中国寄生虫学与寄生虫病杂志 ›› 2022, Vol. 40 ›› Issue (2): 140-145.doi: 10.12140/j.issn.1000-7423.2022.02.002
收稿日期:
2021-12-27
修回日期:
2022-02-21
出版日期:
2022-03-31
发布日期:
2022-03-31
通讯作者:
王四宝
作者简介:
蒋永茂(1994-),男,博士研究生,从事蚊虫与疟原虫互作机制及防控新策略的研究。E-mail: ymjiang2016@cemps.ac.cn
基金资助:
JIANG Yong-mao(), GAO Han, WANG Si-bao*(
)
Received:
2021-12-27
Revised:
2022-02-21
Online:
2022-03-31
Published:
2022-03-31
Contact:
WANG Si-bao
Supported by:
摘要:
疟疾是一种由疟原虫感染引发的蚊媒传染病。由于缺乏高效的疫苗,目前疟疾防控主要依靠控制蚊虫的杀虫剂以及抗疟药物。然而,杀虫剂的滥用导致蚊虫产生抗药性、以及耐抗疟药物疟原虫株的出现和扩散,使疟疾防控面临严峻挑战。近年来疟疾防控进展缓慢,亟需发展新的防控策略和工具。利用肠道共生菌阻断疟原虫传播的技术是一种新型的源头防控策略,该策略近年来取得显著的进展。本文对该技术的发展及研究现状进行综述,并对应用该技术面临的挑战进行探讨。
中图分类号:
蒋永茂, 高涵, 王四宝. 疟疾防控新策略:利用按蚊肠道共生菌阻断疟原虫传播[J]. 中国寄生虫学与寄生虫病杂志, 2022, 40(2): 140-145.
JIANG Yong-mao, GAO Han, WANG Si-bao. New strategies for malaria control: using mosquito symbiotic bacteria to block malaria transmission[J]. Chinese Journal of Parasitology and Parasitic Diseases, 2022, 40(2): 140-145.
表1
用于共生菌阻断疟原虫传播技术的抗疟效应分子
效应分子 | 靶向疟原虫类型 | 靶向阶段 | 作用机制 | 参考文献 | ||
---|---|---|---|---|---|---|
毒杀疟原虫 | ||||||
Scorpine | 恶性疟原虫、伯氏疟原虫 | 配子体-动合子 | 裂解疟原虫 | [ | ||
Shiva1 | 恶性疟原虫、伯氏疟原虫 | 同上 | 裂解疟原虫 | [ | ||
Shiva3 | 恶性疟原虫、伯氏疟原虫 | 同上 | 裂解疟原虫 | [ | ||
CecB | 恶性疟原虫 | 卵囊 | 裂解疟原虫 | [ | ||
Gambicin | 恶性疟原虫、伯氏疟原虫 | 动合子 | 裂解疟原虫 | [ | ||
靶向结合疟原虫 | ||||||
EPIP | 恶性疟原虫、伯氏疟原虫 | 动合子 | 抑制血纤维蛋白溶酶原与动合子结合,阻止疟原虫侵入按蚊中肠 | [ | ||
Pro: EPIP | 恶性疟原虫、伯氏疟原虫 | 动合子 | 阻断动合子穿越中肠围食膜,并防止血纤维蛋白溶酶原与动合子结合 | [ | ||
Pbs21scFv-Shiva1 | 恶性疟原虫、伯氏疟原虫 | 配子体-卵囊 | 一种单链单克隆抗体(scFv),以动合子表面主要蛋白Pbs21为靶点,并与裂解肽Shiva1结合发挥作用 | [ | ||
PfNPNA-1 | 恶性疟原虫 | 子孢子 | 识别恶性疟原虫表面环孢子虫蛋白的重复区(Asn-Pro-Asn-Ala) | [ | ||
与蚊虫中肠或唾液腺 上皮细胞相互作用 | ||||||
SM1/[SM1]2/[SM1]8 | 恶性疟原虫、伯氏疟原虫 | 动合子、子孢子 | 阻断动合子对中肠上皮细胞的侵袭和子孢子对唾液腺上皮细胞的侵袭 | [ | ||
MP2 | 恶性疟原虫、伯氏疟原虫 | 动合子 | 阻断动合子对中肠上皮细胞的侵袭 | [ | ||
mPLA2 | 恶性疟原虫、伯氏疟原虫 | 动合子 | 通过改变中肠上皮膜的特性,抑制动合子入侵中肠 | [ | ||
Pro | 恶性疟原虫、伯氏疟原虫 | 动合子 | 抑制几丁质酶和阻断动合子穿越中肠围食膜 | [ | ||
Pchtscfv | 恶性疟原虫 | 动合子 | 抑制几丁质酶和阻断动合子穿越中肠围食膜 | [ |
表2
转基因共生菌阻断疟原虫传播研究进展
底盘菌及表达的抗疟效应因子 | 针对的疟原虫种类 | 效果 | 备注 | 参考文献 |
---|---|---|---|---|
