Mucosally Delivered Salmonella Typhi Expressing the Yersinia pestis F1 Antigen Elicits Mucosal and Systemic Immunity Early in Life and Primes the Neonatal Immune System for a Vigorous Anamnestic Response to Parenteral F1 Boost
Mucosally Delivered Salmonella Typhi Expressing the Yersinia pestis F1 Antigen Elicits Mucosal and Systemic Immunity Early in Life and Primes the Neonatal Immune System for a Vigorous Anamnestic Response to Parenteral F1 Boost
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DOI：
10.4049/jimmunol.182.2.1211
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发表时间：
2009-01-15
影响因子：
4.4
通讯作者：
Pasetti, Marcela F.
中科院分区：
文献类型：
--
作者：
Ramirez, Karina;Capozzo, Alejandra V. E.;Pasetti, Marcela F.
新生儿对常规疫苗的反应很差。这部分归因于新生儿树突状细胞的不成熟，其缺乏Ag呈递和T细胞刺激的全部能力。我们设计了一株减毒伤寒沙门氏菌，表达并输出了Y.鼠疫（S.伤寒（F1）），并使用异源初免-加强方案研究其在生命早期的免疫原性。新生小鼠鼻内注射单剂量的S。伤寒杆菌（F1）在免疫后1周引起粘膜Ab和IFN-γ分泌细胞。他们还开发了一个有效的和快速的回忆反应，随后与F1明矾，这超过了小鼠引发和加强与S。伤寒（F1）或F1-明矾。新生儿用S.与用F1-明矾引发相反，伤寒（FI）导致更平衡的IgG 2a/IgG 1谱，增强的亲合力成熟和B记忆细胞的刺激，以及强的Th 1型细胞介导的免疫。S.伤寒杆菌（F1）增强新生儿CD 11 c（+）树突状细胞的活化和成熟，表现为CD 80、CD 86、CD 40和MHC-II细胞表面标志物的表达增加以及促炎细胞因子IL-12、TNF-α、IL-6和MCP-1的产生增加。S.经伤寒杆菌（Typhi，F1）刺激的新生DC在体外提呈抗原和刺激T细胞的能力增强，过继转移给新生小鼠后可诱导F1特异性CD 4（+）和CD 8（+）T细胞应答。用S.表达外源抗原的伤寒杆菌可有效地启动新生儿免疫系统，对胃肠外抗原加强免疫产生有效、快速和更广泛的反应。这种战略可以在生命早期预防传染病，包括那些被认为是生物战威胁的传染病。免疫学杂志，2009，182：1211-1222.
Neonates respond poorly to conventional vaccines. This has been attributed, in part, to the immaturity of neonatal dendritic cells that lack full capacity for Ag presentation and T cell stimulation. We engineered an attenuated Salmonella Typhi strain to express and export the F1 Ag of Y. pestis (S. Typhi(F1)) and investigated its immunogenicity early in life using a heterologous prime-boost regimen. Newborn mice primed intranasally with a single dose of S. Typhi(F1) elicited mucosal Ab- and IFN-gamma-secreting cells 1 wk after immunization. They also developed a potent and fast anamnestic response to a subsequent parenteral boost with F1-alum, which surpassed those of mice primed and boosted with S. Typhi(F1) or F1-alum. Neonatal priming with S. Typhi(FI), as opposed to priming with F1-alum, resulted in a more balanced IgG2a/IgG1 profile, enhanced avidity maturation and stimulation of B memory cells, and strong Th1-type cell-mediated immunity. S. Typhi(Fl) enhanced the activation and maturation of neonatal CD11c(+) dendritic cells, shown by increased expression of CD80, CD86, CD40, and MHC-II cell surface markers and production of proinflammatory cytokines IL-12, TNF-alpha, IL-6, and MCP-1. S. Typhi(F1)-stimulated neonatal DC had improved capacity for Ag presentation and T cell stimulation in vitro and induced F1specific CD4(+) and CD8(+) T cell responses when adoptively transferred to newborn mice. Mucosal immunization with S. Typhi expressing a foreign Ag effectively primes the neonatal immune system for potent, fast, and broader responses to a parenteral Ag boost. Such a strategy can prevent infectious diseases, including those considered biowarfare threats, early in life. The Journal of Immunology, 2009, 182: 1211-1222.