Activation of Complement Components on Circulating Blood Monocytes From COVID-19 Patients.

The coronavirus disease-2019 (COVID-19) caused by the SARS-CoV-2 virus may vary from asymptomatic to severe infection with multi-organ failure and death. Increased levels of circulating complement biomarkers have been implicated in COVID-19-related hyperinflammation and coagulopathy. We characterized systemic complement activation at a cellular level in 49-patients with COVID-19. We found increases of the classical complement sentinel C1q and the downstream C3 component on circulating blood monocytes from COVID-19 patients when compared to healthy controls (HCs). Interestingly, the cell surface-bound complement inhibitor CD55 was also upregulated in COVID-19 patient monocytes in comparison with HC cells. Monocyte membrane-bound C1q, C3 and CD55 levels were associated with plasma inflammatory markers such as CRP and serum amyloid A during acute infection. Membrane-bounds C1q and C3 remained elevated even after a short recovery period. These results highlight systemic monocyte-associated complement activation over a broad range of COVID-19 disease severities, with a compensatory upregulation of CD55. Further evaluation of complement and its interaction with myeloid cells at the membrane level could improve understanding of its role in COVID-19 pathogenesis.

The Bacterial Mucosal Immunotherapy MV130 Protects Against SARS-CoV-2 Infection and Improves COVID-19 Vaccines Immunogenicity.

COVID-19-specific vaccines are efficient prophylactic weapons against SARS-CoV-2 virus. However, boosting innate responses may represent an innovative way to immediately fight future emerging viral infections or boost vaccines. MV130 is a mucosal immunotherapy, based on a mixture of whole heat-inactivated bacteria, that has shown clinical efficacy against recurrent viral respiratory infections. Herein, we show that the prophylactic intranasal administration of this immunotherapy confers heterologous protection against SARS-CoV-2 infection in susceptible K18-hACE2 mice. Furthermore, in C57BL/6 mice, prophylactic administration of MV130 improves the immunogenicity of two different COVID-19 vaccine formulations targeting the SARS-CoV-2 spike (S) protein, inoculated either intramuscularly or intranasally. Independently of the vaccine candidate and vaccination route used, intranasal prophylaxis with MV130 boosted S-specific responses, including CD8+-T cell activation and the production of S-specific mucosal IgA antibodies. Therefore, the bacterial mucosal immunotherapy MV130 protects against SARS-CoV-2 infection and improves COVID-19 vaccines immunogenicity.

Targeting Macrophage Dysregulation for Viral Infections: Novel Targets for Immunomodulators.

A major barrier to human immunodeficiency virus (HIV-1) cure is the latent viral reservoir, which persists despite antiretroviral therapy (ART), including across the non-dividing myeloid reservoir which is found systemically in sanctuary sites across tissues and the central nervous system (CNS). Unlike activated CD4+ T cells that undergo rapid cell death during initial infection (due to rapid viral replication kinetics), viral replication kinetics are delayed in non-dividing myeloid cells, resulting in long-lived survival of infected macrophages and macrophage-like cells. Simultaneously, persistent inflammation in macrophages confers immune dysregulation that is a key driver of co-morbidities including cardiovascular disease (CVD) and neurological deficits in people living with HIV-1 (PLWH). Macrophage activation and dysregulation is also a key driver of disease progression across other viral infections including SARS-CoV-2, influenza, and chikungunya viruses, underscoring the interplay between macrophages and disease progression, pathogenesis, and comorbidity in the viral infection setting. This review discusses the role of macrophages in persistence and pathogenesis of HIV-1 and related comorbidities, SARS-CoV-2 and other viruses. A special focus is given to novel immunomodulatory targets for key events driving myeloid cell dysregulation and reservoir maintenance across a diverse array of viral infections.

Beta-Glucans from Fungi: Biological and Health-Promoting Potential in the COVID-19 Pandemic Era.

Beta-glucans comprise a group of polysaccharides of natural origin found in bacteria, algae, and plants, e.g., cereal seeds, as well as microfungi and macrofungi (mushrooms), which are characterized by diverse structures and functions. They are known for their metabolic and immunomodulatory properties, including anticancer, antibacterial, and antiviral. Recent reports suggest a potential of beta-glucans in the prevention and treatment of COVID-19. In contrast to ß-glucans from other sources, ß-glucans from mushrooms are characterized by ß-1,3-glucans with short ß-1,6-side chains. This structure is recognized by receptors located on the surface of immune cells; thus, mushroom ß-glucans have specific immunomodulatory properties and gained BRM (biological response modifier) status. Moreover, mushroom beta-glucans also owe their properties to the formation of triple helix conformation, which is one of the key factors influencing the bioactivity of mushroom beta-glucans. This review summarizes the latest findings on biological and health-promoting potential of mushroom beta-glucans for the treatment of civilization and viral diseases, with particular emphasis on COVID-19.

