Herbal Immunomodulators: A Powerful Preventive Weapon for COVID-19

The Corona Virus Disease of 2019 is characterized by a serious epidemic (COVID-19). The acute respiratory syndrome is caused by the coronavirus, which is followed by an inflammatory response in the host. Systemic inflammatory response syndrome (SIRS) is a condition in which the body causes acute breathing problems, multiple organ impairment disorder, and even in the early stages of multiple organ failure extreme COVID-19. Increased development of anti-inflammatory cytokines in the late stages of serious disease causes the immune system's reaction to becoming controlled, resulting in immune fatigue. Pandemics have wreaked havoc on humanity's strata, wiped out whole nations, and strengthening immunity is long overdue. A strong immune system is needed to fight a viral infection. Multivitamin-rich diets improve pathogen immunity by triggering immune responses in several immune cells, as an example. Various immune-stimulating herbs, plants, and spices like chicory, Tinospora cordifolia, Withania somnifera, myrrh, ginger, etc., must be included to counteract the pathogens. © 2022 by the authors.

Mechanisms of gastrointestinal barrier dysfunction in COVID-19 patients.

Coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a major global public health event, resulting in a significant social and economic burden. Although COVID-19 was initially characterized as an upper respiratory and pulmonary infection, recent evidence suggests that it is a complex disease including gastrointestinal symptoms, such as diarrhea, nausea, and vomiting. Moreover, it remains unclear whether the gastrointestinal symptoms are caused by direct infection of the gastrointestinal tract by SARS-CoV-2 or are the result of systemic immune activation and subsequent dysregulation of homeostatic mechanisms. This review provides a brief overview of the mechanisms by which SARS-CoV-2 disrupts the integrity of the gastrointestinal barrier including the mechanical barrier, chemical barrier, microbial barrier, and immune barrier.

Chimeric antigen receptor-based therapies beyond cancer.

Adoptive cell transfer (ACT) therapies have gained renewed interest in the field of immunotherapy following the advent of chimeric antigen receptor (CAR) technology. This immunological breakthrough requires immune cell engineering with an artificial surface protein receptor for antigen-specific recognition coupled to an intracellular protein domain for cell activating functions. CAR-based ACT has successfully solved some hematological malignancies, and it is expected that other tumors may soon benefit from this approach. However, the potential of CAR technology is such that other immune-mediated disorders are beginning to profit from it. This review will focus on CAR-based ACT therapeutic areas other than oncology such as infection, allergy, autoimmunity, transplantation, and fibrotic repair. Herein, we discuss the results and limitations of preclinical and clinical studies in that regard.

Pathophysiology of SARS-CoV-2 Infection and COVID-19

A detailed understanding of the pathophysiologic mechanisms of severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) infection and Coronavirus disease 2019 (COVID-19) is vital for improving patient management - to facilitate prompt recognition of progression to severe disease and effective therapeutic strategies. This chapter summarizes the underlyingpathophysiology in the lungs and other organs of COVID- 19 patients. The roles of the cytokine storm culminating in exaggerated inflammatory responses and formation of neutrophil extracellular traps (NETs) are discussed. Pathological features of the various stages from the onset of COVID-19 are outlined - progressing from early mild infection to severe clinical illness to the critically ill phase. © 2023 by World Scientific Publishing Co. Pte. Ltd.

Little to no expression of angiotensin-converting enzyme-2 on most human peripheral blood immune cells but highly expressed on tissue macrophages.

Angiotensin-converting enzyme-2 (ACE2) has been recognized as the binding receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Flow cytometry demonstrated that there was little to no expression of ACE2 on most of the human peripheral blood-derived immune cells including CD4+ T, CD8+ T, activated CD4+ /CD8+ T, Tregs, Th17, NKT, B, NK cells, monocytes, dendritic cells, and granulocytes. There was no ACE2 expression on platelets and very low level of ACE2 protein expression on the surface of human primary pulmonary alveolar epithelial cells. The ACE2 expression was markedly upregulated on the activated type 1 macrophages (M1). Immunohistochemistry demonstrated high expressions of ACE2 on human tissue macrophages, such as alveolar macrophages, Kupffer cells within livers, and microglial cells in brain at steady state. The data suggest that alveolar macrophages, as the frontline immune cells, may be directly targeted by the SARS-CoV-2 infection and therefore need to be considered for the prevention and treatment of COVID-19.

