Serine incorporator (SERINC) proteins 1–5 (SERINC1-5) are involved in the progression of several diseases. SERINC2-4 are carrier proteins that incorporate the polar amino acid serine into membranes to facilitate the synthesis of phosphatidylserine and sphingolipids. SERINC genes are also differentially expressed in tumors. Abnormal expression of SERINC proteins occurs in human cancers of the breast, lung, colon, liver, and various glands, as well as in mouse testes. SERINC proteins also affect cleft lip and palate and nerve-related diseases, such as seizure Parkinsonism and borderline personality. Moreover, SERINC proteins have garnered significant interest as retroviral restriction factors, spurring efforts to define their function and elucidate the mechanisms through which they operate when associated with viruses. Human SERINC proteins possess antiviral potential against human immunodeficiency virus (HIV), SARS-COV-2, murine leukemia virus (MLV), equine infectious anemia virus (EIAV), and hepatitis B virus (HBV). Furthermore, the crystal structure is known, and the critical residues of SERINC5 that act against HIV have been identified. In this review, we discuss the most prevalent mechanisms by which SERINC3 and SERINC5 antagonize viruses and focus on the potential therapeutic applications of SERINC5/3 against HIV.
Influenza is still one of leading causes of morbidity and mortality around the world, despite of annual influenza immunization in many countries. New strategies are urgently needed for developing effective vaccines and therapeutics against influenza viruses. In this study, we have constructed new recombinant influenza viruses, named host-targeted self-attenuated influenza viruses (SAIVs), which can express functional mammalian species-specific artificial microRNAs (amiRNAs). The expression of these amiRNAs can inhibit expression of some host factors critical for influenza replication, and therefore the resultant recombinant influenza viruses are replication restricted and attenuated in the host cells. One of these SAIVs, which can express an amiRNA that inhibits expression of the host cellular Cdc2-like kinase 1 (CLK1), was produced in embryonic chicken eggs and evaluated in a mouse model of influenza infection. It elicited robust antibody responses against influenza virus and demonstrated significantly protective efficacy against lethal infection with wild type influenza virus H1N1 PR8 after single dose of intranasal vaccination. Additionally, post-exposure treatment with this CLK1-targeted SAIV showed therapeutic effect against PR8 lethal-dose infection. Our research finding provided a proof of concept that the new host targeted self-attenuated influenza virus can be further developed to a therapeutic vaccine for prophylactic and therapeutic use against influenza.
Supported by a research grant from National Institute of Allergy and Infectious Diseases (AI133207).
Anthrax is a serious disease caused by Bacillus anthracis, a bacterium that can form spores for long-term survival and secrete anthrax toxins including protective antigen (PA), lethal factor (LF), and edema factor (EF). However, current anthrax postexposure treatments are inadequate at later stages of infection. Previously, our research have shown RNA inhibition (RNAi) on host cells silences anthrax toxin receptors (ATRs): tumor endothelial marker 8 (TEM8), capillary morphogenesis protein 2 (CMG2). This approach was protective against the cytotoxicity of anthrax toxins, indicating that ATR-targeted RNAi can be used as a therapy against anthrax. However, inefficient cytosolic delivery and toxicity of siRNA delivery vehicles limit the use siRNA as therapeutics. In this study, we have developed a detoxified anthrax edema toxin, which consists of PA and nontoxic N-terminal fragment of EF (EFn) conjugated with a peptide nona-D-arginine residues (EFn-9dR) to enable siRNA binding. The detoxified toxin was able to deliver specific siRNA to induce cmg2 gene silencing in different cell lines and C57BL/6 mice, and provide significant protection against anthrax lethal toxin challenge in vitro and in mice. Survived mice from toxin challenge were fully protected against lethal challenge with B. anthracis Sterne spores. The immune protective mechanism is mainly due to the significantly high serum neutralizing antibody response against anthrax toxins in these mice. These results suggest that detoxified anthrax toxin provides a tool for delivery of host-targeted siRNA into anthrax pathogenesis-associated host cells, and this new system could potentially be developed as a lifesaving postexposure therapeutic vaccine against anthrax.
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