大肠埃希菌(E. coli) 表达的Pbs21scFv-Shiva1 | 伯氏疟原虫 | 受感染的蚊虫数量和卵囊密度显著降低 | 这是一种减毒的实验室细菌,在蚊的肠道中存活率很低;重组效应分子附着在细菌表面影响效果 | [ |
大肠埃希菌(E. coli) 表达的SM1和mPLA2 | 伯氏疟原虫 | 显著抑制伯氏疟原虫对按蚊中肠的感染 | 非共生菌;重组效应分子形成包涵体,影响阻断效果;吸血后96 h蚊体内无法检测到 | [ |
绿僵菌(Metarhizium anisopliae) 表达的[SM1]8、PfNPNA-1、 Scorpine | 恶性疟原虫 | 显著抑制疟原虫传播,对子孢子阶段抑制率分别为71%、85%、90% | 杀蚊真菌 | [ |
成团泛菌(Pantoea agglomerans) 表达多种效应分子如[(SM1)2]、mPLA2、pbs21scFv-Shiva1、Scorpine、Pro:EPIP(EPIP)4 | 恶性疟原虫、 伯氏疟原虫 | ① 利用大肠埃希菌HlyA系统分泌多种抗疟原虫效应蛋白 ② 对恶性疟原虫和伯氏疟原虫抑制率高达98% ③ 转基因共生菌对自身和按蚊的生长发 育无影响 | Pantoea具有一定的共生能力,不具有水平或垂直传播能力 | [ |
沙雷氏菌属新菌株AS1(Serratia)表达的(MP2)2-scorpine-(EPIP)4-Shiva1-(SM2)2 | 恶性疟原虫 | ① 首次发现了能在按蚊中代代相传的肠 道共生细菌 ② 成功构建了抗疟效应分子的高效分泌 表达系统,能显著抑制疟原虫感染 ③ 攻克了驱动抗疟原虫基因快速散播到整个蚊群的关键难题 | AS1具有优异的定植和跨代传播能力,可快速散播到整个蚊群 | [ |
Asaia通过血液诱导型启动子条件性表达的scorpine | 伯氏疟原虫 | ① 较好地抑制疟原虫感染 ② 与组成性表达相比,条件性表达表现 出更好的适应度 | 通过诱导型启动子促进肠道菌的适应性 | [ |
[1] |
Gao H,, Cui C,, Wang L, et al. Mosquito microbiota and implications for disease control[J]. Trends Parasitol, 2020, 36(2): 98-111.
doi: 10.1016/j.pt.2019.12.001 |
[2] | World Health Organization. World malaria report 2021[R]. Geneva: WHO, 2021. |
[3] | Feng J,, Zhou SS. From control to elimination: the historical retrospect of malaria control and prevention in China[J]. Chin J Parasitol Parasit Dis, 2019, 37(5): 505-513. (in Chinese) |
(丰俊,, 周水森. 从控制走向消除:我国疟疾防控的历史回顾[J]. 中国寄生虫学与寄生虫病杂志, 2019, 37(5): 505-513.) | |
[4] | Feng J,, Zhang L,, Xia ZG, et al. Malaria elimination in China: an eminent milestone in the anti-malaria campaign and challenges in the post-elimination stage[J]. Chin J Parasitol Parasit Dis, 2021, 39(4): 421-428. (in Chinese) |
(丰俊,, 张丽,, 夏志贵, 等. 中国消除疟疾: 重要里程碑意义及消除后的挑战[J]. 中国寄生虫学与寄生虫病杂志, 2021, 39(4): 421-428.) | |
[5] |
Greenwood BM,, Fidock DA,, Kyle DE, et al. Malaria: progress, perils, and prospects for eradication[J]. J Clin Invest, 2008, 118(4): 1266-1276.
doi: 10.1172/JCI33996 pmid: 18382739 |
[6] |
Sougoufara S,, Ottih EC,, Tripet F. The need for new vector control approaches targeting outdoor biting Anopheline malaria vector communities[J]. Parasit Vectors, 2020, 13(1): 295.
