Respiratory Syncytial Virus–Mediated Gas6/Axl Axis Induces Hyporesponsive Macrophages to Promote Pneumococcal Proliferation in the Nasopharynx

BACKGROUND: Streptococcus pneumoniae commonly colonizes the nasopharynx asymptomatically, but certain conditions trigger its transition to invasive disease. The mechanisms driving this expansion are not fully understood. METHODS: We used a murine model of pneumococcal nasopharyngeal colonization followed by respiratory syncytial virus (RSV) infection to investigate bacterial expansion. We measured bacterial loads in nasal and bronchoalveolar lavage fluids and analyzed growth arrest-specific protein 6 (Gas6) expression. The effect of the Axl receptor inhibitor BGB324 (bemcentinib) on RSV-mediated growth was assessed, and macrophage phenotypes were analyzed in vivo and in vitro. RESULTS: RSV infection increased bacterial loads and upregulated Gas6 expression in the nasal cavity. Inhibition of the Axl receptor with BGB324 effectively attenuated RSV-mediated pneumococcal growth. Furthermore, RSV infection decreased M1-like macrophage markers in the nasal cavity. In vitro assays confirmed that Gas6 suppresses M1 polarization, fostering an environment conducive to bacterial proliferation. CONCLUSIONS: Our findings reveal that the RSV-induced Gas6/Axl axis facilitates pneumococcal overgrowth by modulating macrophage function. Targeting this axis or modulating macrophage polarization may offer novel therapeutic strategies for preventing severe pneumococcal infections exacerbated by RSV.