Of bats and men: Immunomodulatory treatment options for COVID-19 guided by the immunopathology of SARS-CoV-2 infection.

In humans, SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is highly infective, often causes severe acute and/or long-term illness, and elicits a high rate of mortality, even in countries with sophisticated medical systems. Detailed knowledge on the immune responses underpinning COVID-19 (coronavirus disease 2019), and on strategies SARS-CoV-2 uses to evade them, can provide pivotal guidance to researchers and clinicians developing and administering potentially life-saving immunomodulatory therapies. The need for such therapies in COVID-19 is unlikely to abate soon given the emergence of variants of concern that may pose new challenges for some vaccines and neutralizing antibodies. Here, we summarize current knowledge on COVID-19 immunopathogenesis in relation to three clinical disease stages and focus on immune evasion strategies used by pathogenic coronaviruses such as skewing type I, II, and III interferon responses and inhibiting detection via pattern recognition and antigen presentation. Insights gained from bats, which exhibit minimal disease in response to SARS-CoV-2 infection, offer an informative perspective and may guide future development of new therapies. We also discuss how knowledge of immunopathology may inform therapeutic decisions, for example, on selecting the most appropriate immunotherapeutic agents and timing their administration, to reduce morbidity and mortality of COVID-19.

Membrane Microvesicles as Potential Vaccine Candidates.

The prevention and control of infectious diseases is crucial to the maintenance and protection of social and public healthcare. The global impact of SARS-CoV-2 has demonstrated how outbreaks of emerging and re-emerging infections can lead to pandemics of significant public health and socio-economic burden. Vaccination is one of the most effective approaches to protect against infectious diseases, and to date, multiple vaccines have been successfully used to protect against and eradicate both viral and bacterial pathogens. The main criterion of vaccine efficacy is the induction of specific humoral and cellular immune responses, and it is well established that immunogenicity depends on the type of vaccine as well as the route of delivery. In addition, antigen delivery to immune organs and the site of injection can potentiate efficacy of the vaccine. In light of this, microvesicles have been suggested as potential vehicles for antigen delivery as they can carry various immunogenic molecules including proteins, nucleic acids and polysaccharides directly to target cells. In this review, we focus on the mechanisms of microvesicle biogenesis and the role of microvesicles in infectious diseases. Further, we discuss the application of microvesicles as a novel and effective vaccine delivery system.

BPIFB4 Circulating Levels and Its Prognostic Relevance in COVID-19.

Aging and comorbidities make individuals at greatest risk of COVID-19 serious illness and mortality due to senescence-related events and deleterious inflammation. Long-living individuals (LLIs) are less susceptible to inflammation and develop more resiliency to COVID-19. As demonstrated, LLIs are characterized by high circulating levels of BPIFB4, a protein involved in homeostatic response to inflammatory stimuli. Also, LLIs show enrichment of homozygous genotype for the minor alleles of a 4 missense single-nucleotide polymorphism haplotype (longevity-associated variant [LAV]) in BPIFB4, able to counteract progression of diseases in animal models. Thus, the present study was designed to assess the presence and significance of BPIFB4 level in COVID-19 patients and the potential therapeutic use of LAV-BPIFB4 in fighting COVID-19. BPIFB4 plasma concentration was found significantly higher in LLIs compared to old healthy controls while it significantly decreased in 64 COVID-19 patients. Further, the drop in BPIFB4 values correlated with disease severity. Accordingly to the LAV-BPIFB4 immunomodulatory role, while lysates of SARS-CoV-2-infected cells induced an inflammatory response in healthy peripheral blood mononuclear cells in vitro, the co-treatment with recombinant protein (rh) LAV-BPIFB4 resulted in a protective and self-limiting reaction, culminating in the downregulation of CD69 activating-marker for T cells (both TCD4+ and TCD8+) and in MCP-1 reduction. On the contrary, rhLAV-BPIFB4 induced a rapid increase in IL-18 and IL-1b levels, shown largely protective during the early stages of the virus infection. This evidence, along with the ability of rhLAV-BPIFB4 to counteract the cytotoxicity induced by SARS-CoV-2 lysate in selected target cell lines, corroborates BPIFB4 prognostic value and open new therapeutic possibilities in more vulnerable people.

