Depletion of Alveolar Macrophages during Influenza Infection Facilitates Bacterial Superinfections

被引:291
作者
Ghoneim, Hazem E. [1 ,2 ,3 ]
Thomas, Paul G. [4 ]
McCullers, Jonathan A. [1 ,5 ]
机构
[1] St Jude Childrens Res Hosp, Dept Infect Dis, Memphis, TN 38105 USA
[2] Univ Tennessee, Hlth Sci Ctr, Microbiol Immunol & Biochem Grad Program, Memphis, TN 38103 USA
[3] Cairo Univ, Fac Pharm, Dept Microbiol & Immunol, Cairo 11562, Egypt
[4] St Jude Childrens Res Hosp, Dept Immunol, Memphis, TN 38105 USA
[5] Univ Tennessee, Hlth Sci Ctr, Dept Pediat, Memphis, TN 38103 USA
关键词
GM-CSF; STREPTOCOCCUS-PNEUMONIAE; LUNG MACROPHAGES; BLOOD MONOCYTES; INNATE IMMUNITY; PULMONARY; VIRUS; RESISTANCE; SUBPOPULATIONS; CLEARANCE;
D O I
10.4049/jimmunol.1300014
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Viruses such as influenza suppress host immune function by a variety of methods. This may result in significant morbidity through several pathways, including facilitation of secondary bacterial pneumonia from pathogens such as Streptococcus pneumoniae. PKH26-phagocytic cell labeling dye was administered intranasally to label resident alveolar macrophages (AMs) in a well-established murine model before influenza infection to determine turnover kinetics during the course of infection. More than 90% of resident AMs were lost in the first week after influenza, whereas the remaining cells had a necrotic phenotype. To establish the impact of this innate immune defect, influenza-infected mice were challenged with S. pneumoniae. Early AM-mediated bacterial clearance was significantly impaired in influenza-infected mice: similar to 50% of the initial bacterial inoculum could be harvested from the alveolar airspace 3 h later. In mock-infected mice, by contrast, >95% of inocula up to 50-fold higher was efficiently cleared. Coinfection during the AM depletion phase caused significant body weight loss and mortality. Two weeks after influenza, the AM population was fully replenished with successful re-establishment of early innate host protection. Local GMCSF treatment partially restored the impaired early bacterial clearance with efficient protection against secondary pneumococcal pneumonia. We conclude that resident AM depletion occurs during influenza infection. Among other potential effects, this establishes a niche for secondary pneumococcal infection by altering early cellular innate immunity in the lungs, resulting in pneumococcal outgrowth and lethal pneumonia. This novel mechanism will inform development of novel therapeutic approaches to restore lung innate immunity against bacterial superinfections.
引用
收藏
页码:1250 / 1259
页数:10
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