key: cord-0042441-mor0wpx7 authors: Brownstein, David G. title: SENDAI VIRUS date: 2012-12-02 journal: Viral and Mycoplasmal of Laboratory Rodents DOI: 10.1016/b978-0-12-095785-9.50012-3 sha: bf24328586a9d32f89cf4ac116fe034f836e7840 doc_id: 42441 cord_uid: mor0wpx7 nan Sendai virus emerged as a spontaneous contaminant of laboratory rodent colonies a little over 30 years ago during attempts to recover human respiratory viruses in mice at Tokohu University Hospital in Sendai, Japan (1). The attendant confusion over the original host for this parainfluenza 1 virus has yet to be resolved. Irrespective of its origin, Sendai virus is today the most prevalent adventitious viral infection of laboratory rat, hamster, and possibly guinea pig colonies in the United States and it shares this status with coronaviruses in mouse colonies. The impact of Sendai virus on research involving rodents is therefore potentially great. Nevertheless, most of our assumptions about the sub-clinical effects of Sendai virus on rodents are based on anecdotes or on poorly controlled studies of naturally infected rodent colonies. There have been several excellent reviews of Sendai virus infection covering the period of 1953 to 1980. Ishida and Homma chronicled the events leading to the emergence of Sendai virus as an important rodent pathogen and reviewed its biology and epizootiology (2) . Parker and Richter extensively covered the infection in mice (3) . Jakab compiled a comprehensive bibliography (127 references) and reviewed the interaction of Sendai virus and bacterial pathogens in the murine lung (4) . Brownstein detailed the pathology of Sendai virus infection (5) . This review covers significant advances in Sendai virus research since 1980. Background information is summarized where necessary for continuity and perspective. Certain topics, such as properties and pathogenesis, are emphasized because they are areas of most active research. Sendai virus, genus Paramyxovirus of the family Paramyxoviridae, is the only recognized parainfulenza 1 virus to naturally infect animals. Some of the properties of this virus are listed in Table 1 . Sendai virus has a linear single-stranded RNA genome which codes for four non-glycosylated and two glycosylated structural proteins, and a lipid envelope. Viral RNA transcription and translation occur in the cytoplasm of host cells. Virions are assembled at the plasma membrane. The two glycosylated proteins, HN and F, project as spikes from the envelope; the other structural proteins are internal. M protein, one of the four non-glycosylated structural proteins, is the rate-limiting protein in virion assembly (8) . M protein migrates to the plasma membrane where it forms orthogonal crystalline aggregates within the inner lipid leaflet which serve as attachment sites for ribonucleoproteins destined for incorporation into virions (9) . It therefore only appears at the plasma membrane where virions are forming (10) . M protein synthesis is deficient relative to ribonucleoprotein synthesis about twofold (8) . Redundant ribonucleoproteins, not committed to virion formation, accumulate in large numbers in the cytosol and serve as viral RNA transcriptive complexes (8) . HN, the larger of the two surface glycoproteins, has hemagglutinating and neuraminidase activities and mediates virus attachment to sialic acid-containing cellular receptors. It usually forms dimers or tetramers on the envelope surface (11). There appear to be approximately four antigenic sites on the HN glycoprotein (12, 13) . Studies using monoclonal antibodies directed at these sites and using temperature sensitive mutants (14) suggest that neuraminidase and hemagglutinin activities reside on different regions of the molecule· The hemagglutinin of HN binds to slight variations on two sialyloligosaccharide sequences which are components of membrane gangliosides or glycoproteins and these serve as the viral receptors (15) (16) (17) (18) . The oligosaccharide sequences are shown in Figure 1 . It is still unclear whether the actual viral receptors are oligosialogangliosides or oligosialoproteins. Wu and co-worker reported that lipsomes incorporating HeLa cell glycoconjugates bound Sendai virus weakly when sialogangliosides were incorporated and avidly The virus recovered usually has characteristics which differ from the original wild-type virus. These include temperature sensitivity of M or P synthesis (28) (29) (30) , protease activation mutants (27) , weak cytopathogenicity (31) , and defective interfering viruses (32) . Although there is clearly a selective advantage for these variant strains in persistently