Recent updates on immunological, pharmacological, and alternative approaches to combat COVID-19.

The pandemic coronavirus disease 2019 (COVID-19) is instigated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that is mainly transmitted via the inhalation route and characterized by fever, coughing and shortness of breath. COVID-19 affects all age groups with no single cure. The drug discovery, manufacturing, and safety studies require extensive time and sources and, therefore, struggled to match the exponential spread of COVID-19. Yet, various repurposed drugs (antivirals, immune-modulators, nucleotide analogues), and convalescent plasma therapy have been authorized for emergency use against COVID-19 by Food and Drug Administration under certain limits and conditions. The discovery of vaccine is the biggest milestone achieved during the current pandemic era. About nine vaccines were developed for human use with varying claims of efficacy. The rapid emergence of mutations in SARS-CoV-2, suspected adverse drug reactions of current therapies in special population groups and limited availability of drugs in developing countries necessitate the development of more efficacious, safe and cheap drugs/vaccines for treatment and prevention of COVID-19. Keeping in view these limitations, the current review provides an update on the efficacy and safety of the repurposed, and natural drugs to treat COVID-19 as well as the vaccines used for its prophylaxis.

The preparation of N-IgY targeting SARS-CoV-2 and its immunomodulation to IFN-γ production in vitro.

Specific antibodies against SARS-CoV-2 structural protein have a wide range of effects in the diagnose, prevention and treatment of the COVID-19 epidemic. Among them, egg yolk immunoglobulin Y (IgY), which has high safety, high yield, and without inducing antibody-dependent enhancement, is an important biological candidate. In this study, specific IgY against the conservative nucleocapsid protein (NP) of SARS-CoV-2 was obtained by immunizing hens. Through a series of optimized precipitation and ultrafiltration extraction schemes, its purity was increased to 98%. The hyperimmune IgY against NP (N-IgY) at a titer of 1:50,000 showed strong NP binding ability, which laid the foundation of N-IgY's application targeting NP. In an in vitro immunoregulatory study, N-IgY (1 mg/mL) modulated NP-induced immune response by alleviating type II interferon secretion stimulated by NP (20 µg/mL). In summary, N-IgY can be mass produced by achievable method, which endows it with potential value against the current COVID-19 pandemic.

Interleukin-6: obstacles to targeting a complex cytokine in critical illness.

Circulating concentrations of the pleiotropic cytokine interleukin-6 (IL-6) are known to be increased in pro-inflammatory critical care syndromes, such as sepsis and acute respiratory distress syndrome. Elevations in serum IL-6 concentrations in patients with severe COVID-19 have led to renewed interest in the cytokine as a therapeutic target. However, although the pro-inflammatory properties of IL-6 are widely known, the cytokine also has a series of important physiological and anti-inflammatory functions. An adequate understanding of the complex processes by which IL-6 signalling occurs is crucial for the correct interpretation of IL-6 concentrations in the blood or lung, the use of IL-6 as a critical care biomarker, or the design of effective anti-IL-6 strategies. Here, we outline the role of IL-6 in health and disease, explain the different types of IL-6 signalling and their contribution to the net biological effect of the cytokine, describe the approaches to IL-6 inhibition that are currently available, and discuss implications for the future use of treatments such as tocilizumab in the critical care setting.

Drug delivery systems as immunomodulators for therapy of infectious disease: Relevance to COVID-19.

The emergence of SARS-CoV-2, and the ensuing global pandemic, has resulted in an unprecedented response to identify therapies that can limit uncontrolled inflammation observed in patients with moderate to severe COVID-19. The immune pathology behind COVID-19 is complex and involves the activation and interaction of multiple systems including, but not limited to, complement, inflammasomes, endothelial as well as innate and adaptive immune cells to bring about a convoluted profile of inflammation, coagulation and tissue damage. To date, therapeutic approaches have focussed on inhibition of coagulation, untargeted immune suppression and/or cytokine-directed blocking agents. Regardless of recently achieved improvements in individual patient outcomes and survival rates, improved and focussed approaches targeting individual systems involved is needed to further improve prognosis and wellbeing. This review summarizes the current understanding of molecular and cellular systems involved in the pathophysiology of COVID-19, and their contribution to pathogen clearance and damage to then discuss possible therapeutic options involving immunomodulatory drug delivery systems as well as summarising the complex interplay between them.

Society on NeuroImmune Pharmacology COVID-19 Virtual Workshop.

