sphingosine-1-phosphate and Virus-Diseases

Viruses can create a unique cellular environment that facilitates replication and transmission. Sphingosine kinases (SphKs) produce sphingosine-1-phosphate (S1P), a bioactive sphingolipid molecule that performs both physiological and pathological effects primarily by activating a subgroup of the endothelial differentiation gene family of G-protein coupled cell surface receptors known as S1P receptors (S1PR1-5). A growing body of evidence indicates that the SphK/S1P axis is crucial for regulating cellular activities in virus infections like respiratory viruses, enteroviruses, hepatitis viruses, herpes viruses, and arboviruses replicate. Depending on the type of virus, pro- or anti-viral activities of the SphK/S1P axis sometimes rely on the host immune system and sometimes directly through intracellular signalling pathways or cell proliferation. Recent research has shown novel roles of S1P and SphK in viral replication. Sphingosine kinase isoforms (SphK1 and SphK2) levels can be manipulated by several viruses to promote the effects that are expected. Regulation of cellular signalling pathways plays a significant role in the mechanism. The purpose of this review is to provide insight of the characters played by the SphK/S1P axis throughout diverse viral infection processes. We then assess potential therapeutic methods that are based on S1P signalling and metabolism during viral infections.

Topics: Humans; Lysophospholipids; Phosphotransferases (Alcohol Group Acceptor); Signal Transduction; Sphingosine; Virus Diseases; Virus Replication; Viruses

Sphingolipids are essential components of all eukaryotic membranes. The bioactive sphingolipid molecule, Sphingosine 1-Phosphate (S1P), regulates various important biological functions. This review aims to provide a comprehensive overview of the role of S1P signaling pathway in various immune cell functions under different pathophysiological conditions including bacterial and viral infections, autoimmune disorders, inflammation, and cancer. We covered the aspects of S1P pathways in NOD/TLR pathways, bacterial and viral infections, autoimmune disorders, and tumor immunology. This implies that targeting S1P signaling can be used as a strategy to block these pathologies. Our current understanding of targeting various components of S1P signaling for therapeutic purposes and the present status of S1P pathway inhibitors or modulators in disease conditions where the host immune system plays a pivotal role is the primary focus of this review.

Topics: Autoimmune Diseases; Humans; Signal Transduction; Sphingolipids; Sphingosine; Virus Diseases

Sphingolipids are important structural membrane components and, together with cholesterol, are often organized in lipid rafts, where they act as signaling molecules in many cellular functions. They play crucial roles in regulating pathobiological processes, such as cancer, inflammation, and infectious diseases. The bioactive metabolites ceramide, sphingosine-1-phosphate, and sphingosine have been shown to be involved in the pathogenesis of several microbes. In contrast to ceramide, which often promotes bacterial and viral infections (for instance, by mediating adhesion and internalization), sphingosine, which is released from ceramide by the activity of ceramidases, kills many bacterial, viral, and fungal pathogens. In particular, sphingosine is an important natural component of the defense against bacterial pathogens in the respiratory tract. Pathologically reduced sphingosine levels in cystic fibrosis airway epithelial cells are normalized by inhalation of sphingosine, and coating plastic implants with sphingosine prevents bacterial infections. Pretreatment of cells with exogenous sphingosine also prevents the viral spike protein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) from interacting with host cell receptors and inhibits the propagation of herpes simplex virus type 1 (HSV-1) in macrophages. Recent examinations reveal that the bactericidal effect of sphingosine might be due to bacterial membrane permeabilization and the subsequent death of the bacteria.

Topics: Animals; Bacterial Infections; Cell Wall; Ceramides; Disease Models, Animal; Herpesvirus 1, Human; Humans; Lysophospholipids; Membrane Microdomains; Mycoses; SARS-CoV-2; Signal Transduction; Sphingolipids; Sphingosine; Virus Diseases

The sphingosine 1-phosphate (S1P) metabolic pathway is a dynamic regulator of multiple cellular and disease processes. Identification of the immune regulatory role of the sphingosine analog FTY720 led to the development of the first oral therapy for the treatment of an autoimmune disease, multiple sclerosis. Furthermore, inhibitors of sphingosine kinase (SphK), which mediate S1P synthesis, are being evaluated as a therapeutic option for the treatment of cancer. In conjunction with these captivating discoveries, S1P and S1P-metabolizing enzymes have been revealed to display vital functions during virus infections. For example, S1P lyase, which is known for metabolizing S1P, inhibits influenza virus replication by promoting antiviral type I interferon innate immune responses. In addition, both isoforms of sphingosine kinase have been shown to regulate the replication or pathogenicity of many viruses. Pro- or antiviral activities of S1P-metabolizing enzymes appear to be dependent on diverse virus-host interactions and viral pathogenesis. This review places an emphasis on summarizing the functions of S1P-metabolizing enzymes during virus infections and discusses the opportunities for designing pioneering antiviral drugs by targeting these host enzymes.

