Murine respirovirus, now Respirovirus muris, formerly Sendai virus (SeV) and previously also known as murine parainfluenza virus type 1 or hemagglutinating virus of Japan (HVJ), is an enveloped, 150–200 nm diameter, negative sense, single-stranded RNA virus of the family Paramyxoviridae. It typically infects rodents and it is not pathogenic for humans or domestic animals.
Respirovirus muris is a member of the genus Respirovirus. The virus was isolated in the city of Sendai in Japan in the early 1950s. Since then, it has been actively used in research as a model pathogen. The virus is infectious for many cancer cell lines (see below), and has oncolytic properties demonstrated in animal models and in naturally occurring cancers in animals. Its ability to fuse eukaryotic cells and to form syncytium was used to produce hybridoma cells capable of manufacturing monoclonal antibodies in large quantities.
Recent applications of SeV-based vectors include the reprogramming of somatic cells into induced pluripotent stem cells and vaccine creation. For vaccination purpose the Sendai virus-based constructs could be delivered in a form of nasal drops, which may be beneficial in inducing a mucosal immune response. SeV has several features that are important in a vector for a successful vaccine: the virus does not integrate into the host genome, it does not undergo genetic recombination, it replicates only in the cytoplasm without DNA intermediates or a nuclear phase and it does not cause any disease in humans or domestic animals. Sendai virus is used as a backbone for vaccine development against Mycobacterium tuberculosis that causes tuberculosis, against HIV-1 that causes AIDS and against other viruses, including those that cause severe respiratory infections in children. The latter include human respiratory syncytial virus (HRSV), human metapneumovirus (HMPV) and human parainfluenza viruses (HPIV).
The vaccine studies against M. tuberculosis, HMPV, HPIV1 and, HPIV2 are in the pre-clinical stage, against HRSV a phase I clinical trial has been completed. The phase I clinical studies of SeV-based vaccination were also completed for HPIV1. They were done in adults and in 1–6-year-old children. As a result of vaccination against HPIV1, a significant boost in virus-specific neutralizing antibodies was observed. A SeV-based vaccine development against HIV-1 has reached a phase II clinical trial. In Japan intranasal Sendai virus-based SARS-CoV-2 vaccine was created and tested in a mouse model.
More recent applications (2024–2025) include non-integrative gene delivery for fertility restoration in mouse models, enhanced transduction in pancreatic cancer, and temperature-sensitive platforms for CRISPR-Cas9 editing in human stem cells and viral genome engineering.
As an infection agent SeV replication occurs exclusively in the cytoplasm of the host cell. The virus is using its own RNA polymerase. One replication cycle takes approximately 12–15 hours with one cell yielding thousands of virions.
Susceptible animals The virus is responsible for a highly transmissible respiratory tract infection in mice, hamsters, guinea pigs, rats, and occasionally marmosets, with infection passing through both air and direct contact routes. Natural infection occurs by way of the respiratory tract. In animal facility airborne transmission can occur over a distance of 5–6 feet as well as through air handling systems. The virus can be detected in mouse colonies worldwide, generally in suckling to young adult mice. A study in France reported antibodies to SeV in 17% of mouse colonies examined. Epizootic infections of mice are usually associated with a high mortality rate, while enzootic disease patterns suggest that the virus is latent and can be cleared over the course of a year. Sub-lethal exposure to SeV can promote long-lasting immunity to further lethal doses of SeV. The virus is immunosuppressive and may predispose to secondary bacterial infections. There are no scientific studies, which were performed using modern detection methods, which would identify SeV as an infectious and decease causative for humans or domestic animals.
Variable susceptibility to infection in mouse and rat strains Inbred and outbred mouse and rat strains have very different susceptibility to Sendai virus infection. Visualization of SeV infection in live animals demonstrates this difference. The 129/J mice tested were approximately 25,000-fold more sensitive than SJL/J mice. C57BL/6 mice are highly resistant to the virus, while DBA/2J mice are sensitive. C57BL/6 mice showed slight loss of body weight after SeV administration, which returned to normal later. Only 10% mortality rate was observed in C57BL/6 mice after the administration of very high virulent dose of 1*105 TCID50. It was shown that resistance to the lethal effects of Sendai virus in mice is genetically controlled and expressed through control of viral replication within the first 72 hours of infection. Treatment of both strains with exogenous IFN before and during viral infection led to an increase in survival time in C57BL/6 mice, but all animals of both strains ultimately succumb to SeV caused disease. If a mouse survives a SeV infection, it develops a lifelong immunity to subsequent viral infections.
There are SeV-resistant F344 rats and susceptible BN rats.
Course of infection In the host airways the virus titer reaches a peak after 5–6 days post infection initiation that decreases to undetectable levels by day 14. The virus promotes a descending respiratory infection, which begins in the nasal passages, passes through the trachea into the lungs and causes necrosis of the respiratory epithelium. The necrosis is mild in the first few days of infection, but later became severe by peaking around day 5. By day 9, the cells of the surface of the airways regenerate. Focal interstitial pneumonia can developed accompanied by inflammation and lesions of various degrees on the lungs. Usually, the respiratory system shows signs of healing within 3 weeks of infection, however, residual lesions, inflammation, or permanent scarring can occur. 6–8 days after the infection initiation serum antibodies appear. They remain detectable for about 1 year.
