Oxysterols in the Immune Response to Bacterial and Viral Infections

Oxidized cholesterols, the so-called oxysterols, are widely known to regulate cholesterol homeostasis. However, more recently oxysterols have emerged as important lipid mediators in the response to both bacterial and viral infections. This review summarizes our current knowledge of selected oxysterols and their receptors in the control of intracellular bacterial growth as well as viral entry into the host cell and viral replication. Lastly, we briefly discuss the potential of oxysterols and their receptors as drug targets for infectious and inflammatory diseases.

Download Full-text

Host Cell Restriction Factors of Bunyaviruses and Viral Countermeasures

Viruses ◽

10.3390/v13050784 ◽

2021 ◽

Vol 13 (5) ◽

pp. 784

Author(s):

Solène Lerolle ◽

Natalia Freitas ◽

François-Loïc Cosset ◽

Vincent Legros

Keyword(s):

Host Cell ◽

Viral Entry ◽

Current Knowledge ◽

Restriction Factors ◽

Antiviral State ◽

Cellular Factors ◽

Pathogenic Viruses ◽

Genome Transcription ◽

Infected Cells ◽

Molecular Patterns

The Bunyavirales order comprises more than 500 viruses (generally defined as bunyaviruses) classified into 12 families. Some of these are highly pathogenic viruses infecting different hosts, including humans, mammals, reptiles, arthropods, birds, and/or plants. Host cell sensing of infection activates the innate immune system that aims at inhibiting viral replication and propagation. Upon recognition of pathogen-associated molecular patterns (PAMPs) by cellular pattern recognition receptors (PRRs), numerous signaling cascades are activated, leading to the production of interferons (IFNs). IFNs act in an autocrine and paracrine manner to establish an antiviral state by inducing the expression of hundreds of IFN-stimulated genes (ISGs). Some of these ISGs are known to restrict bunyavirus infection. Along with other constitutively expressed host cellular factors with antiviral activity, these proteins (hereafter referred to as “restriction factors”) target different steps of the viral cycle, including viral entry, genome transcription and replication, and virion egress. In reaction to this, bunyaviruses have developed strategies to circumvent this antiviral response, by avoiding cellular recognition of PAMPs, inhibiting IFN production or interfering with the IFN-mediated response. Herein, we review the current knowledge on host cellular factors that were shown to restrict infections by bunyaviruses. Moreover, we focus on the strategies developed by bunyaviruses in order to escape the antiviral state developed by the infected cells.

Download Full-text

Antimalarial drugs—are they beneficial in rheumatic and viral diseases?—considerations in COVID-19 pandemic

Clinical Rheumatology ◽

10.1007/s10067-021-05805-5 ◽

2021 ◽

Author(s):

Bogna Grygiel-Górniak

Keyword(s):

Connective Tissue ◽

Viral Infections ◽

Current Knowledge ◽

Inflammatory Diseases ◽

Antiviral Drugs ◽

In Vivo Studies ◽

Viral Diseases ◽

Cardiac Complications

AbstractThe majority of the medical fraternity is continuously involved in finding new therapeutic schemes, including antimalarial medications (AMDs), which can be useful in combating the 2019-nCoV: coronavirus disease (COVID-19). For many decades, AMDs have been widely used in the treatment of malaria and various other anti-inflammatory diseases, particularly to treat autoimmune disorders of the connective tissue. The review comprises in vitro and in vivo studies, original studies, clinical trials, and consensus reports for the analysis, which were available in medical databases (e.g., PubMed). This manuscript summarizes the current knowledge about chloroquine (CQ)/hydroxychloroquine (HCQ) and shows the difference between their use, activity, recommendation, doses, and adverse effects on two groups of patients: those with rheumatic and viral diseases (including COVID-19). In the case of connective tissue disorders, AMDs are prescribed for a prolonged duration in small doses, and their effect is observed after few weeks, whereas in the case of viral infections, they are prescribed in larger doses for a short duration to achieve a quick saturation effect. In rheumatic diseases, AMDs are well tolerated, and their side effects are rare. However, in some viral diseases, the effect of AMDs is questionable or not so noticeable as suggested during the initial prognosis. They are mainly used as an additive therapy to antiviral drugs, but recent studies have shown that AMDs can diminish the efficacy of some antiviral drugs and may cause respiratory, kidney, liver, and cardiac complications.

