Enhanced control of Mycobacterium tuberculosis extrapulmonary dissemination in mice by an arabinomannan-protein conjugate vaccine.
Enhanced control of Mycobacterium tuberculosis extrapulmonary dissemination in mice by an arabinomannan-protein conjugate vaccine.
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DOI：
10.1371/journal.ppat.1006250
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发表时间：
2017-03
期刊：
影响因子：
6.7
通讯作者：
Casadevall A
中科院分区：
文献类型：
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作者：
Prados-Rosales R;Carreño L;Cheng T;Blanc C;Weinrick B;Malek A;Lowary TL;Baena A;Joe M;Bai Y;Kalscheuer R;Batista-Gonzalez A;Saavedra NA;Sampedro L;Tomás J;Anguita J;Hung SC;Tripathi A;Xu J;Glatman-Freedman A;Jacobs WR Jr;Chan J;Porcelli SA;Achkar JM;Casadevall A
目前，有十几种新的候选疫苗在临床试验中用于预防结核病（TB），每种制剂都试图通过增强细胞介导的免疫力（CMI）来引起保护。相比之下，大多数针对其他细菌病原体的批准疫苗被认为通过引发抗体应答来介导保护。然而，由于难以可靠地引发保护性抗体，因此难以将该公式应用于结核病。在这里，我们通过将分枝杆菌荚膜阿拉伯甘露聚糖（AM）连接到Mt B Ag 85 B或B来开发荚膜多糖缀合物。炭疽保护性抗原（PA）。此外，我们还通过ELISA和AM聚糖微阵列研究了它们的免疫原性和小鼠保护效果。用Abg 85 b-AM或PA-AM缀合物免疫在小鼠中引发AM特异性抗体应答。AM结合抗体刺激Mtb的转录变化。从AM缀合物免疫小鼠的血清对广谱的AM结构变体和特异性识别的阿拉伯聚糖片段的反应。结合物疫苗免疫的小鼠感染结核分枝杆菌后，肺和脾中的细菌数量较低，并且比对照小鼠存活时间更长。这些发现提供了额外的证据，体液免疫可以有助于防止结核分枝杆菌。结核病领域的疫苗设计一直受到试图引起强细胞介导的应答的迫切性的驱动。然而，近几十年来，越来越多的证据表明，体液免疫可以通过多种机制抵御许多细胞内病原体。在这项工作中，我们证明了免疫接种分枝杆菌荚膜阿拉伯甘露聚糖（AM）共轭物引起的反应，有助于防止结核分枝杆菌感染。我们开发了两种不同的缀合物，包括与Mt B相关蛋白Ag 85 B连接的荚膜AM或与来自B的Mt B无关的PA。炭疽菌的免疫接种，并发现与AM共轭物引发的抗体群体具有不同的特异性。这些表面特异性抗体可以直接改变分枝杆菌的转录谱和代谢。此外，我们观察到延长的生存期和减少在肺和脾中的细菌数量的Ag 85 b-AM缀合物免疫小鼠感染结核分枝杆菌后，AM结合抗体的存在与适度延长生存期和显着减少分枝杆菌传播。最后，我们表明，AM是抗原可变的，并可能形成基于血清型的分枝杆菌的血清学表征的基础。
Currently there are a dozen or so of new vaccine candidates in clinical trials for prevention of tuberculosis (TB) and each formulation attempts to elicit protection by enhancement of cell-mediated immunity (CMI). In contrast, most approved vaccines against other bacterial pathogens are believed to mediate protection by eliciting antibody responses. However, it has been difficult to apply this formula to TB because of the difficulty in reliably eliciting protective antibodies. Here, we developed capsular polysaccharide conjugates by linking mycobacterial capsular arabinomannan (AM) to either Mtb Ag85b or B. anthracis protective antigen (PA). Further, we studied their immunogenicity by ELISA and AM glycan microarrays and protection efficacy in mice. Immunization with either Abg85b-AM or PA-AM conjugates elicited an AM-specific antibody response in mice. AM binding antibodies stimulated transcriptional changes in Mtb. Sera from AM conjugate immunized mice reacted against a broad spectrum of AM structural variants and specifically recognized arabinan fragments. Conjugate vaccine immunized mice infected with Mtb had lower bacterial numbers in lungs and spleen, and lived longer than control mice. These findings provide additional evidence that humoral immunity can contribute to protection against Mtb. Vaccine design in the TB field has been driven by the imperative of attempting to elicit strong cell-mediated responses. However, in recent decades evidence has accumulated that humoral immunity can protect against many intracellular pathogens through numerous mechanisms. In this work, we demonstrate that immunization with mycobacterial capsular arabinomannan (AM) conjugates elicited responses that contributed to protection against Mtb infection. We developed two different conjugates including capsular AM linked to the Mtb related protein Ag85b or the Mtb unrelated PA from B. anthracis and found that immunization with AM conjugates elicited antibody populations with different specificities. These surface-specific antibodies could directly modify the transcriptional profile and metabolism of mycobacteria. In addition, we observed a prolonged survival and a reduction in bacterial numbers in lungs and spleen in mice immunized with Ag85b-AM conjugates after infection with Mtb and that the presence of AM-binding antibodies was associated with modest prolongation in survival and a marked reduction in mycobacterial dissemination. Finally, we show that AM is antigenically variable and could potentially form the basis for a serological characterization of mycobacteria based on serotypes.