JPC SYSTEMIC PATHOLOGY
Signalment (GV-5): Mouse; age, gender, and strain unknown
HISTORY: Dyspnea of unknown duration
HISTOPATHOLOGIC DESCRIPTION: Lung, multiple sections: Affecting up to 95% of the section, alveolar septa are expanded up to 10x normal diameter by an inflammatory infiltrate composed of macrophages, lymphocytes, plasma cells, and fewer neutrophils as well as abundant fibrin and edema. Multifocally, alveolar septa are discontinuous and replaced with cellular and karyorrhectic debris (alveolar septal necrosis). Multifocally, alveoli contain eosinophilic fluid (edema), and in severely affected areas, alveolar lumina contain an exudate composed of the previously described inflammatory cells. Multifocally, terminal airways and alveoli are lined by hyperplastic cuboidal to columnar epithelial cells with large vesiculate nuclei, 1-3 distinct nucleoli, and frequent mitotic figures which form dense clusters or papillary projections (atypical type II pneumocyte hyperplasia), and occasional multinucleate syncytial cells with up to 20 nuclei. Bronchiolar epithelium is similarly hyperplastic with tightly packed tall columnar cells piled up to 5 cell layers deep. Rarely, hyperplastic epithelia contain 1-3 um eosinophilic intracytoplasmic viral inclusions. Occasionally, bronchiolar epithelium is lost (ulcerated) or attenuated with intraluminal exudate composed of low to moderate numbers of foamy macrophages and neutrophils, necrotic debris, fibrin, and edema. Multifocally, peribronchial and peribronchiolar lymphoid tissue is mildly hyperplastic (BALT hyperplasia) and there is infiltration of lymphocytes in the perivascular interstitium and dilated lymphatics.
MORPHOLOGIC DIAGNOSIS: Lung: Pneumonia, bronchointerstitial, lymphoplasmacytic and histiocytic, subacute, multifocal, moderate with atypical type II pneumocyte hyperplasia, respiratory epithelial hyperplasia and syncytia, and rare eosinophilic intracytoplasmic viral inclusion bodies, strain unspecified, mouse, rodent.
ETIOLOGIC DIAGNOSIS: Sendai viral pneumonia
CAUSE: Sendai virus
SYNONYMS: Murine parainfluenza virus-1
- Single-stranded, pleomorphic, enveloped RNA virus, approximately 100-300 nm long; genus Respirovirus, family Paramyxoviridae; Paramyxoviruses produce cytoplasmic inclusions and giant (syncytial) cells
- Closely related antigenically to human Parainfluenza 1 virus; debate as to human or mouse origin and whether humans are susceptible
- Used to be common and significant in laboratory settings, but prevalence has declined and is now extremely rare
- Labile, highly contagious virus primarily seen in mice
- Epizootic and enzootic types:
- The epizootic type is generally acute, with high morbidity and mortality and an unexplained seasonal pattern
- Enzootic infections: virus exists in a latent state; maternal passive immunity is strongly protective; infection is usually subclinical except in naive or immunocompromised populations
- 129, DBA/2 and CH3 especially susceptible; B6, AKR, SJL, and Swiss mice resistant
- Infected animals are predisposed to Mycoplasma pulmonis or other bacterial pneumonias, otitis media, and otitis interna; accordingly, outbreaks of vestibular disease and bacterial pneumonia can often be associated with recent Sendai virus
- Infection may influence experimental carcinogenesis
- Unique among murine viruses in that it can cause significant clinical illness in immunocompetent adult mice
- Transmission via aerosol, direct contact, or contaminated fomites à descending infection of respiratory epithelium (nose, trachea, bronchi, bronchioles, middle ears), including type I and type II pneumocytes à respiratory epithelium, infection abrogated by cell-mediated response that clears the infection but also generates disease (CD8+ cytotoxic T-cells trigger apoptosis of infected epithelial cells, resulting in nonuniform exfoliation/erosion of the epithelium and interstitial alveolar inflammation)
- The level to which the infection descends the respiratory tree depends on host mucociliary clearance, virus burden, and immune response kinetics
- DBA/2 infants and aged are exquisitely sensitive to severe disease due to effective but delayed immune response, allowing infection to extend deep into respiratory tree then mounting a zealous inflammatory response
- B6 often have subclinical infection due to rapid immune response that precludes viral proliferation deep within the respiratory tree
- T-cell immunodeficient mice lacking effective cell-mediated response have lesions solely due to mild but progressive viral cytopathic effect
