A novel Salmonella vaccine to protect against extra intestinal pathogenic E. coli

描述（由申请人提供）：肠道外致病性大肠杆菌（ExPEC）菌株引起的人类感染，包括尿路感染（uti）、新生儿脑膜炎（NBM）、腹部败血症和败血症，导致显著的发病率和死亡率，估计每年花费美国医疗保健系统数十亿美元。由于控制、死亡和处理尸体的成本，exc菌株也会感染鸡，给家禽业造成经济损失，家禽业是美国和全球的一个重要经济部门。鸡肉产品被怀疑是人类感染大肠杆菌的来源，大肠杆菌菌株现在被认为是一种新的食源性病原体。此外，由于耐多药，exc感染的治疗经常失败。免疫功能低下人群（包括老年人）数量的增加，加上耐多药耐药的肠外结核菌菌株，将对肠外结核菌感染的治疗构成挑战，并可能在不久的将来增加治疗费用。开发一种有效的疫苗的困难与它们的系统发育多样性有关。多价疫苗虽然具有挑战性，但仍是必要的。在过去的几年里，我们一直在阐明ExPECs和沙门氏菌的毒力因子。我们构建了动物和人用重组减毒沙门氏菌疫苗载体系统，能够诱导对禽致病性大肠杆菌（APEC）和其他肠道病原体的交叉保护免疫。最近对该系统的研究结果非常令人鼓舞，并表明使用减毒沙门氏菌预防细菌感染的成功；然而，需要更多的研究来提高人类治疗的安全性和有效性。我们建议使用我们成熟的技术来开发疫苗，以预防和减少人类的exp感染。我们的目标包括：(i)完成鼠伤寒沙门氏菌的构建，以表达携带在expc质粒上的多种抗原，以保护小鼠免受多种expc感染；（ii）利用毒素-抗毒素系统作为一种新的生物控制系统，在RASV中构建和评估一种受调节的延迟裂解，该系统与有效的疫苗接种相一致；（iii）评估我们的RASV与调节延迟裂解系统对小鼠尿道、脑膜炎和败血症感染的保护作用。

DESCRIPTION (provided by applicant): Human infections due to extraintestinal pathogenic E. coli (ExPEC) strains, including urinary tract infections (UTIs), newborn meningitis (NBM), abdominal sepsis, and septicemia, result in significant morbidity, mortality and are estimated to cost the US health care system billions of dollars annually. ExPEC strains also infect chickens causing economic losses for the poultry industry, a significant economic sector in the US and globally, due to costs of containment, mortality, and disposal of carcasses. Chicken products are suspected to be a source of ExPEC infections in humans, and the ExPEC strains are now considered a new food-born pathogen. In addition, the treatment of ExPEC infections often fails because of multidrug- resistance. The increase in numbers of immunocompromised populations, including the elderly, coupled with multidrug-resistance among ExPEC strains, will challenge the treatment of ExPEC infections and likely increase cost of treatment in the near future. The difficulty of developing an effective vaccine against ExPEC is related to their phylogenic diversity. A polyvalent vaccine although challenging, is needed. We have spent the last few years elucidating the virulence factors of ExPECs and Salmonella. We have constructed recombinant attenuated Salmonella vaccine vector systems for animals and humans that are capable of inducing cross-protective immunity to avian pathogenic E. coli (APEC) and other enteric pathogens. The results of recent studies of this system are very encouraging and suggest the success of using attenuated Salmonella to prevent bacterial infections; however more studies are needed to increase both the safety and efficacy of the treatment in humans. We propose to use our proven technologies to develop vaccines to prevent and reduce ExPEC infections in humans. Our objectives include: (i) complete construction of S. Typhimurium to express multiple antigens carried on an ExPEC plasmid to protect against multiple ExPEC infections in mice; (ii) construction and evaluation of a regulated delayed lysis in RASV using a toxin-antitoxin system as a new biological containment system consistent with an efficacious vaccination; and (iii) evaluation of our RASV with a regulated delayed lysis system to protect against urethral, meningitis, and sepsis infections in mice. PUBLIC HEALTH RELEVANCE: Our project proposes a unique strategy to engineer a safe, easy to use Salmonella-based treatment that will be effective in eradicating ExPEC infections that are responsible for significant loss of life and cost billions of dollars to the US health care system annually. Moreover, if successful, the delayed-attenuated lysis system proposed can be used in any live bacterial vaccine to increase their safety and efficacy in delivering antigens.