Symptoms in animals Source: Sneezing Hunched posture Respiratory distress Porphyrin discharge from eyes and/or nose Lethargy Failure to thrive in surviving babies and young rats Anorexia
Diagnosis and prophylaxis SeV induces lesions within the respiratory tract, usually associated with bacterial inflammation of the trachea and lung (tracheitis and bronchopneumonia, respectively). However, the lesions are limited, and aren't indicative solely of SeV infection. Detection, therefore, makes use of SeV-specific antigens in several serological methods, including ELISA, immunofluorescence, and hemagglutination assays, with particular emphasis on use of the ELISA for its high sensitivity (unlike the hemagglutination assay) and its fairly early detection (unlike the immunofluorescence assay).
In a natural setting, the respiratory infection of Sendai virus in mice is acute. From the extrapolation of the infection of laboratory mice, the presence of the virus may first be detected in the lungs 48 to 72 hours following exposure. As the virus replicates in the respiratory tract of an infected mouse, the concentration of the virus grows most quickly during the third day of infection. After that, the growth of the virus is slower but consistent. Typically, the peak concentration of the virus is on the sixth or seventh day, and rapid decline follows that by the ninth day. A fairly vigorous immune response mounted against the virus is the cause of this decline. The longest period of detected presence of the virus in a mouse lung is fourteen days after infection.
Eaton et al. advises that, when controlling an outbreak of SeV, disinfecting the laboratory environment and vaccinating the breeders, as well as eliminating infected animals and screening incoming animals, should clear the problem very quickly. Imported animals should be vaccinated with SeV and placed in quarantine, while, in the laboratory environment, breeding programs should be discontinued, and the non-breeding adults isolated for two months.
Virus-induced immunosuppression The virus is a powerful immunomodulator. SeV can act in both directions: it can activate or suppress the immune response depending on the type of cell, host and time period after infection initiation. The virus can suppress the IFN production and response pathways as well as inflammation pathway.
Apoptosis inhibition Sendai virus P gene encodes a nested set of proteins (C', C, Y1 and Y2), which are named to collectively as the C proteins (see the section "Genome structure" below). C proteins of SeV are able to suppress apoptosis. The antiapoptotic activity of the C proteins supports SeV infection in the host cells.
Interferon production and signal transduction inhibition The virus prevents the stimulation of type 1 IFN production and subsequent cell apoptosis in response to virus infection by inhibiting the activation of IRF-3. Two virus proteins: C and V are mainly involved in this process. SeV can attenuate cell defense mechanisms and allow itself to escape from host innate immunity by inhibiting the interferon response pathway in addition to inhibiting the interferon production. The table below demonstrates the inhibition mechanism. +Viral proteins and their function in immunosuppressionproteinmapped to amino-acidsbinding witheffectC-proteinIKKα serine / threonine kinaseThe binding prevents the phosphorylation of IRF7 and inhibits a pathway that includes a Toll-like receptor (TLR7) and TLR9-induction of IFN-alpha in plasmacytoid dendritic cells.interferon-alpha/beta receptor subunit 2 (IFNAR2)The binding inhibits IFN-α-stimulated tyrosine phosphorylation of the upstream receptor-associated kinases TYK2 and JAK1.99-204N-terminal domain of STAT1The binding suppresses the signal transduction pathways of interferon alpha/beta (IFN-α/β) and IFN-γThe C-protein inhibits the production of nitric oxide (NO) by murine macrophages that has cytotoxic activity against viruses.The C protein decreases generation of dsRNA, therefore it is keeping PKR inactive to maintain proteins translation in a host cell.V-proteinMDA5The binding inhibits downstream MDA5 activation of the IFN promoter.RIG-IThe binding prevents downstream RIG-I signaling to the mitochondrial antiviral signaling protein (MAVS) by disrupting TRIM25 -mediated ubiquitination of RIG-I. The binding suppresses inducible NO synthase (iNOS) via the RIG-I/TRIM25 pathway and decreases the production of nitric oxide (NO) in infected macrophages.TRIM25The V-protein suppresses the production of interleukin-1β, by inhibiting the assembly of the inflammasome NLRP3.Y1-protein149-157RanThe nuclear translocation of viral protein is mediated by Ran GTPase. The amino acids represent nuclear localization, which is believed to suppress IFN-induced gene expression. Anti-IFN activity of C protein is shared across the family Paramyxoviridae, and therefore appears to play an important role in paramyxovirus immune evasion. Human parainfluenza virus type 1 (HPIV1), which is a close relative of SeV and is (in contrast to SeV) a successful human pathogen, does not express V proteins, only C proteins. So, all needed functions provided by V in SeV can be provided by C in HPIV1. Thus, C and V have these "overlapping functions" because of the multi-faceted nature of host defense that can be countered at so many places, and exactly how well and where will in part explain host restriction.
The C-protein also appears to be responsible for limiting the production of NO in infected macrophages, which in turn reduces inflammation.
Host restriction and safety for domestic animals