infected cell cultures it is unclear whether they are necessary for persistence. Antigenic variants arise at about a hundredfold greater frequency in persistently infected cultures than in lytically infected cultures (27) . Viral persistence in cell cultures is also influenced by host cell metabolism since virion assembly, and nucleic acid and protein synthesis are governed by the phase of the cell cycle. Confluent cultures support less virus replication than growing cultures (33) . Host cells may also selectively suppress the synthesis of specific structural proteins as has been shown for M protein in rat glial cells (34) . Naturally transmitted Sendai virus replicates primarily in respiratory epithelium. This localization occurs despite widely distributed susceptible tissues that express the appropriate viral receptors (35, 36) . One attractive explanation for the respiratory tropism for Sendai virus and other parainfluenza viruses is the availability of fusionactivating proteases in respiratory tissues. Tashiro and Homma have shown that mouse lungs contain a specific trypsin-like enzyme which efficiently cleaves FQ to F\ and F2 when infected with wild-type Sendai virus (37, 38) . Respiratory tissues are therefore able to release infectious virus progeny and support multiple replication cycles. Similar to the situation in susceptible continuous cell lines which lack the requisite enzyme, susceptible nonrespiratory tissues lacking the appropriate protease would only be able to support single cycle replication. This could explain the observations of several investigators that Sendai virus can be recovered from non-respiratory tissues of mice infected intransally but titers are far lower than those developing in the lung (39, 40) . For example, Stewart and Tucker reported up to a 66% recovery rate from nonrespiratory tissues but titers were less than 2.0 log^o versus 7.0 logio for lung (40) . The lung protease that activates FQ is apparently associated with the apical plasma membrane of the target epithelium since virtually all intracellular F glycoprotein is FQ (23) and the protease cannot be identified in supernatants of lung organ cultures (38) . It is only available to activate FQ of nascent virions and not of incoming virus since wild-type Sendai virus bearing FQ does not replicate in rodent lungs (37) . The protease is specific for the FQ of wild-type virus; chymotrypsin or elastase activation mutants recovered from persistently infected cell cultures complete only a single replication cycle in mouse lungs (37) . Sendai virus replicates in the respiratory tract for approximately six or seven days in outbred mice and rats (41) (42) (43) and for up to twice that long in inbred mice (44, 45) . During the phase of virus replication a series of non-specific and then specific antiviral defense mechanisms are mobilized which terminate the infection. In mice and probably in rats, abrogation of the infection ultimately depends on an intact immune system and is strongly thymus dependent. The best studied of the non-specific defense mechanisms activated by Sendai virus is the interferon response. Sendai virus is a potent interferon inducer in the mouse and the lung interferon response after aerosol exposure is protracted, closely emulating the kinetics of virus replication (46) . By contrast, rats mount a relatively attenuated lung interferon response which does not follow viral replication kinetics. The peak interferon response in rats occurs about 20 hours after infection and is barely detectable after 24 hours (47) . Serum interferon levels during respiratory Sendai virus infection parallel lung interferon titers but are far lower and may be undetectable (Brownstein, D., unpublished observation). De Maeyer and De Maeyer-Guignard reported that the interferon response to Sendai virus is under complex genetic control in inbred mice with at least two autosomal genes controlling the response (48) . The role of interferon in limiting Sendai virus infection in rodents is unclear but the crucial role of the immune system precludes a pivotal role. Degre and Rollag were unable to improve survival in inbred mice infected with 1 LD50 of Sendai virus by augmenting the endogenous lung interferon response with exogenous interferon (49) . Mean survival times improved somewhat. Sendai virus induces interferon in mice by a variety of mechanisms. In addition to the classical induction of interferona , B (IFN-a ,B) by functional viral RNA after penetration of host cells, the HN glycoprotein, functioning as a lectin, can trigger IFN-a,B production by spleen cells in vitro (50) . Cloned Sendai virus-specific