An Impaired Inflammatory and Innate Immune Response in COVID-19

The recent appearance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected millions of people around the world and caused a global pandemic of coronavirus disease 2019 (COVID-19). It has been suggested that uncontrolled, exaggerated inflammation contributes to the adverse outcomes of COVID-19. In this review, we summarize our current understanding of the innate immune response elicited by SARS-CoV-2 infection and the hyperinflammation that contributes to disease severity and death. We also discuss the immunological determinants behind COVID-19 severity and propose a rationale for the underlying mechanisms.     

Humoral Immunity against SARS-CoV-2 and the Impact on COVID-19 Pathogenesis

It has been more than a year since severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first emerged. Many studies have provided insights into the various aspects of the immune response in coronavirus disease 2019 (COVID-19). Especially for antibody treatment and vaccine development, humoral immunity to SARS-CoV-2 has been studied extensively, though there is still much that is unknown and controversial. Here, we introduce key discoveries on the humoral immune responses in COVID-19, including the immune dynamics of antibody responses and correlations with disease severity, neutralizing antibodies and their cross-reactivity, how long the antibody and memory B-cell responses last, aberrant autoreactive antibodies generated in COVID-19 patients, and the efficacy of currently available therapeutic antibodies and vaccines against circulating SARS-CoV-2 variants, and highlight gaps in the current knowledge.     

Immunological aspects of COVID-19: What do we know?

The newly emerged coronavirus (severe acute respiratory syndrome coronavirus 2 SARS-CoV-2) and the disease that it causes coronavirus disease 2019 (COVID-19) have changed the world we know. Yet, the origin and evolution of SARS-CoV-2 remain mostly vague. Many virulence factors and immune mechanisms contribute to the deteriorating effects on the organism during SARS-CoV-2 infection. Both humoral and cellular immune responses are involved in the pathophysiology of the disease, where the principal and effective immune response towards viral infection is the cell-mediated immunity. The clinical picture of COVID-19, which includes immune memory and reinfection, remains unclear and unpredictable. However, many hopes are put in developing an effective vaccine against the virus, and different therapeutic options have been implemented to find effective, even though not specific, treatment to the disease. We can assume that the interaction between the SARS-CoV-2 virus and the individual's immune system determines the onset and development of the disease significantly.     

SARS-CoV-2 cell receptor gene ACE2 -mediated immunomodulation in breast cancer subtypes

The recent outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has impacted the world severely. The binding of the SARS-CoV-2 virus to the angiotensin-converting enzyme 2 (ACE2) and its intake by the host cell is a necessary step for infection. ACE2 has garnered widespread therapeutic possibility as it is entry/interactive point for SARS-CoV-2, responsible for coronavirus disease 2019 (COVID-19) pandemic and providing a critical regulator for immune modulation in various disease. Patients with suffering from cancer always being on the verge of being immune compromised therefore gaining knowledge about how SARS-CoV-2 viruses affecting immune cells in human cancers will provides us new opportunities for preventing or treating virus-associated cancers. Despite COVID-19 pandemic got center stage at present time, however very little research being explores, which increase our knowledge in context with how SARS-CoV-2 infection affect cancer a cellular level. Therefore, in light of the ACE-2 as an important contributor of COVID-19 global, we analyzed correlation between ACE2 and tumor immune infiltration (TIL) level and the type markers of immune cells were investigated in breast cancer subtypes by using TIMER database. Our findings shed light on the immunomodulatory role of ACE2 in the luminal A subtype which may play crucial role in imparting therapeutic resistance in this cancer subtype.     

Human Organoids as a Promising Platform for Fighting COVID-19

The coronavirus disease 2019 (COVID-19) global pandemic evoked by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has triggered a major public health problem with significant morbidity and mortality. Understanding the pathogenesis and molecular mechanisms underlying this novel virus is crucial for both fundamental research and clinical trials in order to devise effective therapies and vaccination regimens. Basic research on SARS-CoV-2 largely depends on ex vivo models that allow viral invasion and replication. Organoid models are now emerging as a valuable tool to investigate viral biology and disease progression, serving as an efficient platform to investigate potential therapies for COVID-19. Here, we summarize various human stem cell-derived organoid types employed in SARS-CoV-2 studies. We highlight key findings from these models, including cell tropisms and molecular mechanisms in viral infection. We also describe their use in identifying potential therapeutic agents against SARS-CoV-2. As more and more advanced organoids emerge, they will facilitate the understanding of disease pathogenesis for drug development in this dreaded pandemic.     

