PDF(Pubmed)
Abstract：
Iron acquisition is a key feature dictating the success of pathogen colonization and infection. Pathogens scavenging iron from the host must contend with other members of the microbiome similarly competing for the limited pool of bioavailable iron, often in the form of heme. In this study, we identify a beneficial role for the heme-binding protein hemophilin (Hpl) produced by the non-pathogenic bacterium Haemophilus haemolyticus against its close relative, the opportunistic respiratory tract pathogen non-typeable Haemophilus influenzae (NTHi). Using a mouse model, we found that pre-exposure to H. haemolyticus significantly reduced NTHi colonization of the upper airway and impaired NTHi infection of the lungs in an Hpl-dependent manner. Further, treatment with recombinant Hpl was sufficient to decrease airway burdens of NTHi without exacerbating lung immunopathology or systemic inflammation. Instead, mucosal production of the neutrophil chemokine CXCL2, lung myeloperoxidase, and serum pro-inflammatory cytokines IL-6 and TNFα were lower in Hpl-treated mice. Mechanistically, H. haemolyticus suppressed NTHi growth and adherence to human respiratory tract epithelial cells through the expression of Hpl, and recombinant Hpl could recapitulate these effects. Together, these findings indicate that heme sequestration by non-pathogenic, Hpl-producing H. haemolyticus is protective against NTHi colonization and infection.
OBJECTIVE: The microbiome provides a critical layer of protection against infection with bacterial pathogens. This protection is accomplished through a variety of mechanisms, including interference with pathogen growth and adherence to host cells. In terms of immune defense, another way to prevent pathogens from establishing infections is by limiting the availability of nutrients, referred to as nutritional immunity. Restricting pathogen access to iron is a central component of this approach. Here, we uncovered an example where these two strategies intersect to impede infection with the respiratory tract bacterial pathogen Haemophilus influenzae. Specifically, we find that a non-pathogenic (commensal) bacterium closely related to H. influenzae called Haemophilus haemolyticus improves protection against H. influenzae by limiting the ability of this pathogen to access iron. These findings suggest that beneficial members of the microbiome improve protection against pathogen infection by effectively contributing to host nutritional immunity.
OBJECTIVE: The microbiome provides a critical layer of protection against infection with bacterial pathogens. This protection is accomplished through a variety of mechanisms, including interference with pathogen growth and adherence to host cells. In terms of immune defense, another way to prevent pathogens from establishing infections is by limiting the availability of nutrients, referred to as nutritional immunity. Restricting pathogen access to iron is a central component of this approach. Here, we uncovered an example where these two strategies intersect to impede infection with the respiratory tract bacterial pathogen Haemophilus influenzae. Specifically, we find that a non-pathogenic (commensal) bacterium closely related to H. influenzae called Haemophilus haemolyticus improves protection against H. influenzae by limiting the ability of this pathogen to access iron. These findings suggest that beneficial members of the microbiome improve protection against pathogen infection by effectively contributing to host nutritional immunity.
摘要：
铁的获取是决定病原体定植和感染成功的关键特征。从宿主中清除铁的病原体必须与微生物组的其他成员竞争，同样竞争有限的生物可利用铁库，通常以血红素的形式。在这项研究中,我们确定了一个有益的作用血红素结合蛋白血友病产生的非致病性细菌溶血嗜血杆菌（Hpl）对其近亲，机会性呼吸道病原体不可分型流感嗜血杆菌（NTHi）。使用鼠标模型，我们发现,溶血嗜血杆菌暴露前显著减少了NTHi在上呼吸道的定植,并以Hpl依赖性方式损害了肺的NTHi感染.Further,用重组Hpl治疗足以降低NTHi的气道负担,而不加重肺免疫病理学或全身性炎症。相反，中性粒细胞趋化因子CXCL2，肺髓过氧化物酶，在Hpl处理的小鼠中,血清促炎细胞因子IL-6和TNFα较低。机械上,嗜血杆菌通过Hpl的表达抑制NTHi的生长和对人呼吸道上皮细胞的粘附，重组Hpl可以概括这些作用。一起,这些发现表明血红素通过非致病性螯合，产生Hpl的溶血嗜血杆菌对NTHi定植和感染具有保护性。重要微生物组为防止细菌病原体感染提供了关键的保护层。这种保护是通过各种机制来实现的，包括干扰病原体生长和对宿主细胞的粘附。在免疫防御方面，防止病原体感染的另一种方法是限制营养素的可用性，被称为营养免疫。限制病原体接触铁是这种方法的核心组成部分。这里,我们发现了一个例子，其中这两种策略相交，以阻止呼吸道细菌病原体流感嗜血杆菌感染。具体来说,我们发现，一种与流感嗜血杆菌密切相关的非致病性（共生）细菌，称为溶血嗜血杆菌，通过限制该病原体获取铁的能力来改善对流感嗜血杆菌的保护。这些发现表明，微生物组的有益成员通过有效促进宿主营养免疫来改善对病原体感染的保护。
