Instituto Gulbenkian de Ciência, Oeiras, Portugal.
Front Immunol. 2019 Jul 30;10:1771. doi: 10.3389/fimmu.2019.01771. eCollection 2019.
Despite significant progress in combating malaria in recent years the burden of severe disease and death due to infections remains a global public health concern. Only a fraction of infected people develops severe clinical syndromes motivating a longstanding search for genetic determinants of malaria severity. Strong genetic effects have been repeatedly ascribed to mutations and allelic variants of proteins expressed in red blood cells but the role of inflammatory response genes in disease pathogenesis has been difficult to discern. We revisited genetic evidence provided by inflammatory response genes that have been repeatedly associated to malaria, namely TNF, NOS2, IFNAR1, HMOX1, TLRs, CD36, and CD40LG. This highlighted specific genetic variants having opposing roles in the development of distinct malaria clinical outcomes and unveiled diverse levels of genetic heterogeneity that shaped the complex association landscape of inflammatory response genes with malaria. However, scrutinizing genetic effects of individual variants corroborates a pathogenesis model where pro-inflammatory genetic variants acting in early infection stages contribute to resolve infection but at later stages confer increased vulnerability to severe organ dysfunction driven by tissue inflammation. Human genetics studies are an invaluable tool to find genes and molecular pathways involved in the inflammatory response to malaria but their precise roles in disease pathogenesis are still unexploited. Genome editing in malaria experimental models and novel genotyping-by-sequencing techniques are promising approaches to delineate the relevance of inflammatory response gene variants in the natural history of infection thereby will offer new rational angles on adjuvant therapeutics for prevention and clinical management of severe malaria.
尽管近年来在防治疟疾方面取得了重大进展，但感染导致的严重疾病和死亡负担仍然是全球公共卫生关注的问题。只有一小部分感染者会发展出严重的临床综合征，这促使人们长期以来一直在寻找疟疾严重程度的遗传决定因素。已有强有力的遗传效应归因于红细胞中表达的蛋白质的突变和等位基因变异，但炎症反应基因在疾病发病机制中的作用一直难以确定。我们重新审视了炎症反应基因的遗传证据，这些基因已被反复与疟疾相关联，即 TNF、NOS2、IFNAR1、HMOX1、TLRs、CD36 和 CD40LG。这突出了特定的遗传变异在不同疟疾临床结局的发展中具有相反的作用，并揭示了遗传异质性的不同程度，这些异质性塑造了炎症反应基因与疟疾之间复杂的关联景观。然而，仔细研究个体变异的遗传效应证实了一种发病机制模型，即早期感染阶段起促炎作用的遗传变异有助于清除感染，但在后期阶段，它们会增加对严重器官功能障碍的易感性，这种功能障碍是由组织炎症引起的。人类遗传学研究是发现参与疟疾炎症反应的基因和分子途径的宝贵工具，但它们在疾病发病机制中的确切作用仍未得到充分利用。疟疾实验模型中的基因组编辑和新型测序技术的基因分型是描绘炎症反应基因变异在感染自然史中的相关性的有前途的方法，从而为预防和临床管理严重疟疾的辅助治疗提供新的合理角度。