COVID-19: systemic pathology and its implications for therapy

Responding to the coronavirus disease 2019 (COVID-19) pandemic has been an unexpected and unprecedented global challenge for humanity in this century. During this crisis, specialists from the laboratories and frontline clinical personnel have made great efforts to prevent and treat COVID-19 by revealing the molecular biological characteristics and epidemic characteristics of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Currently, SARS-CoV-2 has severe consequences for public health, including human respiratory system, immune system, blood circulation system, nervous system, motor system, urinary system, reproductive system and digestive system. In the review, we summarize the physiological and pathological damage of SARS-CoV-2 to these systems and its molecular mechanisms followed by clinical manifestation. Concurrently, the prevention and treatment strategies of COVID-19 will be discussed in preclinical and clinical studies. With constantly unfolding and expanding scientific understanding about COVID-19, the updated information can help applied researchers understand the disease to build potential antiviral drugs or vaccines, and formulate creative therapeutic ideas for combating COVID-19 at speed.     

A Comprehensive Review of Animal Models for Coronaviruses: SARS-CoV-2, SARS-CoV,and MERS-CoV

The recent outbreak of coronavirus disease(COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) has already affected a large population of the world. SARS-CoV-2 belongs to the same family of severe acute respiratory syndrome coronavirus(SARS-CoV) and Middle East respiratory syndrome coronavirus(MERSCoV). COVID-19 has a complex pathology involving severe acute respiratory infection, hyper-immune response, and coagulopathy. At present, there is no therapeutic drug or vaccine approved for the disease. There is an urgent need for an ideal animal model that can reflect clinical symptoms and underlying etiopathogenesis similar to COVID-19 patients which can be further used for evaluation of underlying mechanisms, potential vaccines, and therapeutic strategies. The current review provides a paramount insight into the available animal models of SARS-CoV-2, SARS-CoV, and MERS-CoV for the management of the diseases.     

Epigenetic regulation of autophagy in coronavirus disease 2019 (COVID-19)

The coronavirus disease 2019 (COVID-19) pandemic has become the most serious global public health issue in the past two years, requiring effective therapeutic strategies. This viral infection is a contagious disease caused by new coronaviruses (nCoVs), also called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Autophagy, as a highly conserved catabolic recycling process, plays a significant role in the growth and replication of coronaviruses (CoVs). Therefore, there is great interest in understanding the mechanisms that underlie autophagy modulation. The modulation of autophagy is a very complex and multifactorial process, which includes different epigenetic alterations, such as histone modifications and DNA methylation. These mechanisms are also known to be involved in SARS-CoV-2 replication. Thus, molecular understanding of the epigenetic pathways linked with autophagy and COVID-19, could provide novel therapeutic targets for COVID-19 eradication. In this context, the current review highlights the role of epigenetic regulation of autophagy in controlling COVID-19, focusing on the potential therapeutic implications.     

The NLRP3 inflammasome and COVID-19: Activation,pathogenesis and therapeutic strategies

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), exhibits a wide spectrum of clinical presentations, ranging from asymptomatic cases to severe pneumonia or even death. In severe COVID-19 cases, an increased level of proinflammatory cytokines has been observed in the bloodstream, forming the so-called “cytokine storm”. Generally, nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome activation intensely induces cytokine production as an inflammatory response to viral infection. Therefore, the NLRP3 inflammasome can be a potential target for the treatment of COVID-19. Hence, this review first introduces the canonical NLRP3 inflammasome activation pathway. Second, we review the cellular/molecular mechanisms of NLRP3 inflammasome activation by SARS-CoV-2 infection (e.g., viroporins, ion flux and the complement cascade). Furthermore, we describe the involvement of the NLRP3 inflammasome in the pathogenesis of COVID-19 (e.g., cytokine storm, respiratory manifestations, cardiovascular comorbidity and neurological symptoms). Finally, we also propose several promising inhibitors targeting the NLRP3 inflammasome, cytokine products and neutrophils to provide novel therapeutic strategies for COVID-19.     

A lipidomic view of SARS-CoV-2

The global pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which started in late 2019, has caused huge social and economic losses. A growing number of investigators are focusing on understanding the interaction of SARS-CoV-2 with host cellular processes to find therapeutic approaches. New data suggest that lipid metabolism may play a significant role in regulating the response of immune cells like macrophages to viral infection, thereby affecting the outcome of the disease. Therefore, understanding the role of lipid metabolism could help develop new therapeutic approaches to mitigate the social and economic cost of coronavirus disease 2019 (COVID-19).     

