challenges and current approaches in the diagnosis and treatment of Long COVID, emphasizing the need for multidisciplinary care and individualized management strategies.

Epidemiology of COVID-19.

This chapter provides a detailed exploration of the epidemiology of COVID-19, focusing on several key aspects that offer valuable insights into the disease progression. A comprehensive comparison is made between the three related coronaviruses: SARS-CoV, MERS-CoV, and SARS-CoV-2, elucidating their similarities and differences in terms of transmission dynamics, clinical presentation, laboratory and radiological findings, infection mechanisms, and mortality rates. The concept of herd immunity is then discussed, exploring its relevance and potential implications for controlling the spread of COVID-19. Next, the chapter delves into the changing epidemiology of the disease, examining how various factors such as human behavior, public health interventions, and viral mutations have influenced its transmission patterns and severity over time. Finally, the timelines and evolution of COVID-19 are outlined, tracing the origins of the virus, its rapid global spread, and the emergence of new variants.

Structural biology of SARS-CoV-2.

This chapter provides a comprehensive overview of the techniques employed to unravel the structural biology of SARS-CoV-2, facilitating a deeper understanding of the virus for developing future therapeutic strategies. Various techniques such as Electron microscopy (EM) for capturing high-resolution images of the virus and X-ray crystallography used for determining atomic-level structures of viral proteins are discussed. Cryo-electron microscopy (cryo-EM) imaging is also examined as a powerful tool for visualizing the virus's structure in its native state. Intracellular detection and tracking of SARS-CoV-2 are discussed, highlighting the techniques employed to study the virus's behavior within host cells. The chapter further explores how cryo-EM has been instrumental in delivering high-quality structural information on SARS-CoV-2, enabling researchers to better understand its mechanisms of infection and replication. The structural visualization of SARS-CoV-2 is then presented, focusing on key components such as the spike protein structure, RNA polymerase structure, and the visualization of intact and in-situ virions using cryo-electron tomography (cryo-ET). Lastly, the chapter touches upon the application of nuclear magnetic resonance (NMR) spectroscopy for studying the dynamics and interactions of viral proteins.

SARS-CoV-2 variant biology and immune evasion.

This chapter discusses the SARS-CoV-2 variants and their immune evasion strategies, shedding light on the dynamic nature of the COVID-19 pandemic. The ecological dynamics and viral evolution of SARS-CoV-2 are explored, considering carriers of infection, individual immunity profiles, and human movement as key factors in the emergence and dissemination of variants. The chapter discusses SARS-CoV-2 mutation, including mutation rate, substitution rate, and recombination, influencing genetic diversity and evolution. Transmission bottlenecks are highlighted as determinants of dominant variants during viral spread. The evolution phases of the pandemic are outlined, from limited early evolution to the emergence of notable changes like the D614G substitution and variants with heavy mutations. Variants of Concern (VOCs), including Alpha, Beta, Gamma, and the recent Omicron variant, are examined, with insights into inter-lineage and intra-lineage dynamics. The origin of VOCs and the Omicron variant is explored, alongside the role of the furin cleavage site (FCS) in variant emergence. The impact of structural and non-structural proteins on viral infectivity is assessed, as well as innate immunity evasion strategies employed by SARS-CoV-2 variants. The chapter concludes by considering future possibilities, including ongoing virus evolution, the need for surveillance, vaccine development, and public health measures.

B cell responses to SARS-CoV-2.