This brief report collects the program and abstracts of the Society on NeuroImmune Pharmacology (SNIP) COVID-19 Virtual Workshop held on April 9, 2021. The workshop consisted of four symposia: Symposium 1: Molecular approaches to COVID-19 pathogenesis and underlying mechanisms; Symposium 2: Therapeutic and vaccine approaches to COVID-19; Symposium 3: Early Career Investigator talks; and Symposium 4: Diversity and Inclusion SNIP Committee (DISC) program: Well-being and reflections. The workshop also featured four special talks on COVID-19 and funding opportunities from the National Institute on Alcohol Abuse and Alcoholism (NIAAA); COVID-19 and funding opportunities from the National Institute on Drug Abuse (NIDA); opportunities from NIH for early career investigator (ECI) fellows; and neurologic and psychiatric complications of SARS-CoV-2 infection. Presenters included NIH officials, SNIP members, and non-member scientists whose abstracts were submitted and accepted for inclusion in the virtual event hosted by the University of Nebraska Medical Center via Zoom webinar. A special theme issue of SNIP's official journal, the Journal of Neuroimmune Pharmacology (JNIP), will collect select papers from the workshop along with other related manuscripts in a special theme issue titled "Neuroimmune Pharmacology of SARS-CoV-2."

Immunomodulatory agents as potential therapeutic or preventive strategies for COVID-19.

Currently, the COVID-19 pandemic, caused by the novel SARS-CoV-2 coronavirus, represents the greatest global health threat. Most people infected by the virus present mild to moderate respiratory symptoms and recover with supportive treatments. However, certain susceptible hosts develop an acute respiratory distress syndrome (ARDS), associated with an inflammatory "cytokine storm", leading to lung damage. Despite the current availability of different COVID-19 vaccines, the new emerging SARS-CoV-2 genetic variants represent a major concern worldwide, due to their increased transmissibility and rapid spread. Indeed, it seems that some mutations or combinations of mutations might confer selective advantages to the virus, such as the ability to evade the host immune responses elicited by COVID-19 vaccines. Several therapeutic approaches have been investigated but, to date, a unique and fully effective therapeutic protocol has not yet been achieved. In addition, steroid-based therapies, aimed to reduce inflammation in patients with severe COVID-19 disease, may increase the risk of opportunistic infections, increasing the hospitalization time and mortality rate of these patients. Hence, there is an unmet need to develop more effective therapeutic options. Here, we discuss the potential use of natural immunomodulators such as Thymosin α1 (Tα1), all-trans retinoic acid (ATRA), and lactoferrin (LF), as adjunctive or preventive treatment of severe COVID-19 disease. These agents are considered to be multifunctional molecules because of their ability to enhance antiviral host immunity and restore the immune balance, depending on the host immune status. Furthermore, they are able to exert a broad-spectrum antimicrobial activity by means of direct interactions with cellular or molecular targets of pathogens or indirectly by increasing the host immune response. Thus, due to the aforementioned properties, these agents might have a great potential in a clinical setting, not only to counteract SARS-CoV-2 infection, but also to prevent opportunistic infections in critically ill COVID-19 patients.

Evaluation of Th1 and Th2 mediated cellular and humoral immunity in patients with COVID-19 following the use of melatonin as an adjunctive treatment.

Coronavirus (SARS-CoV-2) is spreading rapidly in the world and is still taking a heavy toll. Studies show that cytokine storms and imbalances in T-helper (Th)1/Th2 play a significant role in most acute cases of the disease. A number of medications have been suggested to treat or control the disease but have been discontinued due to their side effects. Melatonin, as an intrinsic molecule, possesses pharmacological anti-inflammatory and antioxidant properties that decreases in concentration with age; as a result, older people are more prone to various diseases. In this study, patients who were hospitalized with a diagnosis of coronavirus disease 2019 (COVID-19) were given a melatonin adjuvant (9 mg daily, orally) for fourteen days. In order to measure markers of Th1 and Th2 inflammatory cytokines (such as interleukin (IL)-2, IL-4, and interferon (IFN)-γ) as well as the expression of Th1 and Th2 regulatory genes (signal transducer and activator of transcription (STAT)4, STAT6, GATA binding protein 3 (GATA3), and T-box expressed in T cell (T-bet)), blood samples were taken from patients at the beginning and end of the treatment. Adjuvant therapy with melatonin controlled and reduced inflammatory cytokines in patients with COVID-19. Melatonin also controlled and modulated the dysregulated genes that regulate the humoral and cellular immune systems mediated by Th1 and Th2. In this study, it was shown for the first time that melatonin can be used as a medicinal adjuvant with anti-inflammatory mechanism to reduce and control inflammatory cytokines by regulating the expression of Th1 and Th2 regulatory genes in patients with COVID-19.

