Sathler-Avelar Renato, Vitelli-Avelar Danielle Marquete, Mattoso-Barbosa Armanda Moreira, Perdigão-de-Oliveira Marcelo, Costa Ronaldo Peres, Elói-Santos Silvana Maria, Gomes Matheus de Souza, Amaral Laurence Rodrigues do, Teixeira-Carvalho Andréa, Martins-Filho Olindo Assis, Dick Edward J, Hubbard Gene B, VandeBerg Jane F, VandeBerg John L
Grupo Integrado de Pesquisas em Biomarcadores, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz-FIOCRUZ, Belo Horizonte, Minas Gerais, Brazil.
Centro Universitário Newton Paiva, Belo Horizonte, Minas Gerais, Brazil.
PLoS Negl Trop Dis. 2016 Jan 25;10(1):e0004302. doi: 10.1371/journal.pntd.0004302. eCollection 2016 Jan.
Cynomolgus macaques (Macaca fascicularis) represent a feasible model for research on Chagas disease since natural T. cruzi infection in these primates leads to clinical outcomes similar to those observed in humans. However, it is still unknown whether these clinical similarities are accompanied by equivalent immunological characteristics in the two species. We have performed a detailed immunophenotypic analysis of circulating leukocytes together with systems biology approaches from 15 cynomolgus macaques naturally infected with T. cruzi (CH) presenting the chronic phase of Chagas disease to identify biomarkers that might be useful for clinical investigations.
Our data established that CH displayed increased expression of CD32+ and CD56+ in monocytes and enhanced frequency of NK Granzyme A+ cells as compared to non-infected controls (NI). Moreover, higher expression of CD54 and HLA-DR by T-cells, especially within the CD8+ subset, was the hallmark of CH. A high level of expression of Granzyme A and Perforin underscored the enhanced cytotoxicity-linked pattern of CD8+ T-lymphocytes from CH. Increased frequency of B-cells with up-regulated expression of Fc-γRII was also observed in CH. Complex and imbricate biomarker networks demonstrated that CH showed a shift towards cross-talk among cells of the adaptive immune system. Systems biology analysis further established monocytes and NK-cell phenotypes and the T-cell activation status, along with the Granzyme A expression by CD8+ T-cells, as the most reliable biomarkers of potential use for clinical applications.
Altogether, these findings demonstrated that the similarities in phenotypic features of circulating leukocytes observed in cynomolgus macaques and humans infected with T. cruzi further supports the use of these monkeys in preclinical toxicology and pharmacology studies applied to development and testing of new drugs for Chagas disease.
食蟹猴（猕猴）是恰加斯病研究的可行模型，因为这些灵长类动物自然感染克氏锥虫后会出现与人类相似的临床症状。然而，尚不清楚这两个物种在临床症状相似的同时，免疫特征是否也相同。我们对15只自然感染克氏锥虫（CH）且处于恰加斯病慢性期的食蟹猴的循环白细胞进行了详细的免疫表型分析，并采用系统生物学方法，以确定可能对临床研究有用的生物标志物。
我们的数据表明，与未感染对照组（NI）相比，CH组单核细胞中CD32+和CD56+的表达增加，NK颗粒酶A+细胞的频率增加。此外，T细胞，尤其是CD8+亚群中CD54和HLA-DR的高表达是CH组的标志。颗粒酶A和穿孔素的高表达突出了CH组CD8+ T淋巴细胞增强的细胞毒性相关模式。CH组还观察到Fc-γRII表达上调的B细胞频率增加。复杂且相互交织的生物标志物网络表明，CH组显示出向适应性免疫系统细胞间相互作用的转变。系统生物学分析进一步确定单核细胞和NK细胞表型以及T细胞活化状态，以及CD8+ T细胞的颗粒酶A表达，是临床应用中最可靠的潜在生物标志物。
总之，这些发现表明，在感染克氏锥虫的食蟹猴和人类中观察到的循环白细胞表型特征的相似性，进一步支持了在用于恰加斯病新药开发和测试的临床前毒理学和药理学研究中使用这些猴子。