This chapter provides an overview of B cell responses in COVID-19, highlighting the structure of SARS-CoV-2 and its impact on B cell immunity. It explores the production and maturation of SARS-CoV-2-specific B cells, with a focus on the two distinct phases of the humoral immune response: the extrafollicular (EF) phase and the germinal center (GC) phase. Furthermore, the interplay between B cells, follicular T helper cells, CD4+ T cells, and plasma cells is discussed, emphasizing their collaborative role in mounting an effective humoral immune response against SARS-CoV-2. The concept of immunological memory is explored, highlighting the roles of plasma cells and B memory cells in providing long-term protection. The chapter delves into the antibody response during SARS-CoV-2 infection, categorizing the types of antibodies generated. This includes a detailed analysis of neutralizing antibodies, such as those directed against the receptor-binding domain (RBD) and the N-terminal domain (NTD), as well as non-neutralizing antibodies. The role of mucosal antibodies, cross-reactive antibodies, and auto-reactive antibodies is also discussed. Factors influencing the dynamics of anti-SARS-CoV-2 antibodies are examined, including the duration and strength of the humoral response. Additionally, the chapter highlights the impact of the Omicron variant on humoral immune responses and its implications for vaccine efficacy and antibody-mediated protection.

Future insights.

This chapter explores two significant aspects of the ongoing COVID-19 pandemic: the realistic prediction of its end and the status of long-term COVID in 2023. While the World Health Organization (WHO) declared an end to COVID-19 as a public health emergency, the possibility of future waves caused by variants remains. Widespread vaccination and prior infections provide substantial protection, but the virus is expected to persist, necessitating continued monitoring and potential reimplementation of control measures. Long-term COVID, characterized by persistent or new symptoms after the acute phase, remains a concern. Recent findings suggest a reduced risk of prolonged COVID with initial Omicron variants. However, targeted treatments are lacking, and current approaches rely on symptomatic and supportive care. Psychological support and multidisciplinary interventions are essential. Comprehensive studies, standardized criteria, and international registries are needed to advance research and develop effective therapies. Understanding these uncertainties will guide us towards effectively managing the pandemic and providing optimal care for long COVID patients.

COVID-19 pathogenesis.

The pathogenesis of COVID-19 involves a complex interplay between host factors and the SARS-CoV-2 virus, leading to a multitude of clinical manifestations beyond the respiratory system. This chapter provides an overview of the risk factors, genetic predisposition, and multisystem manifestations of COVID-19, shedding light on the underlying mechanisms that contribute to extrapulmonary manifestations. The chapter discusses the direct invasion of SARS-CoV-2 into various organs as well as the indirect mechanisms such as dysregulation of the renin-angiotensin-aldosterone system (RAAS), immune response dysfunctions within the innate and adaptive immune systems, endothelial damage, and immunothrombosis. Furthermore, the multisystem manifestations of COVID-19 across different organ systems, including the cardiovascular, renal, gastrointestinal, hepatobiliary, nervous, endocrine and metabolic, ophthalmic, ear-nose-throat, reproductive, hematopoietic, and immune systems are discussed in detail. Each system exhibits unique manifestations that contribute to the complexity of the disease.

Coexistence of proboscis lateralis and multiple craniofacial, neurological, cardiac and spinal deformities: a one-of-a-kind case report.

BACKGROUND: Proboscis lateralis (PL) is an uncommon congenital facial deformity marked by the protrusion of a primitive tubular structure made up of skin and soft tissue that generally emerges from the eye's medial canthus and is associated with some craniofacial deformities. We report the first case of PL with multiple craniofacial, neurological, cardiac, and spinal anomalies. CASE PRESENTATION: A full-term female baby delivered by cesarean section cried immediately at birth. The mother reported having a normal pregnancy but has a history of x-ray during her first trimester. The baby was born with a rare presentation of proboscis lateralis which was accompanied by multiple anomalies, including but not limited to bilateral colpocephaly, corpus callosum agenesis, complex cyanotic congenital heart disease, and hemivertebra of the T10 body. CONCLUSION: PL is an uncommon congenital condition that causes a variety of craniofacial abnormalities. Multiple additional defects affecting various organ systems should also be evaluated in a person diagnosed with PL.

The mechanisms of action of ivermectin against SARS-CoV-2-an extensive review.

