Structural cells are key regulators of organ-specific immune responses.

The mammalian immune system implements a remarkably effective set of mechanisms for fighting pathogens1. Its main components are haematopoietic immune cells, including myeloid cells that control innate immunity, and lymphoid cells that constitute adaptive immunity2. However, immune functions are not unique to haematopoietic cells, and many other cell types display basic mechanisms of pathogen defence3-5. To advance our understanding of immunology outside the haematopoietic system, here we systematically investigate the regulation of immune genes in the three major types of structural cells: epithelium, endothelium and fibroblasts. We characterize these cell types across twelve organs in mice, using cellular phenotyping, transcriptome sequencing, chromatin accessibility profiling and epigenome mapping. This comprehensive dataset revealed complex immune gene activity and regulation in structural cells. The observed patterns were highly organ-specific and seem to modulate the extensive interactions between structural cells and haematopoietic immune cells. Moreover, we identified an epigenetically encoded immune potential in structural cells under tissue homeostasis, which was triggered in response to systemic viral infection. This study highlights the prevalence and organ-specific complexity of immune gene activity in non-haematopoietic structural cells, and it provides a high-resolution, multi-omics atlas of the epigenetic and transcriptional networks that regulate structural cells in the mouse.

SARS-CoV-2-mediated immune system activation and potential application in immunotherapy.

Although novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-mediated pulmonary inflammation has recently attracted great attention, its pathology and pathogenesis are not clear. Notably, due to both its high infective and pathogenicity, SARS-CoV-2 infection may cause a severe sometimes fatal respiratory disease. A specific vaccine, which relies on the analysis of SARS-CoV-2 structural protein-derived antigenic peptides, is indispensable for restraining the spread and reducing the mortality of SARS-CoV-2. SARS-CoV-2 infections activate cytototxic, myeloid-derived suppressor cells, dendritic cells, macrophages, as well as natural killer, B, helper T, and regulatory T cells, thus further stimulating innate and antigen-specific immune responses. Nevertheless, many immune effector cells cause hyperinflammation and pulmonary immunopathology by releasing proinflammatory cytokines and chemokines, including interferon (IFN)-α, IFN-ß, IFN-γ, monocyte chemoattractant protein-1, macrophage inflammatory protein (MIP)-1A, MIP1B, interleukin (IL)-1, IL-2, IL-4, IL-6, IL-7, IL-8, IL-9, IL-12, IL-17, and IL-18, platelet-derived growth factor, fibroblast growth factor, tumor necrosis factor-α, and induced protein 10. Interestingly, related products derived from SARS-CoV-2 are likely to trigger immune evasion. Therefore, investigating SARS-CoV-2-specific vaccines, blocking immunopathology, and prohibiting immune evasion are urgently required for treating SARS-CoV-2 infection. In this review, we emphatically illuminated the development of a SARS-CoV-2-specific vaccine based on the analysis of epitopes, also expounding the molecular mechanisms of SARS-CoV-2-mediated cytokine release syndrome. Furthermore, we comprehensively discussed SARS-CoV-2-associated immune evasion and lung immunopathology. Lastly, potential therapeutic strategies against SARS-CoV-2 were explored.

Interplay between SARS-CoV-2-derived miRNAs, immune system, vitamin D pathway and respiratory system.

The new coronavirus pandemic started in China in 2019. The intensity of the disease can range from mild to severe, leading to death in many cases. Despite extensive research in this area, the exact molecular nature of virus is not fully recognized; however, according to pieces of evidence, one of the mechanisms of virus pathogenesis is through the function of viral miRNAs. So, we hypothesized that SARS-CoV-2 pathogenesis may be due to targeting important genes in the host with its miRNAs, which involved in the respiratory system, immune pathways and vitamin D pathways, thus possibly contributing to disease progression and virus survival. Potential miRNA precursors and mature miRNA were predicted and confirmed based on the virus genome. The next step was to predict and identify their target genes and perform functional enrichment analysis to recognize the biological processes connected with these genes in the three pathways mentioned above through several comprehensive databases. Finally, cis-acting regulatory elements in 5' regulatory regions were analysed, and the analysis of available RNAseq data determined the expression level of genes. We revealed that thirty-nine mature miRNAs could theoretically derive from the SARS-CoV-2 genome. Functional enrichment analysis elucidated three highlighted pathways involved in SARS-CoV-2 pathogenesis: vitamin D, immune system and respiratory system. Our finding highlighted genes' involvement in three crucial molecular pathways and may help develop new therapeutic targets related to SARS-CoV-2.

