Respiratory syncytial virus infection exacerbates pneumococcal pneumonia via Gas6/Axl-mediated macrophage polarization

被引：56

作者：

Shibata, Takehiko ^{[1
]}

Makino, Airi ^{[1
,2
]}

Ogata, Ruiko ^{[3
]}

Nakamura, Shigeki ^{[4
,5
]}

Ito, Toshihiro ^{[3
]}

Nagata, Kisaburo ^{[2
]}

Terauchi, Yoshihiko ^{[6
,7
]}

Oishi, Taku ^{[7
]}

Fujieda, Mikiya ^{[7
]}

Takahashi, Yoshimasa ^{[1
]}

Ato, Manabu ^{[1
,8
]}

机构：

[1] Natl Inst Infect Dis, Dept Immunol, Tokyo, Japan

[2] Toho Univ, Fac Sci, Dept Biomol Sci, Chiba, Japan

[3] Nara Med Univ, Dept Immunol, Nara, Japan

[4] Natl Inst Infect Dis, Dept Chemotherapy & Mycoses, Tokyo, Japan

[5] Tokyo Med Univ, Dept Microbiol, Tokyo, Japan

[6] Natl Inst Infect Dis, Dept Pathol, Tokyo, Japan

[7] Natl Hosp Org Kochi Hosp, Dept Pediat, Kochi, Japan

[8] Natl Inst Infect Dis, Dept Mycobacteriol, Tokyo, Japan

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2020年 / 130卷 / 06期

基金：

日本学术振兴会;

关键词：

INTERFERON-GAMMA PRODUCTION; STREPTOCOCCUS-PNEUMONIAE; TAM RECEPTORS; GENE; 6; PULMONARY; AXL; CHILDREN; DISEASE; PROTEIN; KINASE;

D O I：

10.1172/JCI125505

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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-gamma production and local NO and TNF-alpha 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.

引用

页码：3021 / 3037

页数：17

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[1] Influenza A virus-induced release of interleukin-10 inhibits the anti-microbial activities of invariant natural killer T cells during invasive pneumococcal superinfection [J].