干扰素刺激基因与新型冠状病毒相互作用的研究进展

目前新型冠状病毒(severe acute respiratory syndrome coronavirus 2, SARS-CoV-2)感染所致的新型冠状病毒肺炎(corona virus disease, COVID-19)已成为威胁人类健康和安全的全球性流行性疾病。随着新突变株的不断出现,寻找有效治疗药物和靶点迫在眉睫。干扰素刺激基因(interferon-stimulated genes, ISGs)是由干扰素(interferons, IFNs)诱导后表达上调的一类基因,在宿主抵抗病毒感染过程中发挥着至关重要的作用。研究表明,ISGs能够靶向许多病毒复制的不同阶段发挥抗病毒作用,然而SARS-CoV-2也进化出各种策略干扰或逃避宿主天然免疫。因此,全面了解SARS-CoV-2与ISGs相互作用,对于设计抗病毒策略至关重要。本文简要综述不同ISGs抵抗SARS-CoV-2的作用机制,为开发新型的抗病毒药物提供思路和理论依据。     

Pneumocytes are distinguished by highly elevated expression of the ER stress biomarker GRP78, a co-receptor for SARS-CoV-2, in COVID-19 autopsies

Vaccinations are widely credited with reducing death rates from COVID-19, but the underlying host-viral mechanisms/interactions for morbidity and mortality of SARS-CoV-2 infection remain poorly understood. Acute respiratory distress syndrome (ARDS) describes the severe lung injury, which is pathologically associated with alveolar damage, inflammation, non-cardiogenic edema, and hyaline membrane formation. Because proteostatic pathways play central roles in cellular protection, immune modulation, protein degradation, and tissue repair, we examined the pathological features for the unfolded protein response (UPR) using the surrogate biomarker glucose-regulated protein 78 (GRP78) and co-receptor for SARS-CoV-2. At autopsy, immunostaining of COVID-19 lungs showed highly elevated expression of GRP78 in both pneumocytes and macrophages compared with that of non-COVID control lungs. GRP78 expression was detected in both SARS-CoV-2-infected and un-infected pneumocytes as determined by multiplexed immunostaining for nucleocapsid protein. In macrophages, immunohistochemical staining for GRP78 from deceased COVID-19 patients was increased but overlapped with GRP78 expression taken from surgical resections of non-COVID-19 controls. In contrast, the robust in situ GRP78 immunostaining of pneumocytes from COVID-19 autopsies exhibited no overlap and was independent of age, race/ethnicity, and gender compared with that from non-COVID-19 controls. Our findings bring new insights for stress-response pathways involving the proteostatic network implicated for host resilience and suggest that targeting of GRP78 expression with existing therapeutics might afford an alternative therapeutic strategy to modulate host-viral interactions during SARS-CoV-2 infections.     

Molecular Perspectives of SARS-CoV-2: Pathology,Immune Evasion,and Therapeutic Interventions

The outbreak of coronavirus disease 2019 (COVID-19) has not only affected human health but also diverted the focus of research and derailed the world economy over the past year. Recently, vaccination against COVID-19 has begun, but further studies on effective therapeutic agents are still needed. The severity of COVID-19 is attributable to several factors such as the dysfunctional host immune response manifested by uncontrolled viral replication, type I interferon suppression, and release of impaired cytokines by the infected resident and recruited cells. Due to the evolving pathophysiology and direct involvement of the host immune system in COVID-19, the use of immune-modulating drugs is still challenging. For the use of immune-modulating drugs in severe COVID-19, it is important to balance the fight between the aggravated immune system and suppression of immune defense against the virus that causes secondary infection. In addition, the interplaying events that occur during virus–host interactions, such as activation of the host immune system, immune evasion mechanism of the virus, and manifestation of different stages of COVID-19, are disjunctive and require thorough streamlining. This review provides an update on the immunotherapeutic interventions implemented to combat COVID-19 along with the understanding of molecular aspects of the immune evasion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which may provide opportunities to develop more effective and promising therapeutics.     

Host genetic variability and determinants of severe COVID-19

Since the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak, convergent studies have provided evidence that host genetic background may contribute to the development of severe coronavirus disease (COVID-19). Here, we summarize how some genetic variations, such as in SARS-CoV-2 receptor angiotensin-converting enzyme 2 or interferon signaling pathway, may help to understand why some individuals can develop severe COVID-19.     

Targeting ACLY efficiently inhibits SARS-CoV-2 replication

The Coronavirus Disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the biggest public health challenge the world has witnessed in the past decades. SARS-CoV-2 undergoes constant mutations and new variants of concerns (VOCs) with altered transmissibility, virulence, and/or susceptibility to vaccines and therapeutics continue to emerge. Detailed analysis of host factors involved in virus replication may help to identify novel treatment targets. In this study, we dissected the metabolome derived from COVID-19 patients to identify key host factors that are required for efficient SARS-CoV-2 replication. Through a series of metabolomic analyses, in vitro, and in vivo investigations, we identified ATP citrate lyase (ACLY) as a novel host factor required for efficient replication of SARS-CoV-2 wild-type and variants, including Omicron. ACLY should be further explored as a novel intervention target for COVID-19.     

