Innate Immune Responses in Populations with Differing Susceptibility to Malaria

描述(申请人提供：在感染的最初阶段，循环中的恶性疟原虫引发一连串的事件，触发抗原提呈细胞和自然杀伤(NK)细胞分泌促炎和抗炎细胞因子。这些先天免疫反应的特征似乎是决定寄生虫血症的控制、感染的严重性以及随后的适应性反应的有效性的关键步骤。在布基纳法索，两个主要民族富拉尼族和莫西族控制寄生虫血症的能力不同，这似乎是由于早期干扰素相关反应的差异所致。通过全基因组转录的方法，我们的目标是了解关键的基因表达模式，这些模式解释了富拉尼早期有效的干扰素反应。我们将通过确定关键细胞亚群，特别是NK细胞和T细胞在调节这些强大的干扰素反应中的作用来扩展这些研究。最后，我们将确定通过TLRs加强对血期寄生虫的检测在调节富拉尼细胞中不同的下游干扰素反应中的作用。随着越来越多的证据表明，对疟疾的“硬连线”抵抗力似乎与强大的干扰素反应有关，布基纳法索的族裔群体提供了一个独特的机会来描绘这些保护性早期干扰素反应背后的机制。了解导致对疟疾的这些有效早期反应的关键基因/途径和细胞种群，对于支持正在进行的疫苗努力和开发旨在驾驭这些反应的新型免疫调节剂至关重要。

DESCRIPTION (provided by applicant: During the initial stages of infection, circulating Plasmodium falciparum parasites initiate a cascade of events that trigger antigen presenting cells and natural killer (NK) cells to secrete both pro-inflammatory and anti-inflammatory cytokines. The characteristics of these innate immune responses appear to be a critical step in determining control of parasitemia, severity of infection, and the effectiveness of ensuing adaptive responses. In Burkina Faso, the two main ethnic groups, the Fulani and Mossi, have a differential ability to control parasitemia which appears to be mediated by differences in early IFN-( associated responses. Through a whole genome transcriptional approach, we aim to understand critical gene expression patterns which account for the effective early IFN-( responses in the Fulani. We will extend these studies by defining the role of critical cellular subsets, notably NK cells and T cells, in mediating these robust IFN-( responses. Lastly, we will determine the role of enhanced detection of blood stage parasite through TLRs in mediating the differential downstream IFN-( responses in the Fulani. With growing evidence of what appears to be a "hard-wired" resistance to malaria associated with robust IFN-( responses, the ethnic groups in Burkina Faso offers a unique opportunity to delineate the mechanisms underlying these protective early IFN-( responses. Understanding the key genes/pathways and cell populations that account for these effective early responses to malaria is vital to supporting ongoing vaccine efforts and the development of novel immunomodulatory aimed at harnessing these responses.