Respiratory syncytial virus-mediated Gas6/Axl axis induces hyporesponsive macrophages to promote pneumococcal proliferation in the nasopharynx.

Abstract

Streptococcus pneumoniae commonly colonizes the nasopharynx of children asymptomatically, but under certain conditions, it can cause invasive diseases such as pneumonia. The mechanisms driving this transition are not fully understood. In this study, we utilized a pneumococcal nasopharyngeal colonization model and subsequent respiratory syncytial virus (RSV) infection to investigate the mechanism of bacterial expansion. We observed loads in nasal and bronchoalveolar lavage fluids. We also measured the expression of the growth arrest-specific protein 6 (Gas6) in the nasal lavage. We further assessed the effect of selective inhibition of the Axl receptor using BGB324 on RSV-mediated growth. Macrophage phenotypes were analyzed in vivo using M1-like markers and confirmed in vitro using Gas6-treated bone marrow-derived macrophages. We observed increased loads in nasal and bronchoalveolar lavage fluids following RSV infection. RSV infection also upregulated the expression of Gas6 in the nasal lavage, and selective inhibition of the Axl receptor using BGB324 effectively attenuated RSV-mediated growth. In addition, compared with mice with colonization alone, mice with subsequent RSV infection exhibited decreased expression of M1-like macrophage markers in the nasal cavity. In vitro assays confirmed that Gas6 suppressed M1 macrophage polarization, fostering an immunosuppressive microenvironment conducive to bacterial proliferation. Our findings reveal that the RSV infection-induced Gas6/Axl axis facilitates pneumococcal overgrowth by modulating macrophage function. Targeting the RSV-induced Gas6/Axl axis or modulating macrophage polarization may offer novel therapeutic strategies for preventing or managing severe pneumococcal infections exacerbated by viral pathogens such as RSV.