The possible double-edged sword effects of vitamin D on COVID-19: A hypothesis

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) gains access to host cells by attaching to angiotensin-converting enzyme 2 (ACE2). Vitamin D (VitD) can upregulate ACE2 and has an antagonistic effect on Renin, which exerts a vasodilatation and anti-inflammatory effect against coronavirus disease (COVID-19). However, it may also facilitate viral entry by increasing ACE2 as the main SARS-CoV-2 receptor and mediates ROS production through NADPH oxidase, as a double-edged sword effect. Lung function and the immune system are also influenced by VitD through several mechanisms, including increased natural antibiotics (Defensin and Cathelicidin) and upregulated transforming growth factor-β. A higher IgA, Th2/Th1 ratio, and T-regulatory cells are attributable to VitD effects on the immune cells, while these changes may also be a double-edged sword in COVID-19. Although VitD supplementation might be highly recommended in COVID-19, the administration's dosage and route could be challenging. Furthermore, this issue has not been mentioned in various studies so far. So, the report aimed to explain the current challenges with the application of VitD in COVID-19.     

SARS-CoV-2 infection and oxidative stress: Pathophysiological insight into thrombosis and therapeutic opportunities

The current coronavirus disease 2019 (COVID-19) pandemic has presented unprecedented challenges to global health. Although the majority of COVID-19 patients exhibit mild-to-no symptoms, many patients develop severe disease and need immediate hospitalization, with most severe infections associated with a dysregulated immune response attributed to a cytokine storm. Epidemiological studies suggest that overall COVID-19 severity and morbidity correlate with underlying comorbidities, including diabetes, obesity, cardiovascular diseases, and immunosuppressive conditions. Patients with such comorbidities exhibit elevated levels of reactive oxygen species (ROS) and oxidative stress caused by an increased accumulation of angiotensin II and by activation of the NADPH oxidase pathway. Moreover, accumulating evidence suggests that oxidative stress coupled with the cytokine storm contribute to COVID-19 pathogenesis and immunopathogenesis by causing endotheliitis and endothelial cell dysfunction and by activating the blood clotting cascade that results in blood coagulation and microvascular thrombosis. In this review, we survey the mechanisms of how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces oxidative stress and the consequences of this stress on patient health. We further shed light on aspects of the host immunity that are crucial to prevent the disease during the early phase of infection. A better understanding of the disease pathophysiology as well as preventive measures aimed at lowering ROS levels may pave the way to mitigate SARS-CoV-2-induced complications and decrease mortality.     

Involvement of epigenetics in affecting host immunity during SARS-CoV-2 infection

Coronavirus disease 19 (COVID-19) is caused by a highly contagious RNA virus Severe Acute Respiratory Syndrome coronavirus-2 (SARS-CoV-2), originated in December 2019 in Wuhan, China. Since then, it has become a global public health concern and leads the disease table with the highest mortality rate, highlighting the necessity for a thorough understanding of its biological properties. The intricate interaction between the virus and the host immune system gives rise to diverse implications of COVID-19. RNA viruses are known to hijack the host epigenetic mechanisms of immune cells to regulate antiviral defence. Epigenetics involves processes that alter gene expression without changing the DNA sequence, leading to heritable phenotypic changes. The epigenetic landscape consists of reversible modifications like chromatin remodelling, DNA/RNA methylation, and histone methylation/acetylation that regulates gene expression. The epigenetic machinery contributes to many aspects of SARS-CoV-2 pathogenesis, like global DNA methylation and receptor angiotensin-converting enzyme 2 (ACE2) methylation determines the viral entry inside the host, viral replication, and infection efficiency. Further, it is also reported to epigenetically regulate the expression of different host cytokines affecting antiviral response. The viral proteins of SARS-CoV-2 interact with various host epigenetic enzymes like histone deacetylases (HDACs) and bromodomain-containing proteins to antagonize cellular signalling. The central role of epigenetic factors in SARS-CoV-2 pathogenesis is now exploited as promising biomarkers and therapeutic targets against COVID-19. This review article highlights the ability of SARS-CoV-2 in regulating the host epigenetic landscape during infection leading to immune evasion. It also discusses the ongoing therapeutic approaches to curtail and control the viral outbreak.