The Abundant Larval Transcript-1 and -2 Genes of Brugia malayi Encode Stage-Specific Candidate Vaccine Antigens for Filariasis

Lymphatic filariasis is a major tropical disease caused by the mosquito-borne nematodes Brugia and Wuchereria. About 120 million people are infected and at risk of lymphatic pathology such as acute lymphangitis and elephantiasis. Vaccines against filariasis must generate immunity to the infective mosquito-derived third-stage larva (L3) without accentuating immunopathogenic responses to lymphatic-dwelling adult parasites. We have identified two highly expressed genes, designated abundant larval transcript-1 and -2 (alt-1 and alt-2), from each of which mRNAs account for >1% of L3 cDNAs. ALT-1 and ALT-2 share 79% amino acid identity across 125 residues, including a putative signal sequence and a prominent acidic tract. Expression of alt-1 and alt-2 is initiated midway through development in the mosquito, peaking in the infective larva and declining sharply following entry into the host. Humans exposed to Brugia malayi show a high frequency of immunoglobulin G1 (IgG1) and IgG3 antibodies to ALT-1 and -2, distinguishing them from adult-stage antigens, which are targeted by the IgG4 isotype. Immunization of susceptible rodents (jirds) with ALT-1 elicited a 76% reduction in parasite survival, the highest reported for a single antigen from any filarial parasite. ALT-1 and the closely related ALT-2 are therefore strong candidates for a future vaccine against human filariasis.

淋巴丝虫病（Lymphatic filariasis）是一类由蚊传布鲁氏线虫属（Brugia）与吴策线虫属（Wuchereria）线虫引发的重大热带疾病。目前全球约有1.2亿人群受到感染，且面临急性淋巴管炎、象皮肿等淋巴系统病理损伤风险。抗丝虫病疫苗需诱导针对蚊源感染性三期幼虫（third-stage larva, L3）的免疫力，同时不应加重机体对淋巴寄生成虫的免疫病理反应。本研究已鉴定出两个高表达基因，将其命名为丰富幼虫转录本1和2（abundant larval transcript-1、-2，alt-1和alt-2），二者的mRNA在L3的cDNA库中占比均超过1%。ALT-1与ALT-2在125个氨基酸残基区域的同源性达79%，包含一段推定信号序列与一处显著的酸性结构域。alt-1与alt-2的表达在蚊体内发育中期启动，在感染性幼虫阶段达到表达峰值，进入宿主后迅速下调。曾暴露于马来布鲁氏线虫（Brugia malayi）的人群中，针对ALT-1与ALT-2的免疫球蛋白G1（immunoglobulin G1, IgG1）和IgG3抗体检出率较高，这一特征可与IgG4亚型靶向的成虫期抗原相区分。用ALT-1免疫易感啮齿动物（沙鼠，jirds）后，可使寄生虫存活率降低76%，这是目前已报道的单种丝虫抗原所能实现的最高保护效果。因此，ALT-1及其密切相关的同源蛋白ALT-2均为未来人体淋巴丝虫病疫苗的优质候选抗原。