IMMUNE STATUS AND CYTOKINE SPECTRUM AS PREDICTORS OF THE RISK OF SEVERE DISEASE AND PERFORMANCE INDICATORS OF INTENSIVE THERAPY IN PATIENTS WITH CORONAVIRUS INFECTION COVID-19

The pandemic caused by a new strain of the SARS-CoV-2 coronavirus has swept the whole world but effective methods for treating this severe pathology have not yet been created. It has now been established that a risk of a severe course of COVID-19 is not so much a patient's age itself, but so-called age-related diseases;the renin-angiotensin system (RAS) is directly or indirectly involved into their development. The SARS-CoV-19 virus interacts with one of the main regulatory elements of this system, ACE2, and disrupts the balance between the two RAS branches. This ultimately manifests itself in an increase in levels of angiotensin II, which, through binding to the angiotensin type 1 receptor (AT1R), causes a number of pathological conditions, including hypertension, atherosclerosis, and cardiovascular diseases, enhances cell proliferation, apoptosis, death of vascular endothelial cells, etc. This process has been described in many reviews by Russian and foreign authors. However, cells of innate and adaptive immunity are another less well-described but no less important target of angiotensin II. The consequences of this interaction are analyzed in detail in this review. With COVID-19, dendritic cells are activated, macrophage proliferation and neutrophil infiltration increase with further involvement of CD4-lymphocytes and other cellular elements of the adaptive immunity in this process. Hyperactivation of the immune system is accompanied with the release of a large amount of pro-inflammatory cytokines, which can lead to the occurrence of a cytokine storm. The picture is aggravated by the inhibitory effect produced by the virus itself on the synthesis of signaling interferons at initial stages in its internalization into the cell. A separate section in the review addresses the problem how to predict a risk of a developing serious condition and search for its predictors by analyzing the state of the RAS and ratios of key cellular elements in the immune system. This is extremely important for making decisions concerning the amount of necessary medical care and strategies for subsequent treatment. © Sadykov V.F., Poltavtseva R.A., Chaplygina A.V., Bobkova N.V., 2022

Multi-omics and immune cells' profiling of COVID-19 patients for ICU admission prediction: in silico analysis and an integrated machine learning-based approach in the framework of Predictive, Preventive, and Personalized Medicine.

Background: Intensive care unit admission (ICUA) triage has been urgent need for solving the shortage of ICU beds, during the coronavirus disease 2019 (COVID-19) surge. In silico analysis and integrated machine learning (ML) approach, based on multi-omics and immune cells (ICs) profiling, might provide solutions for this issue in the framework of predictive, preventive, and personalized medicine (PPPM). Methods: Multi-omics was used to screen the synchronous differentially expressed protein-coding genes (SDEpcGs), and an integrated ML approach to develop and validate a nomogram for prediction of ICUA. Finally, the independent risk factor (IRF) with ICs profiling of the ICUA was identified. Results: Colony-stimulating factor 1 receptor (CSF1R) and peptidase inhibitor 16 (PI16) were identified as SDEpcGs, and each fold change (FCij) of CSF1R and PI16 was selected to develop and validate a nomogram to predict ICUA. The area under curve (AUC) of the nomogram was 0.872 (95% confidence interval (CI): 0.707 to 0.950) on the training set, and 0.822 (95% CI: 0.659 to 0.917) on the testing set. CSF1R was identified as an IRF of ICUA, expressed in and positively correlated with monocytes which had a lower fraction in COVID-19 ICU patients. Conclusion: The nomogram and monocytes could provide added value to ICUA prediction and targeted prevention, which are cost-effective platform for personalized medicine of COVID-19 patients. The log2fold change (log2FC) of the fraction of monocytes could be monitored simply and economically in primary care, and the nomogram offered an accurate prediction for secondary care in the framework of PPPM. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-023-00317-5.

Expression and Function of BMP and Activin Membrane-Bound Inhibitor (BAMBI) in Chronic Liver Diseases and Hepatocellular Carcinoma.