doi: 10.1186/s13071-020-04170-7 pmid: 32522290 |
[7] |
Achan J,, Talisuna AO,, Erhart A, et al. Quinine, an old anti-malarial drug in a modern world: role in the treatment of malaria[J]. Malar J, 2011, 10: 144.
doi: 10.1186/1475-2875-10-144 |
[8] |
Tyagi RK,, Gleeson PJ,, Arnold L, et al. High-level artemisinin-resistance with quinine co-resistance emerges in P. falciparum malaria under in vivo artesunate pressure[J]. BMC Med, 2018, 16(1): 181.
doi: 10.1186/s12916-018-1156-x |
[9] |
Dhorda M,, Amaratunga C,, Dondorp AM. Artemisinin and multidrug-resistant Plasmodium falciparum: a threat for malaria control and elimination[J]. Curr Opin Infect Dis, 2021, 34(5): 432-439.
doi: 10.1097/QCO.0000000000000766 pmid: 34267045 |
[10] | Noreen N,, Ullah A,, Salman SM, et al. New insights into the spread of resistance to artemisinin and its analogues[J]. J Glob Antimicrob Re, 2021, 27: 142-149. |
[11] |
Laurens MB. RTS,S/AS01 vaccine (Mosquirix): an overview[J]. Hum Vaccin Immunother, 2020, 16(3): 480-489.
doi: 10.1080/21645515.2019.1669415 |
[12] |
Wang SB,, Jacobs-Lorena M. Genetic approaches to interfere with malaria transmission by vector mosquitoes[J]. Trends Biotechnol, 2013, 31(3): 185-193.
doi: 10.1016/j.tibtech.2013.01.001 |
[13] |
Whitten MM,, Shiao SH,, Levashina EA. Mosquito midguts and malaria: cell biology, compartmentalization and immunology[J]. Parasite Immunol, 2006, 28(4): 121-130.
doi: 10.1111/j.1365-3024.2006.00804.x pmid: 16542314 |
[14] |
Wang S,, Dos-Santos ALA,, Huang W, et al. Driving mosquito refractoriness to Plasmodium falciparum with engineered symbiotic bacteria[J]. Science, 2017, 357(6358): 1399-1402.
doi: 10.1126/science.aan5478 |
[15] |
Cirimotich CM,, Dong Y,, Clayton AM, et al. Natural microbe-mediated refractoriness to Plasmodium infection in Anopheles gambiae[J]. Science, 2011, 332(6031): 855-858.
doi: 10.1126/science.1201618 pmid: 21566196 |
[16] |
Gao H,, Bai L,, Jiang Y, et al. A natural symbiotic bacterium drives mosquito refractoriness to Plasmodium infection via secretion of an antimalarial lipase[J]. Nat Microbiol, 2021, 6(6): 806-817.
doi: 10.1038/s41564-021-00899-8 |
[17] |
Bando H,, Okado K,, Guelbeogo WM, et al. Intra-specific diversity of Serratia marcescens in Anopheles mosquito midgut defines Plasmodium transmission capacity[J]. Sci Rep, 2013, 3: 1641.
doi: 10.1038/srep01641 |
[18] |
Bai L,, Wang LL,, Vega-Rodriguez J, et al. A gut symbiotic bacterium Serratia marcescens renders mosquito resistance to Plasmodium infection through activation of mosquito immune responses[J]. Front Microbiol, 2019, 10(1580): 1-11.
doi: 10.3389/fmicb.2019.00001 |
[19] | Wang S,, Jacobs-Lorena M. Arthropod vector: controller of disease transmission[M]. Salt Lake City: American Academic Press, 2017: 219-234. |
[20] |
Yoshida S,, Ioka D,, Matsuoka H, et al. Bacteria expressing single-chain immunotoxin inhibit malaria parasite development in mosquitoes[J]. Mol Biochem Parasitol, 2001, 113(1): 89-96.
doi: 10.1016/S0166-6851(00)00387-X |
[21] |
Wang S,, Ghosh AK,, Bongio N, et al. Fighting malaria with engineered symbiotic bacteria from vector mosquitoes[J]. Proc Natl Acad Sci USA, 2012, 109(31): 12734-12743.
doi: 10.1073/pnas.1204158109 |
[22] |
Abraham EG,, Jacobs-Lorena M. Mosquito midgut barriers to malaria parasite development[J]. Insect Biochem Mol Biol, 2004, 34(7): 667-671.
