Respiratory syncytial virus infection of newborn CX3CR1-deficient mice induces a pathogenic pulmonary innate immune response
Sudipta Das, … , Anuradha Ray, Prabir Ray
Sudipta Das, … , Anuradha Ray, Prabir Ray
Published September 7, 2017
Citation Information: JCI Insight. 2017;2(17):e94605. https://doi.org/10.1172/jci.insight.94605.
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Research Article Infectious disease Pulmonology

Respiratory syncytial virus infection of newborn CX3CR1-deficient mice induces a pathogenic pulmonary innate immune response

Abstract

Respiratory syncytial virus (RSV) infects almost all infants by 2 years of age, and severe bronchiolitis resulting from RSV infection is the primary cause of hospitalization in the first year of life. Among infants hospitalized due to RSV-induced bronchiolitis, those with a specific mutation in the chemokine receptor CX3CR1, which severely compromises binding of its ligand CX3CL1, were at a higher risk for more severe viral bronchiolitis than those without the mutation. Here, we show that RSV infection of newborn mice deficient in CX3CR1 leads to significantly greater neutrophilic inflammation in the lungs, accompanied by an increase in mucus production compared with that induced in WT mice. Analysis of innate and adaptive immune responses revealed an early increase in the number of IL-17+ γδ T cells in CX3CR1-deficient mice that outnumbered IFN-γ+ γδ T cells as well as IFN-γ+ NK cells, IFN-γ being host protective in the context of RSV infection. This bias toward IL-17+ γδ T cells persisted at a later time. The lungs of CX3CR1-deficient mice expressed higher levels of IL-1β mRNA and protein, and blockade of IL-1β signaling using IL-1 receptor antagonist significantly reduced the number of IL-17+ γδ T cells in the lungs of infected mice. Blockade of IL-17RC abolished RSV-induced lung pathology in infected CX3CR1-deficient mice. We propose that, in infants harboring mutant CX3CR1, targeting the IL-17R may minimize disease severity and hospitalization in early life.

Authors

Sudipta Das, Mahesh Raundhal, Jie Chen, Timothy B. Oriss, Rachael Huff, John V. Williams, Anuradha Ray, Prabir Ray

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Figure 2

CX3CR1 deficiency promotes mucus production and neutrophil accumulation in the lungs but does not influence viral burden after RSV infection.

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CX3CR1 deficiency promotes mucus production and neutrophil accumulation ...
(A) Histological assessment of lung sections after PAS staining showing mucus in the airways of WT and CX3CR1–/– newborn mice on day 7 p.i. by RSV. Original magnification, ×10. Scale bar: 200 μm. (B) Pathological score showing mucus-producing goblet cells in the mentioned groups. CX3CR1–/– mice are referred to as KO. Data shown are mean ± SEM combined from 2 independent experiments, n = 2–3 mice per group per experiment. (C) mRNA expression of mucus-producing genes (Muc5ac and Gob5) and (D) RSV-L polymerase in lungs measured by quantitative RT-PCR on day 7 p.i. Data shown are mean ± SEM of 2 independent combined experiments; n = 6–9 mice per group per experiment. (E) Viral load in total lungs on day 7 p.i. detected by plaque assay using Vero cells. Data shown are mean ± SEM combined from 2 independent experiments, n = 3–5 mice per group per experiment. (F) Detection of neutrophils by immunohistochemical staining of lung sections on day 7 p.i. Neutrophils are indicated by red arrows. Original magnification, ×20. Scale bar: 100 μm. (G) Quantitation of neutrophil accumulation normalized to the total number of cells present, as assessed using Nikon Elements software. Data shown are mean ± SEM combined from 2 independent experiments; n = 2–3 mice per group per experiment. *P ≤ 0.05, **P ≤ 0.01. Kruskal-Wallis (B and G) or Mann-Whitney U test (C–E) was used for statistical analysis.