BAMBI (bone morphogenetic protein and activin membrane-bound inhibitor) is a transmembrane pseudoreceptor structurally related to transforming growth factor (TGF)-ß type 1 receptors (TGF-ß1Rs). BAMBI lacks a kinase domain and functions as a TGF-ß1R antagonist. Essential processes such as cell differentiation and proliferation are regulated by TGF-ß1R signaling. TGF-ß is the best-studied ligand of TGF-ßRs and has an eminent role in inflammation and fibrogenesis. Liver fibrosis is the end stage of almost all chronic liver diseases, such as non-alcoholic fatty liver disease, and at the moment, there is no effective anti-fibrotic therapy available. Hepatic BAMBI is downregulated in rodent models of liver injury and in the fibrotic liver of patients, suggesting that low BAMBI has a role in liver fibrosis. Experimental evidence convincingly demonstrated that BAMBI overexpression is able to protect against liver fibrosis. Chronic liver diseases have a high risk of hepatocellular carcinoma (HCC), and BAMBI was shown to exert tumor-promoting as well as tumor-protective functions. This review article aims to summarize relevant studies on hepatic BAMBI expression and its role in chronic liver diseases and HCC.

Setting a stage: Inflammation during preeclampsia and postpartum.

Preeclampsia (PE) is a leading cause of maternal and fetal mortality worldwide. The immune system plays a critical role in normal pregnancy progression; however, inappropriate inflammatory responses have been consistently linked with PE pathophysiology. This inflammatory phenotype consists of activation of the innate immune system, adaptive immune system, and increased inflammatory mediators in circulation. Moreover, recent studies have shown that the inflammatory profile seen in PE persists into the postpartum period. This manuscript aims to highlight recent advances in research relating to inflammation in PE as well as the inflammation that persists postpartum in women after a PE pregnancy. With the advent of the COVID-19 pandemic, there has been an increase in obstetric disorders associated with COVID-19 infection during pregnancy. This manuscript also aims to shed light on the relationship between COVID-19 infection during pregnancy and the increased incidence of PE in these women.

How Does Vitamin D Affect Immune Cells Crosstalk in Autoimmune Diseases?

Vitamin D is a secosteroid hormone that is highly involved in bone health. Mounting evidence revealed that, in addition to the regulation of mineral metabolism, vitamin D is implicated in cell proliferation and differentiation, vascular and muscular functions, and metabolic health. Since the discovery of vitamin D receptors in T cells, local production of active vitamin D was demonstrated in most immune cells, addressing the interest in the clinical implications of vitamin D status in immune surveillance against infections and autoimmune/inflammatory diseases. T cells, together with B cells, are seen as the main immune cells involved in autoimmune diseases; however, growing interest is currently focused on immune cells of the innate compartment, such as monocytes, macrophages, dendritic cells, and natural killer cells in the initiation phases of autoimmunity. Here we reviewed recent advances in the onset and regulation of Graves' and Hashimoto's thyroiditis, vitiligo, and multiple sclerosis in relation to the role of innate immune cells and their crosstalk with vitamin D and acquired immune cells.

SARS-CoV-2 Infection: A Clinical and Histopathological Study in Pregnancy.

During pregnancy, SARS-CoV-2 infection is associated with several adverse outcomes, including an increased risk of pre-eclampsia, preterm delivery, hypertensive disorders, gestational diabetes, and fetal growth restriction related to the development of placenta vascular abnormalities. We analyzed human placenta from full-term, uncomplicated pregnancies with SARS-CoV-2 infection during the first, second, or third trimesters of gestation. We studied, by the immunohistochemistry technique, the expression of CD34 and podoplanin (PDPN) as markers of vasculogenesis to find any differences. As secondary outcomes, we correlated maternal symptoms with placental histological alterations, including fibrin deposits, lymphocyte infiltration in the villi, edema, and thrombi. Our results showed a PDPN expression around the villous stroma as a plexiform network around the villous nucleus of fetal vessels; significant down-regulation was observed in the villous stroma of women infected during the third trimester. CD34 showed no changes in expression levels. During SARS-CoV-2 infection, the most common maternal symptoms were fever, anosmia, ageusia and asthenia, and the majority were treated with paracetamol, corticosteroids and azithromycin. Patients that required multiple symptomatic treatments evidenced a large amount of fibrin deposition in the villi. Certainly, PDPN plays a key role in healthy placental vasculogenesis and thus in its proper physiology, and SARS-CoV-2 surely alters its normal expression. Further studies are necessary to understand what mechanisms are being altered to try to avoid possible complications for both the mother and fetus in terms of the contagions that will still occur.

CIDP: Analysis of Immunomarkers During COVID-19 mRNA-Vaccination and IVIg-Immunomodulation: An Exploratory Study.