Download Full-text

Trace Elements as Immunoregulators in SARS-CoV-2 and Other Viral Infections

Indian Journal of Clinical Biochemistry ◽

10.1007/s12291-021-00961-6 ◽

2021 ◽

Author(s):

Karthick Dharmalingam ◽

Amandeep Birdi ◽

Sojit Tomo ◽

Karli Sreenivasulu ◽

Jaykaran Charan ◽

...

Keyword(s):

Immune Response ◽

Trace Elements ◽

Viral Entry ◽

Viral Infections ◽

Inhibitory Effect ◽

Antioxidants Activity ◽

Host Immune Responses ◽

Complex Interactions ◽

Downstream Processes

AbstractNutritional deficiency is associated with impaired immunity and increased susceptibility to infections. The complex interactions of trace elements with the macromolecules trigger the effective immune response against the viral diseases. The outcome of various viral infections along with susceptibility is affected by trace elements such as zinc, selenium, iron, copper, etc. due to their immuno-modulatory effects. Available electronic databases have been comprehensively searched for articles published with full text available and with the key words “Trace elements”, “COVID-19”, “Viral Infections” and “Immune Response” (i.e. separately Zn, Se, Fe, Cu, Mn, Mo, Cr, Li, Ni, Co) appearing in the title and abstract. On the basis of available articles we have explored the role of trace elements in viral infections with special reference to COVID-19 and their interactions with the immune system. Zinc, selenium and other trace elements are vital to triggerTH1 cells and cytokine-mediated immune response for substantial production of proinflammatory cytokines. The antiviral activity of some trace elements is attributed to their inhibitory effect on viral entry, replication and other downstream processes. Trace elements having antioxidants activity not only regulate host immune responses, but also modify the viral genome. Adequate dietary intake of trace elements is essential for activation, development, differentiation and numerous functions.

Download Full-text

Epigenetic dysregulation of ACE2 and interferon-regulated genes might suggest increased COVID-19 susceptibility and severity in lupus patients

10.1101/2020.03.30.20047852 ◽

2020 ◽

Cited By ~ 3

Author(s):

Amr H. Sawalha ◽

Ming Zhao ◽

Patrick Coit ◽

Qianjin Lu

Keyword(s):

Oxidative Stress ◽

Immune Response ◽

Viral Entry ◽

Viral Infections ◽

Severe Disease ◽

Disease Course ◽

Vicious Cycle ◽

Respiratory Complications ◽

Disease Remission ◽

Functional Receptor

SummaryInfection caused by SARS-CoV-2 can result in severe respiratory complications and death. Patients with a compromised immune system are expected to be more susceptible to a severe disease course. In this report we suggest that patients with systemic lupus erythematous might be especially prone to severe COVID-19 independent of their immunosuppressed state from lupus treatment. Specially, we provide evidence in lupus to suggest hypomethylation and overexpression of ACE2, which is located on the X chromosome and encodes a functional receptor for the SARS-CoV-2 spike glycoprotein. Oxidative stress induced by viral infections exacerbates the DNA methylation defect in lupus, possibly resulting in further ACE2 hypomethylation and enhanced viremia. In addition, demethylation of interferon-regulated genes, NFκB, and key cytokine genes in lupus patients might exacerbate the immune response to SARS-CoV-2 and increase the likelihood of cytokine storm. These arguments suggest that inherent epigenetic dysregulation in lupus might facilitate viral entry, viremia, and an excessive immune response to SARS-CoV-2. Further, maintaining disease remission in lupus patients is critical to prevent a vicious cycle of demethylation and increased oxidative stress, which will exacerbate susceptibility to SARS-CoV-2 infection during the current pandemic. Epigenetic control of the ACE2 gene might be a target for prevention and therapy in COVID-19.

Download Full-text

New Insights on the Role of pentraxin-3 in Allergic Asthma

Frontiers in Allergy ◽

10.3389/falgy.2021.678023 ◽

2021 ◽

Vol 2 ◽

Author(s):

Latifa Koussih ◽

Samira Atoui ◽

Omar Tliba ◽

Abdelilah S. Gounni

Keyword(s):

Immune Response ◽

Allergic Asthma ◽

Current Knowledge ◽

Inflammatory Diseases ◽

Protective Role ◽

Severe Form ◽

Innate Immune ◽

Pentraxin 3 ◽

Complement Components

Pentraxins are soluble pattern recognition receptors that play a major role in regulating innate immune responses. Through their interaction with complement components, Fcγ receptors, and different microbial moieties, Pentraxins cause an amplification of the inflammatory response. Pentraxin-3 is of particular interest since it was identified as a biomarker for several immune-pathological diseases. In allergic asthma, pentraxin-3 is produced by immune and structural cells and is up-regulated by pro-asthmatic cytokines such as TNFα and IL-1β. Strikingly, some recent experimental evidence demonstrated a protective role of pentraxin-3 in chronic airway inflammatory diseases such as allergic asthma. Indeed, reduced pentraxin-3 levels have been associated with neutrophilic inflammation, Th17 immune response, insensitivity to standard therapeutics and a severe form of the disease. In this review, we will summarize the current knowledge of the role of pentraxin-3 in innate immune response and discuss the protective role of pentraxin-3 in allergic asthma.