T helper cells have also been shown to stimulate IFN-a,B by adherent cells upon recognition of antigen-presenting cells (51) . Augmentation of natural killer cell activity during the course of Sendai virus infection has been recognized for several years and may play an adjunctive role in antiviral defense (52) (53) (54) . Mak et al,have also described non-specific cytotoxic macrophages generated within three days of intraperitoneal exposure to Sendai virus (55) . They described similar macrophages in the lungs of influenza virus infected mice. During the course of Sendai virus infection in mice a complex series of inter-related cellular and humoral immune responses is initiated which ultimately leads to viral elimination and immunopathic lung injury. It is unclear which immune components actually mediate viral clearance: cytotoxic T cells (T c ), T cells mediating delayed-type hypersensitivity (T¿), cells secreting antibody, or combinations of these. Current knowledge concerning the T and B cell subsets generated during Sendai virus infection or in response to viral antigens is fragmentary but includes those listed in Table 3 . Specific T c have been shown to be important in terminating various primary viral infections in mice including influenza virus infection (58) . Evidence supporting a role for T c in Sendai viral clearance is so far lacking. Ertl and Finberg were unable to demonstrate an effect on Sendai virus titers when the respiratory T c response was augmented by adoptive transfer of a specific T helper cell clone 24 hours after experimental infection (59) . These investigators were able to protect mice from lethal Sendai virus infection by immunizing them with anti-idiotype antibody directed against a Sendai virus-specific helper T-cell clone, a procedure which augmented Sendai virusspecific T c in the spleen, but it is not clear whether other components of the immune response were activated as well (60) . There have been many reports on the molecular requirements for Sendai virus specific T c generation in mice (see review by Ada, Leung, and Ertl ref. 58 and 61-64) . Briefly, infectious virus or inactive virus with an active F glycoprotein (F\ and F2) is necessary for viral antigens to be properly presented in association with K and/ or D regions of the major histocompatibility complex (H-2) to serve as stimuli for T c . Although the F glycoprotein is essential, current evidence suggests that the HN glycoprotein is the principal target antigen (65) . In most inbred mouse strains, T c specific for Sendai viral antigens require syngeneity with the H-2K rather than the H-2D region of target cells. BALB/c, DBA and A/J mice may, however, be syngeneic at either locus (66) . Inbred mice bearing the Η-2^ haplotype generate defective secondary T c responses although antibody and proliferative T-cell responses are normal (67) . Antibody responses to Sendai viral antigens are strongly thymus-dependent. They are clearly important in preventing reinfections but their role in controlling primary infections is less certain. Sensitive binding antibody assays of serum, bronchoalveolar washes or lung lysates of mice undergoing primary Sendai viral infections have pushed forward the time of the initial detection of specific antibodies to as early as day 2, sufficiently early to implement viral clearance (56, 68) . Studies of monoclonal antibodies generated in BALB/c mice immunized with purified Sendai virus (or closely related 6/94 virus) or viral components have been reported and provide insights into the humoral component of the immune response (23, 13) . Three months after intraperitoneal immunization with Sendai virus, about 85% of the specific antibody-forming cells in the spleen are forming antibodies to one of the antigenic determinates on the HN glycoprotien with only 15% targeting the F glycoprotein (13) . Over one half of these plasma cells are secreting antibodies of the IgGi isotype, a poor-or non-complement-fixing antibody. Virus neutralization by these antibodies, as measured by end point determinations in embryonated eggs, correlates with their ability to inhibit hemagglutination. Lung virus titers in mice passively immunized with these monoclonal antibodies prior to infection are reduced regardless of their hemagglutinin, neuraminidase, fusion, complementfixing, or neutralizing specificity. This suggests that antibodies mediate protection in Sendai virus infection through antibody-dependent cell-mediated immune mechanisms. Further evidence that the complement system plays a minor role in Sendai viral clearance but a potentially great role in immunopathic lung injury