Highly Improved Bacterial Larvicides for Vector Control

描述（由申请人提供）：拟议研究的目的是开发一系列高度改进的重组细菌杀幼虫剂，用于控制主要人类疾病（包括疟疾、丝虫病、登革热和病毒性脑炎）的蚊子媒介。这些细菌将比目前用于病媒控制的商业细菌杀幼虫剂的活性成分苏云金芽孢杆菌以色列亚种（Bti）和球形芽孢杆菌（Bs）更具成本效益。此外，这些重组体将不太容易诱导蚊子的抗性，这种抗性已经发展到B。sphaericus在巴西、中国和印度的库蚊种群中。初步研究表明，在Bti中产生高水平的Bs2362二元蛋白导致重组菌株比其所来源的亲本菌株有效十倍。这表明高度改进的细菌可以被工程化用于载体控制。尽管有这些令人鼓舞的结果，重组细菌杀幼虫剂的开发仍受到几个主要障碍的困扰，包括投资回报率低，市场规模有限，以及对重组生物体施加的额外监管负担，导致产品开发时间长。目前的项目是加州大学滨江分校和伊利诺伊州利伯蒂维尔的Valent BioSciences之间的合作，将联合收割机双方的专业知识，加速开发用于病媒控制的高度改进的细菌杀幼虫剂。通过集中的工程研究，将开发出一系列基于Cry、Cyt和Bs杀蚊蛋白的更有效的Bti和Bs菌株，并将其商业化，这些菌株也符合美国的监管要求。将开发使用Bs作为宿主细胞的改良菌株，主要用于控制在半污染和高度污染的沃茨中繁殖的库蚊物种（丝虫病和西尼罗河病毒的媒介），而Bti将用作控制伊蚊物种（登革热媒介）和某些疟疾媒介的按蚊的宿主细胞。这项合作的共同目标是在五年内将基于这些重组细菌的新产品推向市场，如果可能的话，更快。

DESCRIPTION (provided by applicant): The objective of the proposed research is to develop a series of highly improved recombinant bacterial larvicides for controlling the mosquito vectors of major human diseases including malaria, filariasis, dengue, and the viral encephalitides. These bacteria will be significantly more cost-effective than Bacillus thuringiensis subsp, israelensis (Bti) and Bacillus sphaericus (Bs), the active ingredients of current commercial bacterial larvicides used in vector control. In addition, these recombinants will be much less prone to induce mosquito resistance, which has already developed to B. sphaericus in Culex populations in Brazil, China, and India. Preliminary studies show that the production of high levels of the Bs2362 binary protein in Bti results in a recombinant strain tenfold more effective than the parental strains from which it was derived. This demonstrates that highly improved bacteria can be engineered for use in vector control. Despite these encouraging results, the development of recombinant bacterial larvicides is plagued by several major hurdles including low returns on investment, limited market size, and additional regulatory burdens imposed on recombinant organisms that result in long product development times. The present project is a collaboration between the University of California, Riverside and Valent BioSciences of Libertyville, Illinois, that will combine the expertise of both parties to accelerate the development highly improved bacterial larvicides for vector control. Through focused engineering research, a series of much more effective strains of Bti and Bs based on Cry, Cyt, and Bs mosquitocidal proteins will be developed and commercialized that also meet U.S. regulatory requirements. Improved strains using Bs as a host cell will be developed primarily for control of Culex species (vectors of filariasis and West Nile Virus) breeding in semi-polluted and highly polluted waters, whereas Bti will be used as the host cell for control of Aedes species (vectors of dengue) and certain anopheline vectors of malaria. This collaboration has the common goal of having new products based on these recombinant bacteria on the market within five years, sooner if possible.