Genome-wide association study of individual differences of human lymphocyte profiles using large-scale cytometry data.

Human immune systems are very complex, and the basis for individual differences in immune phenotypes is largely unclear. One reason is that the phenotype of the immune system is so complex that it is very difficult to describe its features and quantify differences between samples. To identify the genetic factors that cause individual differences in whole lymphocyte profiles and their changes after vaccination without having to rely on biological assumptions, we performed a genome-wide association study (GWAS), using cytometry data. Here, we applied computational analysis to the cytometry data of 301 people before receiving an influenza vaccine, and 1, 7, and 90 days after the vaccination to extract the feature statistics of the lymphocyte profiles in a nonparametric and data-driven manner. We analyzed two types of cytometry data: measurements of six markers for B cell classification and seven markers for T cell classification. The coordinate values calculated by this method can be treated as feature statistics of the lymphocyte profile. Next, we examined the genetic basis of individual differences in human immune phenotypes with a GWAS for the feature statistics, and we newly identified seven significant and 36 suggestive single-nucleotide polymorphisms associated with the individual differences in lymphocyte profiles and their change after vaccination. This study provides a new workflow for performing combined analyses of cytometry data and other types of genomics data.

SARS-CoV-2 pseudovirus infectivity and expression of viral entry-related factors ACE2, TMPRSS2, Kim-1, and NRP-1 in human cells from the respiratory, urinary, digestive, reproductive, and immune systems.

Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a wide spectrum of syndromes involving multiple organ systems and is primarily mediated by viral spike (S) glycoprotein through the receptor-binding domain (RBD) and numerous cellular proteins including ACE2, transmembrane serine protease 2 (TMPRSS2), kidney injury molecule-1 (Kim-1), and neuropilin-1 (NRP-1). In this study, we examined the entry tropism of SARS-CoV-2 and SARS-CoV using S protein-based pseudoviruses to infect 22 cell lines and 3 types of primary cells isolated from respiratory, urinary, digestive, reproductive, and immune systems. At least one cell line or type of primary cell from each organ system was infected by both pseudoviruses. Infection by pseudoviruses is effectively blocked by S1, RBD, and ACE2 recombinant proteins, and more weakly by Kim-1 and NRP-1 recombinant proteins. Furthermore, cells with robust SARS-CoV-2 pseudovirus infection had strong expression of either ACE2 or Kim-1 and NRP-1 proteins. ACE2 glycosylation appeared to be critical for the infections of both viruses as there was a positive correlation between infectivity of either SARS-CoV-2 or SARS-CoV pseudovirus with the level of glycosylated ACE2 (gly-ACE2). These results reveal that SARS-CoV-2 cell entry could be mediated by either an ACE2-dependent or -independent mechanism, thus providing a likely molecular basis for its broad tropism for a wide variety of cell types.

Destabilized adaptive influenza variants critical for innate immune system escape are potentiated by host chaperones.

The threat of viral pandemics demands a comprehensive understanding of evolution at the host-pathogen interface. Here, we show that the accessibility of adaptive mutations in influenza nucleoprotein at fever-like temperatures is mediated by host chaperones. Particularly noteworthy, we observe that the Pro283 nucleoprotein variant, which (1) is conserved across human influenza strains, (2) confers resistance to the Myxovirus resistance protein A (MxA) restriction factor, and (3) critically contributed to adaptation to humans in the 1918 pandemic influenza strain, is rendered unfit by heat shock factor 1 inhibition-mediated host chaperone depletion at febrile temperatures. This fitness loss is due to biophysical defects that chaperones are unavailable to address when heat shock factor 1 is inhibited. Thus, influenza subverts host chaperones to uncouple the biophysically deleterious consequences of viral protein variants from the benefits of immune escape. In summary, host proteostasis plays a central role in shaping influenza adaptation, with implications for the evolution of other viruses, for viral host switching, and for antiviral drug development.

