Otitis media: The Chinchilla model

Streptococcus pneumoniae infection and disease have been modeled in several animal species including infant and adult mice, infant and adult rats, inf ant Rhesus monkeys, and adolescent and adult chinchillas. Most are models o f sepsis arising from intravenous or intraperitoneal inoculation of bacteri a, and a few were designed to study disease arising from intranasal infecti on. Chinchillas provide the only animal model of middle ear pneumococcal in fection in which the disease can be produced by very small inocula injected into the middle ear (ME) or intranasally, and in which the disease remains localized to the ME in most cases. This model, developed at the University of Minnesota in 1975, has been used to study pneumococcal pathogenesis at a mucosal site, immunogenicity and efficacy of pneumococcal capsular polysa ccharide (PS) vaccine antigens, and the kinetics and efficacy of antimicrob ial drugs. Pathogenesis experiments in the chinchilla model have revealed variation in ME virulence among different pneumococcal serotypes, enhancement of ME inf ection during concurrent intranasal influenza A virus infections, and natur al resolution of pneumococcal otitis media (OM) without intervention. Resea rch has explored the relative contribution of pneumococcal and host product s to ME inflammation. Pneumococcal cell wall components and pneumolysin hav e been studied in the model. Host inflammatory responses studied in the chi nchilla ME include polymorphonuclear leukocyte oxidative products, hydrolyt ic enzymes, cytokine and eicosanoid metabolites, and ME epithelial cell adh esion and mucous glycoprotein production. Both clinical (tympanic membrane appearance) and histopathology (ME, Eustachian tube, inner ear) endpoints c an be quantified. Immunologic and inflammatory studies have been facilitated by the productio n of affinity-purified anti-chinchilla immunoglobulin G (IgG), IgM, and sec retory IgA polyclonal antibody reagents, and the identification of cross-re activity between human and chinchilla cytokines, and between guinea pig and chinchilla C3. Alteration of ME mucosa by pneumococcal neuraminidase and a lteration of ME epithelial cell (MEEC) surface carbohydrates during intrana sal pneumococcal infection have been demonstrated. Pathogenesis studies hav e been aided by cultured chinchilla MEEC systems, in which the ability of p latelet activating factor and interleukin (IL)-1 beta to stimulate epitheli al mucous glycoprotein synthesis has recently been demonstrated. Because ch ronic OM with effusion is characterized by presence of large amounts of muc ous glycoprotein in the ME, pneumococcus may have an important role in both acute and chronic ME disease. Both unconjugated PS and PS-protein-conjugated vaccines are immunogenic aft er intramuscular administration without adjuvant in chinchillas. Passive pr otection studies with human hyperimmune immunoglobulin demonstrated that an ti-PS IgG alone is capable of protecting the chinchilla ME from direct ME c hallenge with pneumococci. Active PS immunization studies demonstrated prot ection following direct ME and intranasal pneumococcal challenge with and w ithout concurrent influenza A virus infection. An attenuated influenza A vi rus vaccine also showed protection for pneumococcal OM. Antimicrobial treatment of acute OM has been based almost exclusively on em pirical drug use and clinical trials without a foundation of ME pharmacokin etics. Studies in the chinchilla model have started to bring a rational bas is to drug selection and dosing. Microassays have been developed using high -pressure liquid chromatography for many relevant drugs. Studies have explo red the in vivo ME response in pneumococcal OM to antimicrobial drugs at su pra- and sub-minimum inhibitory concentration (MIC), the effect of concurre nt influenza A virus infection on ME drug penetration, and the effect of tr eatment on sensorineural hearing loss produced by pneumococcal OM.