Pathogenesis of Human Metapneumovirus Lung Infection in BALB/c Mice and Cotton Rats

Abstract

Human metapneumovirus (hMPV) is a newly described member of the Paramyxoviridae family causing acute respiratory tract infections, especially in young children. We studied the pathogenesis of this viral infection in two experimental small animal models (BALB/c mice and cotton rats). Significant viral replication in the lungs of both animals was found following an intranasal challenge of 10 8 50% tissue culture infectious doses (TCID 50 ) and persisted for <2 and <3 weeks in the case of cotton rats and mice, respectively. Peak viral loads were found on day 5 postinfection in both mice (mean of 1.92 ؋ 10 7 TCID 50 /g lung) and cotton rats (mean of 1.03 ؋ 10 5 TCID 50 /g). Clinical symptoms consisting of breathing difficulties, ruffled fur, and weight loss were noted in mice only around the time of peak viral replication. Most significant pulmonary inflammatory changes and peak expression of macrophage inflammatory protein 1␣, gamma interferon, and RANTES occurred at the time of maximal viral replication (day 5) in both models. Cellular infiltration occurred predominantly around and within alveoli and persisted for at least 21 days in mice, whereas it was more limited in time with more peribronchiolitis in cotton rats. Both animal models would be of great value in evaluating different therapeutic agents, as well as vaccine candidates against hMPV.

Human metapneumovirus: Enhanced pulmonary disease in cotton rats immunized with formalin-inactivated virus vaccine and challenged

“…Endpoints used cytopathic effect on the cell monolayers. Virus titers were reported as Log 10 50% tissue culture infectious dose per milliliter of culture supernatant or per gram of lung (Log 10 TCID 50 /ml or Log 10 TCID 50 /g) [10]. TCID 50 was calculated by the method of Reed and Muench.…”

“…Its ability to co-infect with other respiratory infectious agents, including RSV and pneumococci [14,27], combined with its relatively slow replication in cell culture likely accounted for its ability to escape isolation until 2001. Various animal models have been utilized to study hMPV infection including mice, hamsters, and several species of primates [10,12,13,23]. Recent studies indicate that infection of cotton rats with hMPV is associated with efficient viral replication in the lung and reproducible pulmonary pathology [10,28,30].…”

“…Various animal models have been utilized to study hMPV infection including mice, hamsters, and several species of primates [10,12,13,23]. Recent studies indicate that infection of cotton rats with hMPV is associated with efficient viral replication in the lung and reproducible pulmonary pathology [10,28,30]. The cotton rat has also been used extensively to study hRSV especially in the area of enhanced pulmonary disease caused by some vaccine candidates for hRSV [19][20][21][22].…”

Animal models for human Metapneumovirus (HMPV) infections

“…This unusual biphasic growth curve has not been observed for HMPV (or for that matter, RSV) in any other animal model by these or other investigators, and thus the biological significance is unclear. In addition to Alvarez et al [1,2], Hamelin et al [6] observed that the lung virus peaks somewhat earlier at day 5 p.i. in both BALB/c mice and cotton rats, an observation that is supported by Darniot et al [4].…”

“…Several animal species have been determined to be permissive for HMPV infection [1,4,6,9,10,12,18,23,27]. These models, which are described in more detail below, include small animals such as mice, cotton rats, hamsters, guinea pigs, ferrets, and primates, including chimpanzees, rhesus macaques and African green monkeys.…”