Natural and vaccine-mediated immunity to Salmonella Typhimurium is impaired by the helminth Nippostrongylus brasiliensis.
Natural and vaccine-mediated immunity to Salmonella Typhimurium is impaired by the helminth Nippostrongylus brasiliensis.
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天然和疫苗介导的对鼠伤寒沙门氏菌的免疫力受到蠕虫的核心核巴西氏菌的损害。
DOI：
10.1371/journal.pntd.0003341
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发表时间：
2014-12
影响因子：
3.8
通讯作者：
Cunningham AF
中科院分区：
文献类型：
--
作者：
Bobat S;Darby M;Mrdjen D;Cook C;Logan E;Auret J;Jones E;Schnoeller C;Flores-Langarica A;Ross EA;Vira A;López-Macías C;Henderson IR;Alexander J;Brombacher F;Horsnell WG;Cunningham AF
同时或连续暴露于多种病原体对免疫功能的影响尚不清楚。本研究检测了鼠伤寒沙门菌（Salmonella Typhimurium, STm）和巴西尼波圆线虫（Nippostrongylus brasiliensis, Nb）的组合诱导的免疫应答，后者可引起小鼠钩虫感染，并对针对STm的实验性孔蛋白疫苗进行了研究。通过流式细胞术检测，与单独感染小鼠相比，同时感染STm和Nb的小鼠诱导的Th1和Th2淋巴细胞数量相似，尽管在脾细胞再刺激后，ELISA检测到分泌的Th2水平较低，但没有检测到Th1细胞因子。此外，共感染小鼠的T区FoxP3+ T细胞密度低于仅注射Nb的小鼠，但高于注射STm的小鼠。这反映了从脾细胞中检测到的中等水平的IL-10。合并感染降低了两种病原体的清除，在对照组中清除了几周后，小鼠体内仍可检测到蠕虫。尽管在共感染小鼠中改变了细菌和蠕虫定植的控制，但在滤泡外检测到反映Th1和th2的强大的免疫球蛋白开关谱，并同时检测到IgG2a、IgG1和IgE浆细胞。虽然滤泡外抗体反应在合并感染后的第一周保持不变，但GC反应低于仅感染Nb的小鼠。Nb感染导致抗stm IgG反应的长期发展在一定程度上中断。这表明先前的Nb感染可能会调节疫苗接种后保护性抗体反应的诱导。为了评估这一点，我们在STm挑战之前用孔蛋白免疫小鼠，孔蛋白以抗体依赖的方式提供保护。在免疫前解决Nb感染的小鼠诱导较少的抗孔蛋白IgG，并且降低了对感染的保护。这些发现表明，在自然感染和免疫应答过程中，合并感染可以从根本上改变保护性免疫的发展。在动物模型中进行的疫苗接种研究侧重于了解年轻的naïve小鼠的反应。实际上，人类接种疫苗或对感染作出反应是在一生中积累接触多种全身性感染和其他疫苗的情况下进行的，其中一些疫苗本身就是减毒活生物体。这在传染病流行的地区更为明显。我们希望研究感染史对抗感染免疫反应和疫苗接种效果的影响。为此，我们使用了两类病原体来模拟临床上重要的侵袭性感染。一种病原体是鼠伤寒沙门氏菌，我们也开发了一种实验性的孔蛋白疫苗，另一种是侵入性蠕虫，巴西尼波圆线虫，它模拟了钩虫感染的各个方面。我们的研究表明，暴露于第二种不相关的病原体会降低自然感染和接种疫苗后产生的免疫力的效率。这些结果很重要，因为它们有助于确定在感染流行地区改善免疫介导的感染控制和成功接种疫苗的潜在战略。
The impact of exposure to multiple pathogens concurrently or consecutively on immune function is unclear. Here, immune responses induced by combinations of the bacterium Salmonella Typhimurium (STm) and the helminth Nippostrongylus brasiliensis (Nb), which causes a murine hookworm infection and an experimental porin protein vaccine against STm, were examined. Mice infected with both STm and Nb induced similar numbers of Th1 and Th2 lymphocytes compared with singly infected mice, as determined by flow cytometry, although lower levels of secreted Th2, but not Th1 cytokines were detected by ELISA after re-stimulation of splenocytes. Furthermore, the density of FoxP3+ T cells in the T zone of co-infected mice was lower compared to mice that only received Nb, but was greater than those that received STm. This reflected the intermediate levels of IL-10 detected from splenocytes. Co-infection compromised clearance of both pathogens, with worms still detectable in mice weeks after they were cleared in the control group. Despite altered control of bacterial and helminth colonization in co-infected mice, robust extrafollicular Th1 and Th2-reflecting immunoglobulin-switching profiles were detected, with IgG2a, IgG1 and IgE plasma cells all detected in parallel. Whilst extrafollicular antibody responses were maintained in the first weeks after co-infection, the GC response was less than that in mice infected with Nb only. Nb infection resulted in some abrogation of the longer-term development of anti-STm IgG responses. This suggested that prior Nb infection may modulate the induction of protective antibody responses to vaccination. To assess this we immunized mice with porins, which confer protection in an antibody-dependent manner, before challenging with STm. Mice that had resolved a Nb infection prior to immunization induced less anti-porin IgG and had compromised protection against infection. These findings demonstrate that co-infection can radically alter the development of protective immunity during natural infection and in response to immunization. Vaccination studies in animal models have focused on understanding responses in young, previously naïve mice. In reality, humans are vaccinated or respond to infection in the context of a life-time of accumulated exposure to multiple, systemic infections and other vaccines, some of which are themselves attenuated live organisms. This is even more pronounced in areas that are endemic for infectious diseases. We wished to examine the impact infectious history can have on the immune response against infection and the efficacy of vaccination. To do this, we used two classes of pathogens that model clinically important invasive infections. One pathogen is the bacterium, Salmonella Typhimurium against which we have also developed an experimental porin vaccine, and the second is an invasive helminth, Nippostrongylus brasiliensis, that models aspects of hookworm infections. Our studies indicate that exposure to a second, unrelated pathogen can reduce the efficiency of immunity generated during natural infection and immunity generated after vaccination. These results are important as they help to identify potential strategies for improving immune-mediated control of infection and the success of vaccination in infection-endemic regions.
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DOI：
10.1084/jem.20101074
发表时间：
2010-10-25
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Grainger JR;Smith KA;Hewitson JP;McSorley HJ;Harcus Y;Filbey KJ;Finney CA;Greenwood EJ;Knox DP;Wilson MS;Belkaid Y;Rudensky AY;Maizels RM
通讯作者：
Maizels RM
影响因子：
4.4
作者：
Cunningham, AF;Fallon, PG;Toellner, KM
通讯作者：
Toellner, KM
影响因子：
3.1
作者：
Cooper, PJ;Chico, M;Nutman, TB
通讯作者：
Nutman, TB
影响因子：
8
作者：
Horsnell, W. G. C.;Vira, A.;Brombacher, F.
通讯作者：
Brombacher, F.
影响因子：
4.4
作者：
Flores-Langarica, Adriana;Marshall, Jennifer L.;Cunningham, Adam F.
通讯作者：
Cunningham, Adam F.