Innate and Adaptive Immune Response to Pneumonia Virus of Mice in a Resistant and a Susceptible Mouse Strain

Abstract

Respiratory syncytial virus (RSV) is the leading cause of infant bronchiolitis. The closely related pneumonia virus of mice (PVM) causes a similar immune-mediated disease in mice, which allows an analysis of host factors that lead to severe illness. This project was designed to compare the immune responses to lethal and sublethal doses of PVM strain 15 in Balb/c and C57Bl/6 mice. Balb/c mice responded to PVM infection with an earlier and stronger innate response that failed to control viral replication. Production of inflammatory cyto- and chemokines, as well as infiltration of neutrophils and IFN-γ secreting natural killer cells into the lungs, was more predominant in Balb/c mice. In contrast, C57Bl/6 mice were capable of suppressing both viral replication and innate inflammatory responses. After a sublethal infection, PVM-induced IFN-γ production by splenocytes was stronger early during infection and weaker at late time points in C57Bl/6 mice when compared to Balb/c mice. Furthermore, although the IgG levels were similar and the mucosal IgA titres lower, the virus neutralizing antibody titres were higher in C57Bl/6 mice than in Balb/c mice. Overall, the difference in susceptibility of these two strains appeared to be related not to an inherent T helper bias, but to the capacity of the C57Bl/6 mice to control both viral replication and the immune response elicited by PVM.

Intranasal treatment with a novel immunomodulator mediates innate immune protection against lethal pneumonia virus of mice

“…A clear downside of using this animal model is the numerous differences between innate and adaptive immune responses of humans and mice [67]. Additionally, pneumoviruses are known to be species-specific, thus studies in cognate hosts are better suited to obtain an understanding of fundamental immune-mediated mechanisms of severe infection [13]. Other limitations in using rodents as animal models include the distinct neutrophil and lymphocyte ratios in blood, and differences in lung anatomy [13,67,69].…”

“…Additionally, pneumoviruses are known to be species-specific, thus studies in cognate hosts are better suited to obtain an understanding of fundamental immune-mediated mechanisms of severe infection [13]. Other limitations in using rodents as animal models include the distinct neutrophil and lymphocyte ratios in blood, and differences in lung anatomy [13,67,69]. Nonetheless, the RSV mouse model has major advantages, such as the vast availability of reagents, immunological tools, knockout and transgenic strains, cost-effectiveness and ease of housing and handling [6,67,70].…”

“…In turn, this may provide us with a more accurate representation of natural infection and disease [1]. In the last thirty years, the pneumonia virus of mice (PVM) has been considered as a mouse model of natural RSV disease [13,51]. PVM is closely related to RSV, both belonging to the same viral family and subfamily, and inducing similar disorders in their natural hosts [74].…”

“…PVM is closely related to RSV, both belonging to the same viral family and subfamily, and inducing similar disorders in their natural hosts [74]. Unlike RSV infection in mice, PVM replicates in the lower airways to extremely high titers in response to as little as 10 plaque-forming units (pfu) of virus inoculum [12,13,51,69].…”

“…Pre-term babies, newborn infants between 2 and 4 months of age, immunocompromised individuals, and the elderly are at highest risk of developing severe RSV disease [9,12]. In these populations, the virus can infect the lower respiratory tract (LRT), often leading to hospitalizations and in worst cases death [13].…”