Antibodies targeting Candida albicans Als3 and Hyr1 antigens protect neonatal mice from candidiasis.
Antibodies targeting Candida albicans Als3 and Hyr1 antigens protect neonatal mice from candidiasis.
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DOI：
10.3389/fimmu.2022.925821
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发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
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新生儿重症监护病房中的早产儿易患真菌败血症。在这一患者群体中，尽管接受了抗真菌治疗，但白色念珠菌仍然是导致高发病率和死亡率的主要真菌病原体。因此，需要针对新生儿念珠菌病采取新的预防/治疗策略。此前，我们已经报道过，用重组形式的白念珠菌N端的细胞壁蛋白Als3(rAls3p-N)和Hyr1(rHyr1p-N)接种疫苗可以保护成年小鼠免受播散性念珠菌病的侵袭。此外，在1b/2a期，新城疫病毒3A(一种用明矾配制的rAls3p-N)保护妇女免受复发性外阴阴道念珠菌病的侵袭，抗Als3p IgG2同型抗体是疗效的生物标记。在这里，我们进行了一项概念验证研究，以评估抗Als3p或抗Hyr1p抗体对预防新生儿播散性念珠菌病是否重要。当Als3和Hyr1抗原与完全弗氏佐剂(CFA)/不完全弗氏佐剂(IFA)佐剂时，可诱导出较强的抗体反应，其IgG2滴度比用明矾配制的任一种抗原高10倍。通过胎盘转移这些抗体显著减少了小鼠肾脏中的真菌负担，而将已接种疫苗的母亲的血清过继转移到幼鼠体内显示出类似的保护水平。中性粒细胞被发现对这种疗效很重要。最后，抗Hyr1抗血清增强了氟康唑对白色念珠菌感染的保护作用。我们目前的研究首次强调了抗Als3和抗Hyr1抗体在预防新生儿念珠菌病中的重要性。考虑到低出生体重儿中的念珠菌感染是一种致命的感染，使用这些抗原的主动和被动免疫策略可能具有深远的临床意义。
Pre-term infants in neonatal intensive care units are vulnerable to fungal sepsis. In this patient population, Candida albicans remains the predominant fungal pathogen causing high morbidity and mortality, despite antifungal therapy. Thus, new preventative/therapeutic strategies against neonatal candidiasis are needed. Previously, we have reported that vaccination with recombinant forms of the C. albicans N-termini of the cell wall proteins Als3 (rAls3p-N) and Hyr1 (rHyr1p-N) protected adult mice from disseminated candidiasis. Further, in a Phase 1b/2a NDV-3A (an rAls3p-N formulated with alum) protected women from recurrent vulvovaginal candidiasis, with anti-Als3p IgG2 isotype being a biomarker for efficacy. Here, we performed a proof of concept study to evaluate if anti-Als3p or anti-Hyr1p antibodies are important for prevention of disseminated candidiasis in neonates. Als3 and Hyr1 antigens when adjuvanted with complete Freund’s adjuvant (CFA)/incomplete Freund’s adjuvant (IFA) induced a robust antibody response with a ten-fold higher titer of IgG2, than attained by either antigen formulated with alum. Transplacental transfer of these antibodies significantly reduced fungal burden in the kidneys of mice pups, and adoptive transfer of vaccinated mothers’ sera into pups displayed similar levels of protection. Neutrophils were found important for this efficacy. Finally, anti-Hyr1 antisera potentiated the activity of fluconazole in protecting from C. albicans infection. Our current studies are the first in the field to emphasize the importance of anti-Als3 and anti-Hyr1 antibodies in preventing neonatal candidiasis. Considering that Candida infections in low birthweight infants is a lethal infection, active and passive vaccination strategies using these antigens could have profound clinical relevance.