doi: 10.1016/j.ibmb.2004.03.019 |
[23] |
Drexler AL,, Vodovotz Y,, Luckhart S. Plasmodium development in the mosquito: biology bottlenecks and opportunities for mathematical modeling[J]. Trends Parasitol, 2008, 24(8): 333-336.
doi: 10.1016/j.pt.2008.05.005 pmid: 18603475 |
[24] |
Stanczyk NM,, Mescher MC,, De Moraes CM. Effects of malaria infection on mosquito olfaction and behavior: extrapolating data to the field[J]. Curr Opin Insect Sci, 2017, 20: 7-12.
doi: S2214-5745(17)30015-9 pmid: 28602239 |
[25] |
Fang WG,, Vega-Rodriguez J,, Ghosh AK, et al. Development of transgenic fungi that kill human malaria parasites in mosquitoes[J]. Science, 2011, 331(6020): 1074-1077.
doi: 10.1126/science.1199115 |
[26] |
Jaynes JM,, Burton CA,, Barr SB, et al. In vitro cytocidal effect of novel lytic peptides on Plasmodium falciparum and Trypanosoma cruzi[J]. FASEB J, 1988, 2(13): 2878-2883.
pmid: 3049204 |
[27] |
Possani L D,, Zurita M,, Delepierre M, et al. From noxiustoxin to Shiva-3, a peptide toxic to the sporogonic development of Plasmodium berghei[J]. Toxicon, 1998, 36(11): 1683-1692.
pmid: 9792185 |
[28] |
Gwadz RW,, Kaslow D,, Lee JY, et al. Effects of magainins and cecropins on the sporogonic development of malaria parasites in mosquitoes[J]. Infect Immun, 1989, 57(9): 2628-2633.
doi: 10.1128/iai.57.9.2628-2633.1989 pmid: 2759705 |
[29] |
Vizioli J,, Bulet P,, Hoffmann J A, et al. Gambicin: a novel immune responsive antimicrobial peptide from the malaria vector Anopheles gambiae[J]. Proc Natl Acad Sci USA, 2001, 98(22): 12630-12635.
doi: 10.1073/pnas.221466798 |
[30] |
Ghosh AK,, Coppens I,, Gardsvoll H, et al. Plasmodium ookinetes coopt mammalian plasminogen to invade the mosquito midgut[J]. Proc Natl Acad Sci USA, 2011, 108(41): 17153-17161.
doi: 10.1073/pnas.1103657108 |
[31] |
Ghosh AK,, Ribolla PE,, Jacobs-Lorena M. Targeting Plasmodium ligands on mosquito salivary glands and midgut with a phage display peptide library[J]. Proc Natl Acad Sci USA, 2001, 98(23): 13278-13281.
doi: 10.1073/pnas.241491198 |
[32] |
Riehle MA,, Moreira CK,, Lampe D, et al. Using bacteria to express and display anti-Plasmodium molecules in the mosquito midgut[J]. Int J Parasitol, 2007, 37(6): 595-603.
doi: 10.1016/j.ijpara.2006.12.002 |
[33] | Vega-Rodriguez J,, Ghosh AK,, Kanzok SM, et al. Multiple pathways for Plasmodium ookinete invasion of the mosquito midgut[J]. Proc Natl Acad Sci USA, 2014, 111(4): E492-500. |
[34] |
Ito J,, Ghosh A,, Moreira LA, et al. Transgenic Anopheline mosquitoes impaired in transmission of a malaria parasite[J]. Nature, 2002, 417(6887): 452-457.
doi: 10.1038/417452a |
[35] |
Bhatnagar RK,, Arora N,, Sachidanand S, et al. Synthetic propeptide inhibits mosquito midgut chitinase and blocks sporogonic development of malaria parasite[J]. Biochem Biophys Res Commun, 2003, 304(4): 783-787.
doi: 10.1016/S0006-291X(03)00682-X |
[36] |
Li FW,, Patra KP,, Vinetz JM. An anti-chitinase malaria transmission-blocking single-chain antibody as an effector molecule for creating a Plasmodium falciparum-refractory mosquito[J]. J Infect Dis, 2005, 192(5): 878-887.
doi: 10.1086/432552 |
[37] |
Shane JL,, Grogan CL,, Cwalina C, et al. Blood meal-induced inhibition of vector-borne disease by transgenic microbiota[J]. Nat Commun, 2018, 9(1): 4127.
doi: 10.1038/s41467-018-06580-9 |
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