comes from the study by Finnie et al· (69) . They showed that DBA/2 mice can survive a 1 LD50 Sendai virus infection by prior decomplementation with cobra venom factor. Survival is not enhanced when larger viral doses are used. Inbred mouse strains vary widely in their susceptibility to the lethal effects of Sendai virus infection (44), a variation that is genetically determined (70) . Conventional genetic analyses of crosses between resistant C57BL/6 and susceptible DBA/2 mice have shown that resistance is a dominant trait and may be determined by a single autosomal locus when mortality is the phenotype (70) . Nowhere are we less informed about Sendai virus infection than in the area of effects on biomédical research· The subclinical respiratory effects of the infection have received considerable attention but the systemic effects have not been examined experimentally in sufficient detail. (4). Antibacterial mechanisms are maximally suppressed one week after viral inoculation, at a time when virus titers are rapidly declining, and are essentially normal by the end of the second week. Functional paralysis of alveolar macrophages is an indirect effect of the virus. Recent in vitro studies of mouse alveolar macrophages infected with Sendai virus suggest that some of the phagocytic defects observed jji vivo may be mediated by specific antiviral antibody (84) . A key question yet to be answered is whether alveolar macrophages become infected during natural Sendai virus infection and if so how extensively. Jakab reported that 60% of macrophages retrieved by pulmonary lavage during maximal suppression of in situ bacteriacidal mechanisms contained viral antigen (84) In addition to transient functional derangements of pulmonary defense mechanisms Sendai virus infection may result in transient or less commonly persistent morphologic lung changes. The acute and persistent lung change of adult rats and mice have been well described (3, 5) . Castleman described chronic and possibly persistent morphometric changes in Sendai virus infected weanling and suckling rats (85) . Animals infected at 22 days of age had 60% greater specific lung volumes two months post-infection and 42% higher alveolar surface area than control rats. Rats infected at five days of age had 33% greater specific alveolar surface area and 48% greater mean terminal bronchiolar cross section area than control rats at 22 days of age. Sendai virus infection may also have an effect on pulmonary carcinogenesis. Peck et al%reported that Strain A mice enzootically infected with Sendai virus and mouse hepatitis virus develop fewer pulmonary adenomas induced by 10-chloromethyl-9-chloroanthracene and more pulmonary adenomas induced by 7,12-dimethylbenz (a)anthracene than strain A mice enzootically infected with mouse hepatitis alone (86) . Sendai virus is a frequent contaminant to transplantable tumors and other continuous cell lines. This is associated with lowered transplantability and a variety of changes in kinetics and ploidy (87, 88) . The diagnosis of Sendai virus infection in rodents is not difficult. At the host level the infection proceeds through predictable overlapping phases during which certain diagnostic procedures are appropriate. The phases of Sendai virus infection in an idealized rodent host are shown in Figure 2 as well as the intervals during which the diagnostic tests are appropriate· No single diagnostic test can detect the infection during all phases. When at least two tests are properly selected, however, the probability of successful detection is high. Virus isolation is the most definitive but also the most labor-intensive means of diagnosing Sendai virus infection but infectious virus is often not present when animals become clinically ill. Animals selected for virus isolation should therefore be the least clinically affected individuals in contact with sick animals and preferably seronegative to Sendai virus. Sterile lung suspension or nasal washes may be used. Sendai virus can be detected by its cytopathic effects on primary or secondary rhesus or cynomolgous monkey kidney cells. Virus can also be detected in susceptible but non-permissive serial cell lines such as BHK-21, L929, BSC-1, LLC-Mk2, HeLa, and RK-13 by plaque formation using trypsin overlays, visualization of viral antigens using immunofluorescence, or hemadsorption (reviewed in ref. 3) . Histopathology is the least specific and also the least sensitive of the tests employed. Many cases of Sendai virus infection do not involve sufficient respiratory injury to allow a presumptive diagnosis of Sendai virus infection to be made on the basis