A conserved epitope in VAR2CSA is targeted by a cross-reactive antibody originating from Plasmodium vivax Duffy binding protein.
A conserved epitope in VAR2CSA is targeted by a cross-reactive antibody originating from Plasmodium vivax Duffy binding protein.
复制标题
DOI：
10.3389/fcimb.2023.1202276
复制
发表时间：
2023
影响因子：
5.7
通讯作者：
中科院分区：
文献类型：
--
作者：
在妊娠期恶性疟原虫感染期间，VAR2CSA在感染的红细胞（IE）的表面上表达，并介导它们在胎盘中的隔离。因此，VAR2CSA抗体主要限于怀孕期间感染的妇女。然而，我们发现VAR2CSA抗体也可以由间日疟原虫Duffy结合蛋白（PvDBP）引发。我们提出，在非妊娠个体中感染间日疟原虫可以产生与VAR2CSA交叉反应的抗体。为了更好地理解这些抗体的特异性，我们利用了针对PvDBP产生的与VAR2CSA交叉反应的小鼠单克隆抗体（3D10），并鉴定了该抗体靶向的表位。我们从FCR3和NF 54等位基因中筛选了跨越VAR2CSA胞外域的两个肽阵列。基于3D10识别的顶级表位，我们设计了一种34个氨基酸的合成肽，我们称之为CRP 1，它映射到DBL3X中的高度保守区域。特异性赖氨酸残基对于3D10识别是关键的，并且这些相同的氨基酸在DBL3X中的先前定义的硫酸软骨素A（CSA）结合位点内。我们通过等温滴定量热法表明，CRP 1肽可以直接结合到CSA，并且在大鼠中产生的CRP 1抗体在体外显著阻断IE与CSA的结合。在我们的哥伦比亚妊娠和非妊娠个体队列中，至少45%对CRP 1具有血清反应性。在两个队列中，对CRP 1和PvDBP区域II亚结构域1（SD 1）中的3D10天然表位的抗体反应性强烈相关。这些发现表明，由PvDBP产生的抗体可以通过CRP 1中的表位与VAR2CSA交叉反应，并且CRP 1可以是靶向VAR2CSA中的不同CSA结合位点的潜在疫苗候选物。
During Plasmodium falciparum infection in pregnancy, VAR2CSA is expressed on the surface of infected erythrocytes (IEs) and mediates their sequestration in the placenta. As a result, antibodies to VAR2CSA are largely restricted to women who were infected during pregnancy. However, we discovered that VAR2CSA antibodies can also be elicited by P. vivax Duffy binding protein (PvDBP). We proposed that infection with P. vivax in non-pregnant individuals can generate antibodies that cross-react with VAR2CSA. To better understand the specificity of these antibodies, we took advantage of a mouse monoclonal antibody (3D10) raised against PvDBP that cross-reacts with VAR2CSA and identified the epitopes targeted by this antibody. We screened two peptide arrays that span the ectodomain of VAR2CSA from the FCR3 and NF54 alleles. Based on the top epitope recognized by 3D10, we designed a 34-amino acid synthetic peptide, which we call CRP1, that maps to a highly conserved region in DBL3X. Specific lysine residues are critical for 3D10 recognition, and these same amino acids are within a previously defined chondroitin sulfate A (CSA) binding site in DBL3X. We showed by isothermal titration calorimetry that the CRP1 peptide can bind directly to CSA, and antibodies to CRP1 raised in rats significantly blocked the binding of IEs to CSA in vitro. In our Colombian cohorts of pregnant and non-pregnant individuals, at least 45% were seroreactive to CRP1. Antibody reactivities to CRP1 and the 3D10 natural epitope in PvDBP region II, subdomain 1 (SD1), were strongly correlated in both cohorts. These findings suggest that antibodies arising from PvDBP may cross-react with VAR2CSA through the epitope in CRP1 and that CRP1 could be a potential vaccine candidate to target a distinct CSA binding site in VAR2CSA.
影响因子：
7.3
作者：
McLean ARD;Opi DH;Stanisic DI;Cutts JC;Feng G;Ura A;Mueller I;Rogerson SJ;Beeson JG;Fowkes FJI
通讯作者：
Fowkes FJI
影响因子：
7.8
作者：
Mitran CJ;Higa LM;Good MF;Yanow SK
通讯作者：
Yanow SK
影响因子：
6.7
作者：
Andersen, Pernille;Nielsen, Morten A.;Resende, Mafalda;Rask, Thomas S.;Dahlback, Madeleine;Theander, Thor;Lund, Ole;Salanti, Ali
通讯作者：
Salanti, Ali