Cryptosporidium Priming Is More Effective than Vaccine for Protection against Cryptosporidiosis in a Murine Protein Malnutrition Model.
Cryptosporidium Priming Is More Effective than Vaccine for Protection against Cryptosporidiosis in a Murine Protein Malnutrition Model.
复制标题
DOI：
10.1371/journal.pntd.0004820
复制
发表时间：
2016-07
影响因子：
3.8
通讯作者：
Guerrant RL
中科院分区：
文献类型：
--
作者：
Bartelt LA;Bolick DT;Kolling GL;Roche JK;Zaenker EI;Lara AM;Noronha FJ;Cowardin CA;Moore JH;Turner JR;Warren CA;Buck GA;Guerrant RL
隐孢子虫是严重腹泻的主要原因，特别是在营养不良的儿童中。使用小鼠C.微小孢子虫卵囊挑战，概括了严重隐孢子虫病的临床特征，营养不良期间，我们询问蛋白质营养不良（PM）的影响，对初级和次级反应，以C。parvum挑战，并测试了粘膜启动策略克服PM诱导的易感性的差异能力。我们确定，虽然PM从根本上改变了对隐孢子虫的系统和粘膜初级免疫应答，但用C。细小卵囊（106个卵囊）提供了强大的保护性免疫力，尽管持续的PM。C.细小病毒引发恢复粘膜Th 1型效应细胞（CD 3 + CD 8 + CD 103 + T细胞）和细胞因子（IFNγ和IL 12 p40），否则这些细胞因子会随着PM的进行而减少。隐孢子虫抗原的疫苗接种策略。伤寒杆菌载体908 htr不增强对C.在PM期间，尽管疫苗接种强烈增强了受挑战的完全营养宿主的免疫力，但仍存在免疫缺陷。远距离非特异性暴露于衰减的S。Typhi载体单独或TLR 9激动剂CpG ODN-1668可部分减弱C.在PM期间，小孢子虫的严重性，但既不作为有效的可行C。小启动我们的结论是，尽管PM干扰了基础和疫苗增强的对C。通过宿主防御的粘膜激活剂，特别是C.尽管持续的蛋白质营养不良，但细小病毒引发可以引起令人印象深刻的强大的Th 1型保护性免疫。这些发现增加了对营养不良儿童隐孢子虫免疫和未来疫苗策略的潜在相关性的了解。隐孢子虫引起的营养不良儿童的发病率越来越多地被认识到。营养不良究竟如何干扰宿主对肠道病原体的粘膜免疫和粘膜疫苗应答仍不清楚。在隐孢子虫病的实验模型中剖析这些相互作用可以揭示针对病原体的新治疗方法的新见解，目前还没有有效的治疗方法和疫苗。我们证明，虽然营养不良减少基线（原发性）Th 1型粘膜免疫，但这些缺陷可以通过非特异性粘膜策略部分克服（S。伤寒和CpG），并在亚临床（低剂量）暴露于活的C.小的这些结果增加了对预防策略的深入了解，以帮助减轻低资源环境中儿童的隐孢子虫特异性腹泻，并消除长期感染后后遗症。
Cryptosporidium is a major cause of severe diarrhea, especially in malnourished children. Using a murine model of C. parvum oocyst challenge that recapitulates clinical features of severe cryptosporidiosis during malnutrition, we interrogated the effect of protein malnutrition (PM) on primary and secondary responses to C. parvum challenge, and tested the differential ability of mucosal priming strategies to overcome the PM-induced susceptibility. We determined that while PM fundamentally alters systemic and mucosal primary immune responses to Cryptosporidium, priming with C. parvum (106 oocysts) provides robust protective immunity against re-challenge despite ongoing PM. C. parvum priming restores mucosal Th1-type effectors (CD3+CD8+CD103+ T-cells) and cytokines (IFNγ, and IL12p40) that otherwise decrease with ongoing PM. Vaccination strategies with Cryptosporidium antigens expressed in the S. Typhi vector 908htr, however, do not enhance Th1-type responses to C. parvum challenge during PM, even though vaccination strongly boosts immunity in challenged fully nourished hosts. Remote non-specific exposures to the attenuated S. Typhi vector alone or the TLR9 agonist CpG ODN-1668 can partially attenuate C. parvum severity during PM, but neither as effectively as viable C. parvum priming. We conclude that although PM interferes with basal and vaccine-boosted immune responses to C. parvum, sustained reductions in disease severity are possible through mucosal activators of host defenses, and specifically C. parvum priming can elicit impressively robust Th1-type protective immunity despite ongoing protein malnutrition. These findings add insight into potential correlates of Cryptosporidium immunity and future vaccine strategies in malnourished children. Cryptosporidium attributable morbidities in malnourished children are increasingly recognized. Exactly how malnutrition interferes with host mucosal immunity to diarrheal pathogens and mucosal vaccine responses remains unclear. Dissecting these interactions in an experimental model of cryptosporidiosis can uncover new insights into novel therapeutic approaches against a pathogen for which effective therapies and vaccines are currently unavailable. We demonstrate that although malnutrition diminishes baseline (primary) Th1-type mucosal immunity these deficits can be partially overcome via non-specific mucosal strategies (S. Typhi and CpG) and completely restored after a sub-clinical (low-dose) exposure to viable C. parvum. These results add insight into preventive strategies to help alleviate Cryptosporidium-specific diarrhea in children in low-resource settings and abrogate prolonged post-infection sequelae.