Considering the urgency of the ongoing COVID-19 pandemic, detection of new mutant strains and potential re-emergence of novel coronaviruses, repurposing of drugs such as ivermectin could be worthy of attention. This review article aims to discuss the probable mechanisms of action of ivermectin against SARS-CoV-2 by summarizing the available literature over the years. A schematic of the key cellular and biomolecular interactions between ivermectin, host cell, and SARS-CoV-2 in COVID-19 pathogenesis and prevention of complications has been proposed.

Longitudinal observation of antibody responses for 14 months after SARS-CoV-2 infection.

Better understanding of antibody responses against SARS-CoV-2 after natural infection might provide valuable insights into the future implementation of vaccination policies. Longitudinal analysis of IgG antibody titers was carried out in 32 recovered COVID-19 patients based in the Umbria region of Italy for 14 months after Mild and Moderately-Severe infection.Two FDA-approved immunoassays against SARS-CoV-2 Nucleocapsid protein (NCP) and anti-spike-receptor binding domain (S-RBD) were used for sequential serological tests at different time points. The demographics,clinical history and symptom profile associated with the magnitude and longevity of antibody responses were also analyzed. Anti-S-RBD IgG persisted in 96.8% (31 of 32) subjects at 14 months. Patients reporting loss of smell and taste during the clinical course of the disease developed significantly higher antibody titers. Anti-NCP IgG seronegative patients(n=7) at 10 months, tested positive for anti-S-RBD IgG at 12,13 and 14 months emphasizing on a higher false-negative rate for NCP protein-based antibody assays. This study also highlights the importance of adopting specific immunoassays for routine estimation of antibody titers and the decreased rate of re-infections in recovered patients.

A Comprehensive Analysis of Benign Vocal Fold Lesions Causing Hoarseness of Voice and Our Experience with Cold Knife Endolaryngeal Surgery in a Tertiary Healthcare Centre.

Benign vocal fold lesions (BVFL) frequently affect the general population and cause significant hoarseness by interfering with daily communication. Healthcare for low income groups in India is all about affordability and availability without giving up on quality and providing maximum satisfaction. (1) To analyse over a period of 4 years, the demographics, clinical profile, diagnostics and management options of BVFL. (2) To assess the diagnostic potential of rigid laryngoscopy in diagnosing these lesions. (3) Cold knife endolaryngeal surgery as a cost effective, satisfactory and efficient treatment modality to tackle majority of these BVFL. A prospective cross sectional study over a period of 4 years from 2013 to 2017. 114 patients presenting with hoarseness of voice were evaluated by indirect laryngoscopy followed by video laryngoscopy and stroboscopy in the department of ENT, MYH Hospital Indore (M.P.). Male:female ratio of 1.59:1 with male predominance (61.4%) and maximum incidence in the third decade (32%). All cases presented with hoarseness (100%) while vocal fatigue (63%) was the most common associated complaint followed by foreign body sensation (60%). Housewives (32%) were most commonly involved non professional group while teachers (13%) constituted the most common group of professionals. Laryngitis (26%) involving bilateral vocal folds diffusely was the most common finding followed by vocal fold sulcus (18%) and vocal fold cysts (14%). The duration of symptom was 6 months to 1 year in 52% patients. The positive predictive value for rigid laryngoscopy was 100% for vocal nodules, arytenoid granulomas and anterior glottis web. Out of 114 patients, 66 patients improved on conservative management while 48 patients underwent cold knife endolaryngeal surgery. As per the GRBAS scale to assess the post therapeutic prognosis, all had good outcome of voice with only two recurrences due to patient non compliance. In this rapidly evolving era of sophisticated lasers which is a costly affair that requires skilled personnel and safety precautions, the prime goal in a government run setup has always been to provide affordable and quality healthcare to the common man. Cold knife endolaryngeal surgery is a simple, cost effective and efficient way to tackle most of these lesions and hence helps in achieving this goal.