Availability of COVID-19 mRNA vaccine for patients with chronic inflammatory demyelinating polyneuropathy (CIDP) treated with intravenous immunoglobulin (IVIg) raises the question of whether COVID-19 mRNA vaccine influences disease activity or IVIg-mediated immunomodulation in CIDP. In this exploratory study, blood samples of CIDP patients on IVIg treatment were longitudinally analyzed before and after vaccination with a COVID-19 mRNA vaccine. A total of 44 samples of eleven patients were characterized at four timepoints by ELISA and flow cytometry in terms of immunomarkers for disease activity and IVIg-immunomodulation. Apart from a significantly lower expression of CD32b on naïve B cells after vaccination, no significant alteration of immunomarkers for CIDP or IVIg-mediated immunomodulation was observed. Our exploratory study suggests that COVID-19 mRNA vaccine does not have a relevant impact on immune activity in CIDP. In addition, immunomodulatory effects of IVIg in CIDP are not altered by COVID-19 mRNA vaccine. This study was registered in the German clinical trial register (DRKS00025759). Overview over the study design. Blood samples of CIDP patients on recurrent IVIg treatment and vaccination with a COVID-19 mRNA vaccine were obtained at four timepoints for cytokine ELISA and flow cytometry, to assess key cytokines and cellular immunomarkers for disease activity and IVIg-immunomodulation in CIDP.

Beyond energy balance regulation: The underestimated role of adipose tissues in host defense against pathogens.

Although the adipose tissue (AT) is a central metabolic organ in the regulation of whole-body energy homeostasis, it is also an important endocrine and immunological organ. As an endocrine organ, AT secretes a variety of bioactive peptides known as adipokines - some of which have inflammatory and immunoregulatory properties. As an immunological organ, AT contains a broad spectrum of innate and adaptive immune cells that have mostly been studied in the context of obesity. However, overwhelming evidence supports the notion that AT is a genuine immunological effector site, which contains all cell subsets required to induce and generate specific and effective immune responses against pathogens. Indeed, AT was reported to be an immune reservoir in the host's response to infection, and a site of parasitic, bacterial and viral infections. In addition, besides AT's immune cells, preadipocytes and adipocytes were shown to express innate immune receptors, and adipocytes were reported as antigen-presenting cells to regulate T-cell-mediated adaptive immunity. Here we review the current knowledge on the role of AT and AT's immune system in host defense against pathogens. First, we will summarize the main characteristics of AT: type, distribution, function, and extraordinary plasticity. Second, we will describe the intimate contact AT has with lymph nodes and vessels, and AT immune cell composition. Finally, we will present a comprehensive and up-to-date overview of the current research on the contribution of AT to host defense against pathogens, including the respiratory viruses influenza and SARS-CoV-2.

SARS-CoV-2 Omicron (B.1.1.529) shows minimal neurotropism in a double-humanized mouse model.

Although severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) initially infects the respiratory tract, it also directly or indirectly affects other organs, including the brain. However, little is known about the relative neurotropism of SARS-CoV-2 variants of concern (VOCs), including Omicron (B.1.1.529), which emerged in November 2021 and has remained the dominant pathogenic lineage since then. To address this gap, we examined the relative ability of Omicron, Beta (B.1.351), and Delta (B.1.617.2) to infect the brain in the context of a functional human immune system by using human angiotensin-converting enzyme 2 (hACE2) knock-in triple-immunodeficient NGC mice with or without reconstitution with human CD34+ stem cells. Intranasal inoculation of huCD34+-hACE2-NCG mice with Beta and Delta resulted in productive infection of the nasal cavity, lungs, and brain on day 3 post-infection, but Omicron was surprisingly unique in its failure to infect either the nasal tissue or brain. Moreover, the same infection pattern was observed in hACE2-NCG mice, indicating that antiviral immunity was not responsible for the lack of Omicron neurotropism. In independent experiments, we demonstrate that nasal inoculation with Beta or with D614G, an ancestral SARS-CoV-2 with undetectable replication in huCD34+-hACE2-NCG mice, resulted in a robust response by human innate immune cells, T cells, and B cells, confirming that exposure to SARS-CoV-2, even without detectable infection, is sufficient to induce an antiviral immune response. Collectively, these results suggest that modeling of the neurologic and immunologic sequelae of SARS-CoV-2 infection requires careful selection of the appropriate SARS-CoV-2 strain in the context of a specific mouse model.

The m7G Modification Level and Immune Infiltration Characteristics in Patients with COVID-19.

