Cryptococcal genotype influences immunologic response and human clinical outcome after meningitis.
Cryptococcal genotype influences immunologic response and human clinical outcome after meningitis.
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作者：
Wiesner DL;Moskalenko O;Corcoran JM;McDonald T;Rolfes MA;Meya DB;Kajumbula H;Kambugu A;Bohjanen PR;Knight JF;Boulware DR;Nielsen K
在撒哈拉以南非洲，隐球菌性脑膜炎(CM)仍然是艾滋病相关死亡的主要原因。了解毒力和改进临床治疗仍然很重要。为了表征真菌菌株在临床疾病中的作用，我们分析了来自111名患有艾滋病和CM的乌干达人的140株隐球菌分离株。分离株由107株非冗余新生隐球菌变种组成。Grubii菌株和8株新生隐球菌变种。革兰氏阴性杆菌/新生杆菌混合菌株。采用多位点序列分型技术(MLST)进行基因分型，共得到15个序列类型和4个克隆簇。最大的克隆群由74个菌株组成。系统发育分析和系统发育分析结果表明，新生隐球菌属变种。Grubii菌株可分为三个非冗余进化群(Burst群1至群3)。患者死亡率与不同的进化组之间存在差异(P=0.04)，在Burst组1、Burst组2和杂交菌株之间观察到最高的死亡率。与爆发组3菌株相比，爆发组1菌株具有更高的死亡率(P=0.02)，更多的包膜脱落(P=0.02)，并在菌株特异性包膜刺激的体外细胞因子释放试验中诱导更明显的Th2应答(P=0.02)。这些分析的结果表明，隐球菌株的变异可能是人类免疫反应和死亡率的重要决定因素。新生隐球菌是一种常见的威胁生命的人类真菌病原体，据估计，每年有100万例艾滋病毒感染患者发生脑膜炎。已经确定了在人类疾病中重要的毒力因素，但真菌菌株基因对毒力和人类感染结局的影响仍然知之甚少。通过基于体外测试和乌干达艾滋病患者和隐球菌感染患者的临床数据的菌株变异分析，我们报告了菌株基因可以预测免疫反应的类型和死亡风险。这些研究表明，在人类感染期间，对菌株基因的了解可以用于预测疾病结果，并导致改进的治疗方法，旨在针对病原体毒力和宿主反应的特定组合。
In sub-Saharan Africa, cryptococcal meningitis (CM) continues to be a predominant cause of AIDS-related mortality. Understanding virulence and improving clinical treatments remain important. To characterize the role of the fungal strain genotype in clinical disease, we analyzed 140 Cryptococcus isolates from 111 Ugandans with AIDS and CM. Isolates consisted of 107 nonredundant Cryptococcus neoformans var. grubii strains and 8 C. neoformans var. grubii/neoformans hybrid strains. Multilocus sequence typing (MLST) was used to characterize genotypes, yielding 15 sequence types and 4 clonal clusters. The largest clonal cluster consisted of 74 isolates. The results of Burst and phylogenetic analysis suggested that the C. neoformans var. grubii strains could be separated into three nonredundant evolutionary groups (Burst group 1 to group 3). Patient mortality was differentially associated with the different evolutionary groups (P = 0.04), with the highest mortality observed among Burst group 1, Burst group 2, and hybrid strains. Compared to Burst group 3 strains, Burst group 1 strains were associated with higher mortality (P = 0.02), exhibited increased capsule shedding (P = 0.02), and elicited a more pronounced Th2 response during ex vivo cytokine release assays with strain-specific capsule stimulation (P = 0.02). The results of these analyses suggest that cryptococcal strain variation can be an important determinant of human immune responses and mortality. Cryptococcus neoformans is a common life-threatening human fungal pathogen that is responsible for an estimated 1 million cases of meningitis in HIV-infected patients annually. Virulence factors that are important in human disease have been identified, yet the impacts of the fungal strain genotype on virulence and outcomes of human infection remain poorly understood. Using an analysis of strain variation based on in vitro assays and clinical data from Ugandans living with AIDS and cryptococcal infection, we report that strain genotype predicts the type of immune response and mortality risk. These studies suggest that knowledge of the strain genotype during human infections could be used to predict disease outcomes and lead to improved treatment approaches aimed at targeting the specific combination of pathogen virulence and host response.