A murine model for natural primary CMV infections: age-dependent differences in the replication kinetics of murine CMV HaNa1 isolate in BALB/c mice

In healthy individuals, naturally acquired infections of human cytomegalovirus (HCMV) are generally asymptomatic. Animal models mimicking the natural primary HCMV infections are scarce. Here, neonatal (3 days old) and adult (8 weeks old) BALB/c mice were inoculated oronasally with 105TCID50 of a Belgian isolate HaNa1 of murine cytomegalovirus (MCMV). None of the mice showed clinical symptoms. For neonates and adults, viral replication occurred in nasal mucosa from 3 days post inoculation (dpi) till the end of the experiment (49 dpi) and in submandibular glands from 7 dpi till 49 dpi. Virus replication was detected in lungs of neonates from 5 dpi to 17 dpi. In contrast, only at 5 dpi virus was transiently detected in lungs of adults. Only in neonatal mice, virus replication occurred in multiple internal organs such as spleen, kidneys and brains. Immunofluorescence staining showed that for neonates and adults infected cells were observed in the olfactory epithelium and nasopharynx-associated lymphoid tissue (NALT) of nasal mucosa, in the area of pulmonary alveoli of lungs and in the secretory acini of submandibular glands. In the kidneys of neonates, infected cells were found in glomeruli. Neonatal and adult mice developed detectable specific immunoglobulin G (IgG) from 10-14 dpi. Like in adults, the primary response in neonatal mice was biased strongly towards the IgG2a isotype. In adult mice, neutralizing antibodies were not detected until 28 dpi and remained very low (1:2) at 49 dpi. In summary, we have developed a murine model for natural primary HCMV infection, which mimics the range and extent of virus replication during natural primary HCMV infections in healthy infants and adults. This new model may be very helpful in further evaluating the pathogenesis of HCMV infections, testing antivirals and the development of effective vaccines