- Although there are viral receptors in many tissues, the virus has respiratory tropism because it is dependent on apical budding from respiratory epithelium and is dependent on respiratory proteases to cleave its fusion glycoprotein into a biologically active form; without proteases, the virus is restricted to a single cell cycle
- Fusion glycoprotein (F glycoprotein) à host cell fusion and virus entry into host cell à syncytia
- Virus by itself is only mildly cytopathic; mice are only mildly ill in “pre-immune” phase
TYPICAL CLINICAL FINDINGS
- Often subclinical
- Respiratory distress, dyspnea, sneezing, poor coat quality, weight loss, anorexia, neonatal death
- More severe signs are associated with concurrent Mycoplasma infection
- Immunodeficient mice: more protracted clinical course, progressive pneumonia, wasting syndrome
- Pregnant dams: fetal resorption, prolonged gestation, fetal death (although there is no vertical transmission)
TYPICAL GROSS FINDINGS
- Plum-colored consolidation of sharply demarcated foci of the pulmonary hilus, anteroventral lung, or entire lung lobes; these foci may turn grey in surviving mice
- Lymphadenopathy (especially submaxillary lymph nodes), splenomegaly
- T-cell immunodeficient mice: progressive pulmonary consolidation; pale, firm, non-collapsing lungs
TYPICAL LIGHT MICROSCOPIC FINDINGS
- Pre-immune phase: hypertrophic/hyperplastic bronchiolar epithelium with virus-induced syncytia, +/- eosinophilic intracytoplasmic viral inclusions, +/- intranuclear viral inclusions (nude mice only), minimal necrosis, progressing to severe diffuse alveolitis; this phase is most likely seen in immature or immune deficient mice, as these changes are rapidly obscured by immune-mediated necrosis in immunocompetent mice
- Immune phase: segmental necrotizing inflammation of nasal and airway epithelium (necrotizing rhinitis, laryngotracheitis, bronchitis, and bronchiolitis), interstitial pneumonia associated with terminal airways; inflammatory cells vary depending on stage of infection including neutrophils, lymphocytes, macrophages; alveoli may be atelectic or filled with fibrin, leukocytes, and necrotic cells; microscopic features are diagnostic in immunocompetent adult mice
- Resolution: Sloughed airway epithelium is replaced by proliferating hyperplastic epithelium +/- transient marked nonkeratinizing squamous metaplasia; alveoli lined by cuboidal epithelium (type II pneumocyte hyperplasia); lymphoid proliferation within bronchial tree, vascular adventitia, and alveolar septa; severely affected lungs may have foci of fibrosing alveolitis and bronchiolitis obliterans
- Budding virions on the epithelial apical cell surface and intracytoplasmic crystalline aggregates of viral nucleocapsids (16-18 nm diameter, rigid, hollow fibrils)
ADDITIONAL DIAGNOSTIC TESTS
- Serology: ELISA, IFA, immunoassays
- Virus isolation, RT-PCR: acute phase only
- Respiratory disease in mice
- Pneumonia virus of mice (PVM): Similar to immunodeficient (nude, SCID) presentation of Sendai virus; pneumovirus of the family Paramyxoviridae; natural disease only in immunodeficient mice; mild neutrophilic and histiocytic interstitial pneumonia, without bronchiolar epithelial hyperplasia or syncytia
- Mouse hepatitis virus (coronavirus): Respiratory strains with tropism for upper respiratory mucosa (viral replication with subsequent dissemination); syncytia of pulmonary vascular endothelium (immunocompromised mice only)
- Corynebacterium kutscheri: Embolic suppurative pneumonia
- Mycoplasma pulmonis: Bronchopneumonia, large lymphoid aggregates, bronchiectasis
- K Virus (Polyomaviridae): tropic for pulmonary endothelium, can cause neonatal pulmonary endothelial necrosis, edema, and hemorrhage
- CAR Bacillus: silver stain reveals organism paralleling cilia of respiratory epithelia
- Pneumocystis murina: GMS or PAS stain reveals organism within flocculent debris of alveolar lumina
- Pulmonary epithelial proliferation: Pulmonary adenoma, adenocarcinoma
- Sendai virus can cause disease in mice, rats, hamsters, and gerbils, and seroconversion occurs in guinea pigs; can also affect rabbits, ferrets, birds, swine, non‑human primates, and humans; distinct strain variations among all species except rodents
- Sendai virus alone in rats is of little significance
- Gerbils can be carriers
- Other viruses of Respirovirus genus, Paramyxoviridae family: Bovine parainfluenza virus 3, Human parainfluenza viruses 1 and 3
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