of histopathology. Since the principal site of viral replication is the respiratory epithelium, lesions, when present, usually consist of transient erosive or proliferative rhinitis, laryngotracheitis or bronchitisbronchiolitis. When the secondary sites of viral replication become involved, alveolar type II and type I cells, a characteristic bronchointerstitial pneumonia develops which may lead to multifocal adenomatous change, squamous metaplasia or, in severe cases, organizing alveolitis. Such lesions are most likely to be detected in animals susceptible by virtue of age (sucklings, aged), heredity (inbred mouse strains 129, DBA), immune suppression, or debility (reviewed in ref. This is especially true in the areas of molecular biology and immunobiology. In addition, newer insights into the pathogenesis and epizootiology of this infection have allowed us to make more enlightened decisions concerning control, prevention and diagnosis than was possible a few years ago. Nevertheless, certain key areas are poorly investigated and newer developments have posed new questions. One of the most pressing of the unresolved questions about Sendai virus infection is the one posed by this symposium -what is the impact of Sendai virus infection on the suitability of rodents for various types of biomédical investigations? The systemic effects of this localized respiratory infection are especially important and it is in this area that conflicting evidence exists· Are there profound long-term sequelae or are the principal systemic effects short-lived as the experimental evidence suggests? What are the mechanisms mediating these sytemic effects? In the area of pathogenesis, can the respiratory tropism of Sendai virus be accounted for by the availability of specific tissue proteases necessary for virus activation? What is (are) the actual immunologie effector(s) of viral clearance? Is the marked susceptibility of certain inbred mouse strains to the lethal effects of this infection mediated by the same apparently nonimmunological mechanism or are there various susceptibility loci controlling a variety of mechanisms? What are these mechanisms? Besides the mouse, the effects of Sendai virus infection on the other rodent species are poorly studied, especially hamsters and guinea pigs· Sendai virus appears to be the least prevalent parainfluenza virus infection of guinea pigs· What are these other parainfluenza viruses and what is their impact on respiratory diseases which account for much of the morbidity and mortality in guinea pigs? The widespread use of inactivated virus vaccines for prevention and control of Sendai virus infection requires further justification. Available evidence suggests that protection is only partial in the absence of multiple vaccinations. Live protease-activation and temperaturesensitive mutant virus vaccines are potential alternatives to inactivated virus vaccines. Studies reported herein demonstrate their effectiveness in preventing infection by wild-type virus but the possibility of reversion of vaccine strains to wild-type virus requires careful scrutiny. Proliferative responses of spleen cells to stimulation with concanavalin A and delayed type hypersensitivity (DTH) responses to sheep red blood cells (SRBC) were suppressed both in vaccinated and live virus-infected but not in control mice at 7 to 21 days after inoculation. The responses of vaccinated mice had returned to normal levels by 35 to 42 days after treatment. The finding that 10% of cells from vaccinated or infected mice admixed with 90% normal spleen cells suppressed the proliferative response of the normal cells to concanavalin A suggest an indirect effect, e.g., activation of suppressor T cells. In contrast to the suppression described above, direct plaque forming cell responses to SRBC and natural killer (NK) cytotoxic responses were both enhanced at 7 and 21 days after treatment. The NK responses of vaccinated mice returned to normal levels by 35 to 42 days after treatment. These results suggest that investigators wishing to vaccinate mice against Sendai virus and then utilize them in experiments which could be affected by an altered immune status should wait a minimum of five to six weeks after vaccination before using the animals. However, variables such as strain, source, pathogen status, and environment can markedly affect test results and each investigator should check mice in their own system to determine which immune parameters are affected by vaccination and when responses return to control levels. Newborn Virus Pneumonitis (Type Sendai). II. 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