Obesity, COVID-19 and innate immunometabolism.

As COVID-19 continues to spread worldwide, severe disease and mortality have been observed in obese patients. We discuss how obesity and obesity-associated factors such as 'meta-flammation', dietary fat intake and paradoxical suppression of the innate immune response within the pulmonary compartment may be crucial determinants in the host response to a novel viral pathogen. Modulation of immune cell bioenergetics and metabolic potential plays a central role in the innate immune response to infection, and as we strive to combat this new global health threat, immunometabolism of the innate immune system warrants attention.

SARS-COV-2 infection and lung tumor microenvironment.

Coronavirus Disease 2019 (COVID-19) is an acute respiratory syndrome, reported at the end of 2019 in China originally and immediately spread affecting over ten million world population to date. This pandemic is more lethal for the older population and those who previously suffered from other ailments such as cardiovascular diseases, respiratory disorders, and other immune system affecting abnormalities including cancers. Lung cancer is an important comorbidity of COVID-19. In this review, we emphasized the impact of lung tumor microenvironment (TME) on the possibility of enhanced severity of infection caused by the SARS-Co-V2. The compromised lung TME is further susceptible to the attack of viruses. The lung cells are also abundant in the virus entry receptors. Several SARS-Co-V2 proteins can modulate the lung TME by disrupting the fragile immune mechanisms contributing to cytokine storming and cellular metabolic variations. We also discussed the impact of medication used for lung cancer in the scenario of this infection. Since other respiratory infections can be a risk factor for lung cancer, COVID-19 recovered patients should be monitored for tumor development, especially if there is genetic susceptibility or it involves exposure to other risk factors.

Revisiting respiratory syncytial virus's interaction with host immunity, towards novel therapeutics.

Every year there are > 33 million cases of Respiratory Syncytial Virus (RSV)-related respiratory infection in children under the age of five, making RSV the leading cause of lower respiratory tract infection (LRTI) in infants. RSV is a global infection, but 99% of related mortality is in low/middle-income countries. Unbelievably, 62 years after its identification, there remains no effective treatment nor vaccine for this deadly virus, leaving infants, elderly and immunocompromised patients at high risk. The success of all pathogens depends on their ability to evade and modulate the host immune response. RSV has a complex and intricate relationship with our immune systems, but a clearer understanding of these interactions is essential in the development of effective medicines. Therefore, in a bid to update and focus our research community's understanding of RSV's interaction with immune defences, this review aims to discuss how our current knowledgebase could be used to combat this global viral threat.

Susceptibility and Severity of Viral Infections in Obesity: Lessons from Influenza to COVID-19. Does Leptin Play a Role?

The recent pandemic Sars-CoV2 infection and studies on previous influenza epidemic have drawn attention to the association between the obesity and infectious diseases susceptibility and worse outcome. Metabolic complications, nutritional aspects, physical inactivity, and a chronic unbalance in the hormonal and adipocytokine microenvironment are major determinants in the severity of viral infections in obesity. By these pleiotropic mechanisms obesity impairs immune surveillance and the higher leptin concentrations produced by adipose tissue and that characterize obesity substantially contribute to such immune response dysregulation. Indeed, leptin not only controls energy balance and body weight, but also plays a regulatory role in the interplay between energy metabolism and immune system. Since leptin receptor is expressed throughout the immune system, leptin may exert effects on cells of both innate and adaptive immune system. Chronic inflammatory states due to metabolic (i.e., obesity) as well as infectious diseases increase leptin concentrations and consequently lead to leptin resistance further fueling inflammation. Multiple factors, including inflammation and ER stress, contribute to leptin resistance. Thus, if leptin is recognized as one of the adipokines responsible for the low grade inflammation found in obesity, on the other hand, impairments of leptin signaling due to leptin resistance appear to blunt the immunologic effects of leptin and possibly contribute to impaired vaccine-induced immune responses. However, many aspects concerning leptin interactions with inflammation and immune system as well as the therapeutical approaches to overcome leptin resistance and reduced vaccine effectiveness in obesity remain a challenge for future research.