Purpose: The 7-methylguanosine (m7G)-related genes were used to identify the clinical severity and prognosis of patients with coronavirus disease 2019 (COVID-19) and to identify possible therapeutic targets. Patients and Methods: The GSE157103 dataset provides the transcriptional spectrum and clinical information required to analyze the expression of m7G-related genes and the disease subtypes. R language was applied for immune infiltration analysis, functional enrichment analysis, and nomogram model construction. Results: Most m7G-related genes were up-regulated in COVID-19 and were closely related to immune cell infiltration. Disease subtypes were grouped using a clustering algorithm. It was found that the m7G-cluster B was associated with higher immune infiltration, lower mechanical ventilation, lower intensive care unit (ICU) status, higher ventilator-free days, and lower m7G scores. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that differentially expressed genes (DEGs) between m7G-cluster A and B were enriched in viral infection and immune-related aspects, including COVID-19 infection; Th17, Th1, and Th2 cell differentiation, and human T-cell leukemia virus 1 infection. Finally, through machine learning, six disease characteristic genes, NUDT4B, IFIT5, LARP1, EIF4E, LSM1, and NUDT4, were screened and used to develop a nomogram model to estimate disease risk. Conclusion: The expression of most m7G genes was higher in COVID-19 patients compared with that in non-COVID-19 patients. The m7G-cluster B showed higher immune infiltration and milder symptoms. The predictive nomogram based on the six m7G genes can be used to accurately assess risk.

Delivery of mRNA for regulating functions of immune cells.

Abnormal immune cell functions are commonly related to various diseases, including cancer, autoimmune diseases, and infectious diseases. Messenger RNA (mRNA)-based therapy can regulate the functions of immune cells or assign new functions to immune cells, thereby generating therapeutic immune responses to treat these diseases. However, mRNA is unstable in physiological environments and can hardly enter the cytoplasm of target cells; thus, effective mRNA delivery systems are critical for developing mRNA therapy. The two mRNA vaccines of Pfizer-BioNTech and Moderna have demonstrated that lipid nanoparticles (LNPs) can deliver mRNA into dendritic cells (DCs) to induce immunization against severe acute respiratory syndrome coronavirus 2, which opened the floodgates to the development of mRNA therapy. Apart from DCs, other immune cells are promising targets for mRNA therapy. This review summarized the barriers to mRNA delivery and advances in mRNA delivery for regulating the functions of different immune cells.

Infections and immunity: associations with obesity and related metabolic disorders.

About one-fourth of the global population is either overweight or obese, both of which increase the risk of insulin resistance, cardiovascular diseases, and infections. In obesity, both immune cells and adipocytes produce an excess of pro-inflammatory cytokines that may play a significant role in disease progression. In the recent coronavirus disease 2019 (COVID-19) pandemic, important pathological characteristics such as involvement of the renin-angiotensin-aldosterone system, endothelial injury, and pro-inflammatory cytokine release have been shown to be connected with obesity and associated sequelae such as insulin resistance/type 2 diabetes and hypertension. This pathological connection may explain the severity of COVID-19 in patients with metabolic disorders. Many studies have also reported an association between type 2 diabetes and persistent viral infections. Similarly, diabetes favors the growth of various microorganisms including protozoal pathogens as well as opportunistic bacteria and fungi. Furthermore, diabetes is a risk factor for a number of prion-like diseases. There is also an interesting relationship between helminths and type 2 diabetes; helminthiasis may reduce the pro-inflammatory state, but is also associated with type 2 diabetes or even neoplastic processes. Several studies have also documented altered circulating levels of neutrophils, lymphocytes, and monocytes in obesity, which likely modifies vaccine effectiveness. Timely monitoring of inflammatory markers (e.g., C-reactive protein) and energy homeostasis markers (e.g., leptin) could be helpful in preventing many obesity-related diseases.

Immunotherapy strategies and prospects for acute lung injury: Focus on immune cells and cytokines.

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a disastrous condition, which can be caused by a wide range of diseases, such as pneumonia, sepsis, traumas, and the most recent, COVID-19. Even though we have gained an improved understanding of acute lung injury/acute respiratory distress syndrome pathogenesis and treatment mechanism, there is still no effective treatment for acute lung injury/acute respiratory distress syndrome, which is partly responsible for the unacceptable mortality rate. In the pathogenesis of acute lung injury, the inflammatory storm is the main pathological feature. More and more evidences show that immune cells and cytokines secreted by immune cells play an irreplaceable role in the pathogenesis of acute lung injury. Therefore, here we mainly reviewed the role of various immune cells in acute lung injury from the perspective of immunotherapy, and elaborated the crosstalk of immune cells and cytokines, aiming to provide novel ideas and targets for the treatment of acute lung injury.