Characterization of Upper Respiratory Disease in Rats Following Neonatal Inoculation with a Rat-adapted Influenza Virus

Neonatal F344 rats were infected with a rat-adapted influenza virus (RAIV) to use as a potential model to study the combined effects of air pollutant exposure with early life respiratory viral infections. Initially, 6-day-old pups were intranasally inoculated with RAIV or medium alone, and nasal and lower respiratory tract (LRT) tissues were assessed histologically at 1, 3, 6, and 13 days postinoculation (DPI). Immunologic assessments included thymic lymphocyte quantification and anti-RAIV immunoglobulin production. Pups then received two inoculations (at 6 and 30 days of age), with histologic and immunologic assessment 6 and 13 days after the second inoculation and bronchoprovocation testing 5-8 weeks later. Following the single RAIV inoculation, IgM and IgG₁ measurements increased at 6, 11, and 15 DPI, with IgG₁ being greater at 11 and 15 DPI. Nasal lesions were evident as early as 1 DPI and primarily involved the anterior dorsal medial meatus and adjacent dorsal atrio- and nasoturbinates. Alterations included epithelial cell exfoliation and necrosis, mild erosions, suppurative and nonsuppurative inflammation, intraepithelial neutrophil accumulations, and intraluminal exudate. By 3 DPI, olfactory epithelial damage was multifocal or locally diffuse, with degeneration of sensory cells and variable inflammation. By 13 DPI, lesions were essentially repaired. Minimal changes were apparent in the LRT despite evidence of viral replication in the lungs 24 hours after inoculation (>3 log₁₀ plaque-forming units/lung). Pups reinoculated with RAIV at 30 days of age did not develop significant histologic lesions, nor did they exhibit increased airway responsiveness when assessed as young adults. In spite of their immature immune status at the time of initial infection, 13 days after the second RAIV inoculation, IgG, increased substantially. Thus, neonatal RAIV infection resulted in acute nasal epithelial injury and inflammation, alterations that may allow subsequent evaluation of viral disease-air pollutant interactions.