Inflammatory responses to acute pneumovirus infection in neonatal mice

Abstract

Background: The innate immune responses of neonates differ dramatically from those of adults. Here we examine the acute inflammatory responses of neonatal and weanling mice infected with pneumonia virus of mice (PVM), a rodent pathogen (family Paramyxoviridae, genus Pneumovirus) that replicates the sequelae of severe respiratory syncytial virus infection.

Results: We demonstrate that virus replication proceeds indistinguishably in all age groups (inoculated at 1, 2, 3 and 4 weeks of age), although inflammatory responses vary in extent and character. Some of the biochemical mediators detected varied minimally with age at inoculation. Most of the mediators evaluated demonstrated elevated expression over baseline correlating directly with age at the time of virus inoculation. Among the latter group are CCL2, CCL3, and IFN-γ, all cytokines previously associated with PVM-induced inflammatory pathology in mature mice. Likewise, we detect neutrophil recruitment to lung tissue in all age groups, but recruitment is most pronounced among the older (3 - 4 week old) mice. Interestingly, all mice exhibit failure to thrive, lagging in expected weight gain for given age, including the youngest mice that present little overt evidence of inflammation.

Conclusions: Our findings among the youngest mice may explain in part the phenomenon of atypical or minimally symptomatic respiratory infections in human neonates, which may be explored further with this infection model.

Figure 1

Proinflammatory mediators expressed in lung tissue in response to PVM infection. Detection of immunoreactive (A) CCL3 (B) CXCL10 (C) CXCL9 (D) CXCL1 (E) CCL2 and (F) IFNγ in response to PVM infection in mice at 1 week (white bars), 2 weeks (light gray bars), 3 weeks (dark gray bars) or 4 weeks old (black bars) at time of virus inoculation. Detection of immunoreactive protein is shown at days 0, 4, and 7 after inoculation for all mice. Statistical significance, *p < 0.05 vs. mediator levels of mice from younger age groups (inoculated at 1 or 2 weeks old), evaluated at day 7; n = 4 - 6 mice per group.

Figure 2

Histopathologic analysis. Hematoxylin and eosin-(H&E) stained lung tissue from mice inoculated with PVM at (A) 1 week (B) 2 weeks (C) 3 weeks or (D) 4 weeks of age. Lung tissue sample was taken at day 7 after inoculation; original magnification, 10×.

Figure 3

Acute PVM infection results diminished growth. Mice were inoculated with 10 μL/200 pfu PVM J3666 (filled symbols) or phosphate buffered-saline control (open symbols) at 1, 2, 3, or 4 weeks of age as shown. Weight was evaluated at day 0 and at day 7; percent (%) change was measured as [(weight day 7 - weight day 0) × 100/weight day 0.]. Net weight loss was observed in some PVM-infected weanling mice (7 of 44); statistical significance, *p < 0.05, **p < 0.005; n = 19 - 31 mice per group.