Download Full-text

How fragile we are. Influence of STimulator of INterferon Genes, STING, variants on pathogen recognition and immune response efficiency

10.1101/2021.07.12.452045 ◽

2021 ◽

Author(s):

Jeremy Morere ◽

Cecilia Hognon ◽

Tom Miclot ◽

Tao Jiang ◽

Elise Dumont ◽

...

Keyword(s):

Immune Response ◽

Molecular Mechanisms ◽

Viral Infections ◽

Inflammatory Diseases ◽

Dynamical Behavior ◽

Structural Features ◽

Type I Interferons ◽

Machine Learning Techniques ◽

Type I ◽

Interaction Patterns

The STimulator of INterferon Genes (STING) protein is a cornerstone of the human immune response. Its activation by cGAMP upon the presence of cytosolic DNA stimulates the production of type I interferons and inflammatory cytokines which are crucial for protecting cells from infections. STING signaling pathway can also influence both tumor-suppressive and tumor-promoting mechanisms, rendering it an appealing target for drug design. In the human population, several STING variants exist and exhibit dramatic differences in their activity, impacting the efficiency of the host defense against infections. Understanding the differential molecular mechanisms exhibited by these variants is of utmost importance notably towards personalized medicine treatments against diseases such as viral infections (COVID-19, Dengue...), cancers, or auto-inflammatory diseases. Owing to micro-seconds scale molecular modeling simulations and post-processing by contacts analysis and Machine Learning techniques, we reveal the dynamical behavior of four STING variants (wild type, G230A, R293Q, and G230A-R293Q) and we rationalize the variability of efficiency observed experimentally. Our results show that the decrease of STING activity is linked to a stiffening of key-structural features of the binding cavity, together with changes of the interaction patterns within the protein.

Download Full-text

Immunomodulatory Role of Nutrients: How Can Pulmonary Dysfunctions Improve?

Frontiers in Nutrition ◽

10.3389/fnut.2021.674258 ◽

2021 ◽

Vol 8 ◽

Author(s):

Sarah Cristina Gozzi-Silva ◽

Franciane Mouradian Emidio Teixeira ◽

Alberto José da Silva Duarte ◽

Maria Notomi Sato ◽

Luana de Mendonça Oliveira

Keyword(s):

Fatty Acids ◽

Immune Response ◽

Immune System ◽

Viral Infections ◽

Inflammatory Diseases ◽

Dietary Factors ◽

Chronic Inflammatory Diseases ◽

Anti Inflammatory ◽

Lung Health

Nutrition is an important tool that can be used to modulate the immune response during infectious diseases. In addition, through diet, important substrates are acquired for the biosynthesis of regulatory molecules in the immune response, influencing the progression and treatment of chronic lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD). In this way, nutrition can promote lung health status. A range of nutrients, such as vitamins (A, C, D, and E), minerals (zinc, selenium, iron, and magnesium), flavonoids and fatty acids, play important roles in reducing the risk of pulmonary chronic diseases and viral infections. Through their antioxidant and anti-inflammatory effects, nutrients are associated with better lung function and a lower risk of complications since they can decrease the harmful effects from the immune system during the inflammatory response. In addition, bioactive compounds can even contribute to epigenetic changes, including histone deacetylase (HDAC) modifications that inhibit the transcription of proinflammatory cytokines, which can contribute to the maintenance of homeostasis in the context of infections and chronic inflammatory diseases. These nutrients also play an important role in activating immune responses against pathogens, which can help the immune system during infections. Here, we provide an updated overview of the roles played by dietary factors and how they can affect respiratory health. Therefore, we will show the anti-inflammatory role of flavonoids, fatty acids, vitamins and microbiota, important for the control of chronic inflammatory diseases and allergies, in addition to the antiviral role of vitamins, flavonoids, and minerals during pulmonary viral infections, addressing the mechanisms involved in each function. These mechanisms are interesting in the discussion of perspectives associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and its pulmonary complications since patients with severe disease have vitamins deficiency, especially vitamin D. In addition, researches with the use of flavonoids have been shown to decrease viral replication in vitro. This way, a full understanding of dietary influences can improve the lung health of patients.

