tretinoin and Virus-Diseases

Vaccines are not presently available to prevent adherence and transmission of many common pathogens at mucosal surfaces. As a result, sexually transmitted diseases were one of the most commonly reported infections in the US in 1999. New methods are needed to reduce the spread of mucosal infections. Providing nonspecific protective factors, such as lipids and retinoids found in human milk to mucosal surfaces could reduce mucosal infection caused by viruses, e.g., herpes simplex virus-1 (HSV-1) and bacteria, e.g., Pseudomonas aeruginosa. Human milk lipids enzymatically modified to produce monoglycerides were antimicrobial and inactivated enveloped viruses, as well as gram-positive and gram-negative bacteria. Enveloped viruses were inactivated in seconds following contact with antimicrobial lipids, and P. aeruginosa infectivity was reduced by 99.9% after 2 hours. Transmission of pathogens at mucosal surfaces can also be prevented using retinoids that inhibit viral replication. In a human embryonic intestinal cell line the retinoic acid (RA) derivatives all-trans-RA and 9-cis-RA (10 microg/mL) decreased the production of HSV-1 and Echo-6 viruses by 1-2 log10 over a 48-hour period. In addition, all-trans-RA inhibited HSV-1 replication in Vero cells as effectively as interferon beta, reducing viral production by 2.5log10. These studies indicate that lipids and retinoids could be part of a topical microbicide to prevent mucosal infections.

Topics: Anti-Infective Agents, Local; Antiviral Agents; Delivery, Obstetric; Female; Humans; Infections; Infectious Disease Transmission, Vertical; Milk, Human; Sexually Transmitted Diseases; Tretinoin; Vaginal Diseases; Vaginosis, Bacterial; Virus Diseases

Innate immunity provides the first line of host defense against invading microbial pathogens. This defense involves retinoic acid-inducible gene-I-like receptors that detect viral RNA and activate the mitochondrial antiviral-signaling (MAVS) protein, an adaptor protein, leading to activation of the innate antiviral immune response. The mechanisms by which the MAVS signalosome assembles on mitochondria are only partially understood. Here, we identify tripartite motif 14 (TRIM14) as a mediator in the immune response against viral infection. TRIM14 localizes to the outer membrane of mitochondria and interacts with MAVS. Upon viral infection, TRIM14 undergoes Lys-63-linked polyubiquitination at Lys-365 and recruits NF-κB essential modulator to the MAVS signalosome, leading to the activation of both the IFN regulatory factor 3 and NF-κB pathways. Knockdown of TRIM14 disrupts the association between NF-κB essential modulator and MAVS and attenuates the antiviral response. Our results indicate that TRIM14 is a component of the mitochondrial antiviral immunity that facilitates the immune response mediated by retinoic acid-inducible gene-I-like receptors.

Topics: Adaptor Proteins, Signal Transducing; Carrier Proteins; Cell Line; Chromatography, Gel; DNA Primers; Humans; I-kappa B Kinase; Immunity, Innate; Intracellular Signaling Peptides and Proteins; Microscopy, Fluorescence; Multiprotein Complexes; Real-Time Polymerase Chain Reaction; RNA Interference; Signal Transduction; Tretinoin; Tripartite Motif Proteins; Virus Diseases

Retinoic acid (RA) suppressed the production of interferon (IFN) alpha and IFN gamma of human peripheral blood leukocytes in response to stimulation with lectin mitogens, bacterial products, synthetic polynucleotides, viruses, and tumor cell lines in vitro. Virus-induced secretion of IFN alpha of human lymphoblastoid cells was also inhibited. RA-mediated suppression was dose-dependent and required the near-concurrent addition of RA and inducers to human leukocyte cultures, thus suggesting that RA affects an early cellular function in the generation of IFN. Implications of these findings for the use of retinoids in the treatment of human malignancies are discussed.

Topics: Burkitt Lymphoma; Cell Line; Depression, Chemical; Humans; In Vitro Techniques; Interferons; Leukocytes; Mitogens; Neoplasms, Experimental; Polynucleotides; Tretinoin; Virus Diseases

Topics: Adrenal Cortex Hormones; Candidiasis, Oral; Humans; Levamisole; Levodopa; Mouth Diseases; Mycoses; Tretinoin; Virus Diseases; Vitamin A