Interplay of Anti-Viral Vaccines with Biologic Agents and Immunomodulators in Individuals with Autoimmune and Autoinflammatory Diseases.

Vaccines are an essential part of a preventative healthcare strategy. However, response to vaccines may be less predictable in immunocompromised people. While outcomes for individuals with autoimmune and autoinflammatory diseases have dramatically improved with treatment using immunomodulating and biologic agents, infections have caused significant morbidity in these people today often more than due to their underlying diseases. Immune-based biologic therapies contribute to these infectious complications. This review addresses anti-viral vaccines, their effectiveness and safety in patients treated with approved biologic agents and immune targeted therapy with a focus on vaccines against influenza, human papillomavirus, hepatitis B virus and varicella zoster virus. Preliminary information regarding SARS-CoV-2 anti-viral vaccines is addressed. Additionally, we present recommendations regarding the safe use of vaccines in immunocompromised individuals with the goal to enhance awareness of the safety and efficacy of these anti-viral vaccines in these high-risk populations.

α1-Antitrypsin: Key Player or Bystander in Acute Respiratory Distress Syndrome?

Acute respiratory distress syndrome is characterized by hypoxemia, altered alveolar-capillary permeability, and neutrophil-dominated inflammatory pulmonary edema. Despite decades of research, an effective drug therapy for acute respiratory distress syndrome remains elusive. The ideal pharmacotherapy for acute respiratory distress syndrome should demonstrate antiprotease activity and target injurious inflammatory pathways while maintaining host defense against infection. Furthermore, a drug with a reputable safety profile, low possibility of off-target effects, and well-known pharmacokinetics would be desirable. The endogenous 52-kd serine protease α1-antitrypsin has the potential to be a novel treatment option for acute respiratory distress syndrome. The main function of α1-antitrypsin is as an antiprotease, targeting neutrophil elastase in particular. However, studies have also highlighted the role of α1-antitrypsin in the modulation of inflammation and bacterial clearance. In light of the current SARS-CoV-2 pandemic, the identification of a treatment for acute respiratory distress syndrome is even more pertinent, and α1-antitrypsin has been implicated in the inflammatory response to SARS-CoV-2 infection.

Impact of disease-modifying drugs on the severity of COVID-19 infection in multiple sclerosis patients.

Recent evidence suggested that neurological manifestations occur in patients with a severe form of coronavirus disease (COVID-19). On the basis of this issue, neurologists are very concerned about patients with neurological disorders, especially multiple sclerosis (MS), as consumers of immunosuppressive or immune-modulating drugs. Therefore, the administration of proper disease-modifying therapies (DMTs) in MS patients is critical during the pandemic status. On the one hand, both the autoimmune diseases and immunosuppressive drugs increase the risk of infection due to impairment in the immune system, and on the other hand, postponing of MS treatment has serious consequences on the central nervous system. In the present study, we discussed recent literature about the effect of DMTs administration on the severity of COVID-19 in the MS patients. Overall, it seems that DMTs do not provoke the COVID-19 infection in the MS patients by declining immune responses and cytokine storm. However, as a precaution, the supervision of a neurologist is highly recommended.

Propolis antiviral and immunomodulatory activity: a review and perspectives for COVID-19 treatment.

OBJECTIVES: Viral outbreaks are a frequent concern for humans. A great variety of drugs has been used to treat viral diseases, which are not always safe and effective and may induce adverse effects, indicating the need for new antiviral drugs extracted from natural sources. Propolis is a bee-made product exhibiting many biological properties. An overview of viruses, antiviral immunity, propolis safety and its immunomodulatory and antiviral action is reported, as well as perspectives for coronavirus disease 2019 (COVID-19) treatment. PubMed platform was used for data collection, searching for the keywords "propolis", "virus", "antiviral", "antimicrobial" and "coronavirus". KEY FINDINGS: Propolis is safe and exerts antiviral and immunomodulatory activity; however, clinical trials should investigate its effects on individuals with viral diseases, in combination or not with antiviral drugs or vaccines. SUMMARY: Regarding COVID-19, the effects of propolis should be investigated directly on the virus in vitro or on infected individuals alone or in combination with antiviral drugs, due to its immunomodulatory and anti-inflammatory action. Propolis administration simultaneously with vaccines should be analyzed, due to its adjuvant properties, to enhance the individuals' immune response. The search for therapeutic targets may be useful to find out how propolis can help to control COVID-19.