Download Full-text

Residue-level resolution of alphavirus envelope protein interactions in pH-dependent fusion

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1414190112 ◽

2015 ◽

Vol 112 (7) ◽

pp. 2034-2039 ◽

Cited By ~ 17

Author(s):

Xiancheng Zeng ◽

Suchetana Mukhopadhyay ◽

Charles L. Brooks

Keyword(s):

Conformational Changes ◽

Protein Interactions ◽

Viral Entry ◽

Drug Targets ◽

Viral Infections ◽

Driving Forces ◽

Specific Treatment ◽

Icosahedral Symmetry ◽

Endosomal Membranes ◽

Ph Dependent

Alphavirus envelope proteins, organized as trimers of E2–E1 heterodimers on the surface of the pathogenic alphavirus, mediate the low pH-triggered fusion of viral and endosomal membranes in human cells. The lack of specific treatment for alphaviral infections motivates our exploration of potential antiviral approaches by inhibiting one or more fusion steps in the common endocytic viral entry pathway. In this work, we performed constant pH molecular dynamics based on an atomic model of the alphavirus envelope with icosahedral symmetry. We have identified pH-sensitive residues that cause the largest shifts in thermodynamic driving forces under neutral and acidic pH conditions for various fusion steps. A series of conserved interdomain His residues is identified to be responsible for the pH-dependent conformational changes in the fusion process, and ligand binding sites in their vicinity are anticipated to be potential drug targets aimed at inhibiting viral infections.

Download Full-text

Acyl-coenzyme A:cholesterol acyltransferases

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.90926.2008 ◽

2009 ◽

Vol 297 (1) ◽

pp. E1-E9 ◽

Cited By ~ 235

Author(s):

Ta-Yuan Chang ◽

Bo-Liang Li ◽

Catherine C. Y. Chang ◽

Yasuomi Urano

Keyword(s):

Drug Targets ◽

Current Knowledge ◽

Fatty Acyl ◽

Cholesterol Homeostasis ◽

Cholesteryl Esters ◽

Cellular Cholesterol ◽

Related Research ◽

Membrane Bound ◽

Acyl Coenzyme A ◽

Long Chain

The enzymes acyl-coenzyme A (CoA):cholesterol acyltransferases (ACATs) are membrane-bound proteins that utilize long-chain fatty acyl-CoA and cholesterol as substrates to form cholesteryl esters. In mammals, two isoenzymes, ACAT1 and ACAT2, encoded by two different genes, exist. ACATs play important roles in cellular cholesterol homeostasis in various tissues. This chapter summarizes the current knowledge on ACAT-related research in two areas: 1) ACAT genes and proteins and 2) ACAT enzymes as drug targets for atherosclerosis and for Alzheimer's disease.

Download Full-text

Cardiac Glycosides as Immune System Modulators

Biomolecules ◽

10.3390/biom11050659 ◽

2021 ◽

Vol 11 (5) ◽

pp. 659

Author(s):

Jan Škubník ◽

Vladimíra Pavlíčková ◽

Silvie Rimpelová

Keyword(s):

Immune Response ◽

Anticancer Agents ◽

Cardiac Glycosides ◽

Immune Cell ◽

Current Knowledge ◽

Inflammatory Diseases ◽

Large Area ◽

Strongly Connected ◽

Autoimmune And Inflammatory Diseases ◽

Multiple Signaling

Cardiac glycosides (CGs) are natural steroid compounds occurring both in plants and animals. They are known for long as cardiotonic agents commonly used for various cardiac diseases due to inhibition of Na+/K+-ATPase (NKA) pumping activity and modulating heart muscle contractility. However, recent studies show that the portfolio of diseases potentially treatable with CGs is much broader. Currently, CGs are mostly studied as anticancer agents. Their antiproliferative properties are based on the induction of multiple signaling pathways in an NKA signalosome complex. In addition, they are strongly connected to immunogenic cell death, a complex mechanism of induction of anticancer immune response. Moreover, CGs exert various immunomodulatory effects, the foremost of which are connected with suppressing the activity of T-helper cells or modulating transcription of many immune response genes by inhibiting nuclear factor kappa B. The resulting modulations of cytokine and chemokine levels and changes in immune cell ratios could be potentially useful in treating sundry autoimmune and inflammatory diseases. This review aims to summarize current knowledge in the field of immunomodulatory properties of CGs and emphasize the large area of potential clinical use of these compounds.

Download Full-text