Respiratory syncytial virus infection exacerbates pneumococcal pneumonia via Gas6/Axl-mediated macrophage polarization
Takehiko Shibata, … , Yoshimasa Takahashi, Manabu Ato
Takehiko Shibata, … , Yoshimasa Takahashi, Manabu Ato
Published May 4, 2020
Citation Information: J Clin Invest. 2020;130(6):3021-3037. https://doi.org/10.1172/JCI125505.
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Respiratory syncytial virus infection exacerbates pneumococcal pneumonia via Gas6/Axl-mediated macrophage polarization

Abstract

Patients with respiratory syncytial virus (RSV) infection exhibit enhanced susceptibility to subsequent pneumococcal infections. However, the underlying mechanisms involved in this increased susceptibility remain unclear. Here, we identified potentially novel cellular and molecular cascades triggered by RSV infection to exacerbate secondary pneumococcal pneumonia. RSV infection stimulated the local production of growth arrest–specific 6 (Gas6). The Gas6 receptor Axl was crucial for attenuating pneumococcal immunity in that the Gas6/Axl blockade fully restored antibacterial immunity. Mechanistically, Gas6/Axl interaction regulated the conversion of alveolar macrophages from an antibacterial phenotype to an M2-like phenotype that did not exhibit antibacterial activity, and the attenuation of caspase-1 activation and IL-18 production in response to pneumococcal infection. The attenuated IL-18 production failed to drive both NK cell–mediated IFN-γ production and local NO and TNF-α production, which impair the control of bacterial infection. Hence, the RSV-mediated Gas6/Axl activity attenuates the macrophage-mediated protection against pneumococcal infection. The Gas6/Axl axis could be a potentially novel therapeutic target for RSV-associated secondary bacterial infection.

Authors

Takehiko Shibata, Airi Makino, Ruiko Ogata, Shigeki Nakamura, Toshihiro Ito, Kisaburo Nagata, Yoshihiko Terauchi, Taku Oishi, Mikiya Fujieda, Yoshimasa Takahashi, Manabu Ato

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Figure 2

Exogenous Gas6 increases susceptibility to S. pneumoniae infection following RSV infection.

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Exogenous Gas6 increases susceptibility to S. pneumoniae infection follo...
(A) Mice were infected with RSV or treated with recombinant Gas6 (rGas6; 1 μg/dose, 3 doses) before S. pneumoniae infection on day 8 after RSV infection. Animals were euthanized for analysis on days 1, 2, and 3 after S. pneumoniae infection. (B) Changes in the survival rate and (C) body weight after S. pneumoniae infection. (D) Titers of S. pneumoniae in the BAL fluid from RSV-infected or rGas6-injected mice on days 1 and 3 after S. pneumoniae infection. (E) Representative H&E-stained lung tissue sections on day 1 after S. pneumoniae infection. Scale bars: 200 μm (upper), 50 μm (lower). (F) Numbers of inflammatory cells in the BAL fluid from both treatment groups on day 1 after S. pneumoniae infection. (G) The levels of IFN-γ, NO, TNF-α, IL-1β, CXCL1, and CXCL2 in the BAL fluid from both treatment groups on day 1 after S. pneumoniae infection. The data are expressed as the mean ± SEM; n = 10 (B and C), n = 4–6 (except for B and C). Representative results from 2 independent experiments are shown. The following statistical tests were used: Gehan-Breslow-Wilcoxon test (B), 1-way ANOVA (C, D, F, and G). *P < 0.05; **P < 0.01; ***P < 0.001.