A bacteriophages journey through the human body.

The human body is colonized by a diverse collective of microorganisms, including bacteria, fungi, protozoa and viruses. The smallest entity of this microbial conglomerate are the bacterial viruses. Bacteriophages, or phages for short, exert significant selective pressure on their bacterial hosts, undoubtedly influencing the human microbiome and its impact on our health and well-being. Phages colonize all niches of the body, including the skin, oral cavity, lungs, gut, and urinary tract. As such our bodies are frequently and continuously exposed to diverse collections of phages. Despite the prevalence of phages throughout our bodies, the extent of their interactions with human cells, organs, and immune system is still largely unknown. Phages physically interact with our mucosal surfaces, are capable of bypassing epithelial cell layers, disseminate throughout the body and may manipulate our immune system. Here, I establish the novel concept of an "intra-body phageome," which encompasses the collection of phages residing within the classically "sterile" regions of the body. This review will take a phage-centric view of the microbiota, human body, and immune system with the ultimate goal of inspiring a greater appreciation for both the indirect and direct interactions between bacteriophages and their mammalian hosts.

Possible therapeutic effects of Nigella sativa and its thymoquinone on COVID-19.

CONTEXT: COVID-19 is a novel coronavirus that causes a severe infection in the respiratory system. Nigella sativa L. (Ranunculaceae) is an annual flowering plant used traditionally as a natural food supplement and multipurpose medicinal agent. OBJECTIVE: The possible beneficial effects of N. sativa, and its constituent, thymoquinone (TQ) on COVID-19 were reviewed. METHODS: The key words including, COVID-19, N. sativa, thymoquinone, antiviral effects, anti-inflammatory and immunomodulatory effects in different databases such as Web of Science (ISI), PubMed, Scopus, and Google Scholar were searched from 1990 up to February 2021. RESULTS: The current literature review showed that N. sativa and TQ reduced the level of pro-inflammatory mediators including, IL-2, IL-4, IL-6, and IL-12, while enhancing IFN-γ. Nigella sativa and TQ increased the serum levels of IgG1 and IgG2a, and improved pulmonary function tests in restrictive respiratory disorders. DISCUSSION AND CONCLUSIONS: These preliminary data of molecular docking, animal, and clinical studies propose N. sativa and TQ might have beneficial effects on the treatment or control of COVID-19 due to antiviral, anti-inflammatory and immunomodulatory properties as well as bronchodilatory effects. The efficacy of N. sativa and TQ on infected patients with COVID-19 in randomize clinical trials will be suggested.

COVID-19 under spotlight: A close look at the origin, transmission, diagnosis, and treatment of the 2019-nCoV disease.

Months after the outbreak of a new flu-like disease in China, the entire world is now in a state of caution. The subsequent less-anticipated propagation of the novel coronavirus disease, formally known as COVID-19, not only made it to headlines by an overwhelmingly high transmission rate and fatality reports, but also raised an alarm for the medical community all around the globe. Since the causative agent, SARS-CoV-2, is a recently discovered species, there is no specific medicine for downright treatment of the infection. This has led to an unprecedented societal fear of the newly born disease, adding a psychological aspect to the physical manifestation of the virus. Herein, the COVID-19 structure, epidemiology, pathogenesis, etiology, diagnosis, and therapy have been reviewed.

Development of child immunity in the context of COVID-19 pandemic.

Children, because of having an immature immune system, are usually more prone than the adults to the microbial infections and have more severe symptoms, which is especially true for the newborns, and very young children. However, the review of clinical data from the current COVID-19 pandemic indicates otherwise. We discuss here what are the main features and components of children's immune system, the role of maternal transmission of immunity, and what are the possible explanations for the seemingly lower infection rate and severity of COVI-19 in children.

COVID-19: Is there a role for immunonutrition in obese patient?

