Department of Microbiology, Medical School, University of Minnesota, Minneapolis, Minnesota, USA.
mBio. 2012 Sep 25;3(5). doi: 10.1128/mBio.00196-12. Print 2012.
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 Th(2) 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.
在撒哈拉以南非洲地区，隐球菌性脑膜炎（CM）仍然是艾滋病相关死亡的主要原因。了解毒力并改善临床治疗仍然很重要。为了研究真菌菌株基因型在临床疾病中的作用，我们分析了来自 111 名乌干达 AIDS 合并 CM 患者的 140 株隐球菌分离株。分离株包括 107 株非冗余新型隐球菌 var. grubii 株和 8 株新型隐球菌 var. grubii/neoformans 杂交株。多位点序列分型（MLST）用于特征基因型，产生 15 种序列类型和 4 个克隆簇。最大的克隆簇由 74 株分离株组成。Burst 和系统发育分析的结果表明，新型隐球菌 var. grubii 株可分为三个非冗余进化群（Burst 群 1 至群 3）。患者死亡率与不同进化群显著相关（P=0.04），Burst 群 1、群 2 和杂交株的死亡率最高。与 Burst 群 3 株相比，Burst 群 1 株与更高的死亡率相关（P=0.02），在体外细胞因子释放试验中，与菌株特异性荚膜刺激相比，其荚膜脱落增加（P=0.02），并引起更明显的 Th2 反应（P=0.02）。这些分析的结果表明，隐球菌菌株的变异可能是人类免疫反应和死亡率的一个重要决定因素。
新型隐球菌是一种常见的致命性人类真菌病原体，估计每年有 100 万例 HIV 感染患者患有隐球菌性脑膜炎。已经确定了在人类疾病中起重要作用的毒力因子，但真菌菌株基因型对人类感染的毒力和结果的影响仍知之甚少。本研究采用基于体外检测和乌干达 AIDS 合并隐球菌感染者临床资料的菌株变异分析，报告了菌株基因型可预测免疫反应类型和死亡风险。这些研究表明，在人类感染期间了解菌株基因型可用于预测疾病结局，并导致针对病原体毒力和宿主反应特定组合的改进治疗方法。
