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

描述(申请人提供)：由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(UTIs)、新生儿脑膜炎(NBM)、腹部败血症和败血症，导致严重的发病率和死亡率，估计每年给美国医疗保健系统造成数十亿美元的损失。Exc菌株还感染鸡，由于控制、死亡和处理身体的成本，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，ExPEC感染的治疗经常因为多重耐药而失败。包括老年人在内的免疫受损人群数量的增加，加上ExPEC菌株之间的多重耐药性，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。开发有效的ExPEC疫苗的困难与它们的系统发育多样性有关。尽管具有挑战性，但仍需要一种多价疫苗。在过去的几年里，我们一直在阐明ExPEC和沙门氏菌的毒力因素。我们构建了用于动物和人的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，表明使用减毒沙门氏菌预防细菌感染是成功的；然而，还需要更多的研究来提高这种治疗在人类中的安全性和有效性。我们建议使用我们成熟的技术来开发疫苗，以预防和减少人类感染ExPEC。我们的目标包括：(I)完成鼠伤寒沙门氏菌的构建，以表达ExPEC质粒携带的多种抗原，以保护小鼠免受多种ExPEC感染；(Ii)使用毒素-抗毒素系统构建和评估RASV中受调控的延迟裂解系统，作为与有效疫苗一致的新生物遏制系统；以及(Iii)利用受控延迟裂解系统对我们的RASV进行评估，以防止小鼠尿路、脑膜炎和败血症感染。 公共卫生相关性：我们的项目提出了一种独特的战略，以设计一种安全、易于使用的基于沙门氏菌的治疗方法，该方法将有效地根除ExPEC感染，这些感染导致大量生命损失，并每年给美国医疗保健系统造成数十亿美元的损失。此外，如果成功，所提出的延迟减毒裂解系统可以用于任何活细菌疫苗，以提高它们输送抗原的安全性和有效性。

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.