On December 12, 2019 a new coronavirus (SARS-CoV-2) emerged in Wuhan, China, triggering a pandemic of severe acute respiratory syndrome in humans (COVID-19). Today, the scientific community is investing all the resources available to find any therapy and prevention strategies to defeat COVID-19. In this context, immunonutrition can play a pivotal role in improving immune responses against viral infections. Immunonutrition has been based on the concept that malnutrition impairs immune function. Therefore, immunonutrition involves feeding enriched with various pharmaconutrients (Omega 3 Fatty Acids, Vitamin C, Arginine, Glutamine, Selenium, Zinc, Vitamin, E and Vitamin D) to modulate inflammatory responses, acquired immune response and to improve patient outcomes. In literature, significant evidences indicate that obesity, a malnutrition state, negatively impacts on immune system functionality and on host defense, impairing protection from infections. Immunonutrients can promote patient recovery by inhibiting inflammatory responses and regulating immune function. Immune system dysfunction is considered to increase the risk of viral infections, such as SARS-CoV-2, and was observed in different pathological situations. Obese patients develop severe COVID-19 sequelae, due to the high concentrations of TNF-α, MCP-1 and IL-6 produced in the meantime by visceral and subcutaneous adipose tissue and by innate immunity. Moreover, leptin, released by adipose tissue, helps to increase inflammatory milieu with a dysregulation of the immune response. Additionally, gut microbiota plays a crucial role in the maturation, development and functions of both innate and adaptive immune system, as well as contributing to develop obese phenotype. The gut microbiota has been shown to affect lung health through a vital crosstalk between gut microbiota and lungs, called the "gut-lung axis". This axis communicates through a bi-directional pathway in which endotoxins, or microbial metabolites, may affect the lung through the blood and when inflammation occurs in the lung, this in turn can affect the gut microbiota. Therefore, the modulation of gut microbiota in obese COVID-19 patients can play a key role in immunonutrition therapeutic strategy. This umbrella review seeks to answer the question of whether a nutritional approach can be used to enhance the immune system's response to obesity in obese patients affected by COVID-19.

Bacteriophage therapy as a treatment strategy for orthopaedic-device-related infections: where do we stand?

Antibiotic resistance represents a key challenge of the 21st century. Since the pipeline of new antibiotics in development is limited, the introduction of alternative antimicrobial strategies is urgently required. Bacteriophage therapy, the use of bacterial viruses to selectively kill bacterial pathogens, is re-emerging as a potential strategy to tackle difficult-to-treat and multidrug-resistant pathogens. The last decade has seen a surge in scientific investigation into bacteriophage therapy, including targeting orthopaedic-device-related infections (ODRIs) in several successful case studies. However, pharmacological data, knowledge on the interplay with the immune system and, especially in ODRIs, the optimal local application strategy and treatment outcomes remain scarce. The present review reports the state-of-the-art in bacteriophage therapy in ODRIs and addresses the hurdles in establishing bacteriophage therapy under good clinical practice guidelines. These hurdles include a lack of data concerning bacteriophage production, processing, administration and dosing, as well as follow-up clinical monitoring reports. To overcome these challenges, an integrated clinical approach is required, supported by comprehensive legislature to enable expansive and correctly implemented clinical trials.

The unleashing of the immune system in COVID-19 and sepsis: the calm before the storm?

The novel coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is sorely testing health care systems and economies around the world and is rightly considered as the major health emergency in a century. Despite the course of the disease appearing to be mild in many cases, a significant proportion of symptomatic patients develop pneumonia requiring hospitalisation or progress to manifest respiratory complications leading to intensive care treatment. Potential interventions for SARS-CoV2-associated pneumonia are being tested, some of which holding promise, but as of today none of these has yet demonstrated outstanding efficacy in treating COVID-19. In this article, we discuss fresh perspectives and insights into the potential role of immune dysregulation in COVID-19 as well as similarities with systemic inflammatory response in sepsis and the rationale for exploring novel treatment options affecting host immune response.

Systemic Complications of COVID-19.

Coronavirus disease-2019 (COVID-19) creates severe respiratory distress and often a cascade of other systemic complications impacting several organ systems. The immune response includes a cytokine storm that creates many life-threatening problems including coagulopathies, arrhythmias, and secondary infections. This article discusses the multisystem responses to the physical insults created by this corona virus.