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

描述（由申请方提供）：肠外致病性大肠杆菌引起的人类感染。大肠杆菌（ExPEC）菌株，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、死亡率，并且估计每年花费美国卫生保健系统数十亿美元。ExPEC菌株还感染鸡，由于控制、死亡和处理尸体的成本，导致家禽业（美国和全球的重要经济部门）的经济损失。鸡肉产品被怀疑是人类ExPEC感染的来源，ExPEC菌株现在被认为是一种新的食源性病原体。此外，由于多药耐药性，ExPEC感染的治疗经常失败。包括老年人在内的免疫功能低下人群数量的增加，加上ExPEC菌株的多药耐药性，将对ExPEC感染的治疗提出挑战，并可能在不久的将来增加治疗成本。开发针对ExPEC的有效疫苗的困难与它们的遗传多样性有关。多价疫苗虽然具有挑战性，但仍是必要的。过去几年，我们一直致力于阐明ExPEC和沙门氏菌的毒力因子。我们构建了重组减毒沙门氏菌疫苗载体系统，用于动物和人类，能够诱导对禽致病性大肠杆菌的交叉保护性免疫。大肠杆菌（APEC）和其他肠道病原体。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ExPEC感染。我们的目标包括：（1）完成S。鼠伤寒沙门氏菌表达ExPEC质粒上携带的多种抗原，以防止小鼠中的多种ExPEC感染;（ii）使用毒素-抗毒素系统作为与有效疫苗接种一致的新生物遏制系统构建和评估RASV中的调节延迟裂解;以及（iii）评估我们的RASV与调节延迟裂解系统，以防止小鼠中的尿道、脑膜炎和脓毒症感染。 公共卫生相关性：我们的项目提出了一种独特的策略，以设计一种安全，易于使用的沙门氏菌治疗方法，该方法将有效根除导致重大生命损失的ExPEC感染，并每年为美国医疗保健系统花费数十亿美元。此外，如果成功的话，所提出的延迟减毒裂解系统可以用于任何活细菌疫苗中，以增加它们在递送抗原中的安全性和功效。

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.