Topics: Aldehyde-Lyases; Antiviral Agents; Host-Pathogen Interactions; Humans; Immunity, Innate; Interferon Type I; Lysophospholipids; Phosphotransferases (Alcohol Group Acceptor); Sphingosine; Virus Diseases; Virus Replication; Viruses

Sphingosine kinase 1 (SphK1) is an enzyme that phosphorylates the lipid sphingosine to generate sphingosine-1-phosphate (S1P). S1P can act intracellularly as a signaling molecule and extracellularly as a receptor ligand. The SphK1/S1P axis has well-described roles in cell signaling, the cell death/survival decision, the production of a pro-inflammatory response, immunomodulation, and control of vascular integrity. Agents targeting the SphK1/S1P axis are being actively developed as therapeutics for cancer and immunological and inflammatory disorders. Control of cell death/survival and pro-inflammatory immune responses is central to the pathology of infectious disease, and we can capitalize on the knowledge provided by investigations of SphK1/S1P in cancer and immunology to assess its application to selected human infections. We have herein reviewed the growing literature relating viral infections to changes in SphK1 and S1P. SphK1 activity is reportedly increased following human cytomegalovirus and respiratory syncytial virus infections, and elevated SphK1 enhances influenza virus infection. In contrast, SphK1 activity is reduced in bovine viral diarrhea virus and dengue virus infections. Sphingosine analogs that modulate S1P receptors have proven useful in animal models in alleviating influenza virus infection but have shown no benefit in simian human immunodeficiency virus and lymphocytic choriomeningitis virus infections. We have rationalized a role for SphK1/S1P in dengue virus, chikungunya virus, and Ross River virus infections, on the basis of the biology and the pathology of these diseases. The increasing number of effective SphK1 and S1P modulating agents currently in development makes it timely to investigate these roles with the potential for developing modulators of SphK1 and S1P for novel anti-viral therapies.

Topics: Animals; Disease Models, Animal; Humans; Immunologic Factors; Lysophospholipids; Phosphotransferases (Alcohol Group Acceptor); Signal Transduction; Sphingosine; Virus Diseases

Viral infections may have an important role in the precipitation or relapse of multiple sclerosis (MS) and its treatment. This review describes the normal immune response to viral infection, the possible associations between viral infections and MS therapy, and the impact of sphingosine 1-phosphate (S1P) receptor (S1PR) modulation with fingolimod (FTY720) on the immune responses to viral infection. The physiologic immune response to viral infection involves lymphocyte activation and control of the circulation of subsets of lymphocytes with different functions between the lymph nodes, vascular system, and tissues, under the control of the S1P/S1PR signaling mechanism. In MS, it has been postulated that viral infections may play a role in triggering MS relapses, with virus-specific T cells being responsible for the demyelinating lesions within the CNS. Fingolimod-an S1PR modulator approved for the treatment of relapsing MS in some countries-is thought to act by downmodulating lymphatic S1P subtype 1 receptors. This retains naïve T cells and central memory T cells, but not effector memory T cells, within the lymph nodes and prevents their circulation to the CNS. Evidence from infection models supports that the selective effects of fingolimod on T cell subsets allows key immune responses to be preserved during therapy. However, in patients, long-term observation is important as both the risk of cancer and infection is potentially increased by the use of any immunomodulatory agent.

Topics: Animals; Fingolimod Hydrochloride; Gene Expression Regulation; Humans; Immune System; Immunosuppressive Agents; Lymphocytes; Lysophospholipids; Multiple Sclerosis; Propylene Glycols; Receptors, Lysosphingolipid; Signal Transduction; Sphingosine; Virus Diseases

Tissue-resident memory (T

Topics: Animals; CD8-Positive T-Lymphocytes; Cell Movement; Female; Immunologic Memory; Interferon-gamma; Mice; Mice, Inbred C57BL; Positive Regulatory Domain I-Binding Factor 1; Receptors, Antigen, T-Cell; Receptors, CXCR6; Skin; Virus Diseases