Murine Models for Trypanosoma brucei gambiense Disease Progression-From Silent to Chronic Infections and Early Brain Tropism
Murine Models for Trypanosoma brucei gambiense Disease Progression-From Silent to Chronic Infections and Early Brain Tropism
复制标题
甘比坦锥虫疾病进展的小鼠模型--从静默感染到慢性感染和早期脑趋向性
DOI：
10.1371/journal.pntd.0000509
复制
发表时间：
2009-09-01
影响因子：
3.8
通讯作者：
Baltz, Theo
中科院分区：
文献类型：
--
作者：
Giroud, Christiane;Ottones, Florence;Baltz, Theo
背景：由布氏冈比亚锥虫引起的非洲人类锥虫病（HAT）在西非和中非仍然高度流行，如果不及时治疗是致命的。主要的问题是，这种疾病经常发展为慢性或无症状形式，伴有低和波动的寄生虫血症，产生明显的寄生虫血清学怀疑，但由于化疗的毒性而未得到治疗。由于从患者身上分离出的冈比亚锥虫在啮齿类动物中通常不具有传染性，因此限制了分离物的种类，因此很难确定不同类型的感染是由于宿主因素还是寄生虫因素造成的。方法/主要发现：通过体外培养直接从感染患者的脑脊液中培养出冈比亚锥虫，并分析其分子多态性。小鼠感染实验表明，这些分离株可分为三组，它们在体内感染特性、免疫反应和脑侵袭能力方面具有不同的特点。第一个分离物诱发了典型的慢性感染，伴有波动性血液寄生虫血症、中枢神经系统（CNS）的入侵、锥虫特异性抗体反应和动物在6 -8个月内死亡。第二组诱导亚慢性感染，感染后出现单波寄生虫血症，随后出现低水平寄生虫血症，显微镜观察血液未发现寄生虫，但PCR检测到，并且存在特异性抗体反应。第三个分离物诱导了一种无声感染，其特征是在整个过程中没有显微镜可检测到的寄生虫，但在整个感染过程中都可以通过PCR检测到感染。此外，当小鼠感染少量这类寄生虫时，特异性抗体几乎检测不到。生物发光成像显示，在亚慢性和慢性感染中，尽管寄生虫在包括中枢神经系统在内的不同器官中早期传播和生长，但大多数小鼠存活超过一年，没有重大临床症状。结论/意义：虽然所有这些分离株的锥虫特征都属于同类的冈比亚锥虫I群，但它们显然在小鼠中诱导了非常不同的感染，从而模仿了冈比亚锥虫在HAT中观察到的广泛临床多样性。因此，这些小鼠模型将对了解HAT的不同生理病理方面以及开发新的诊断工具和药物非常有用。
Background: Human African trypanosomiasis (HAT) caused by Trypanosoma brucei gambiense remains highly prevalent in west and central Africa and is lethal if left untreated. The major problem is that the disease often evolves toward chronic or asymptomatic forms with low and fluctuating parasitaemia producing apparently aparasitaemic serological suspects who remain untreated because of the toxicity of the chemotherapy. Whether the different types of infections are due to host or parasite factors has been difficult to address, since T.b. gambiense isolated from patients is often not infectious in rodents thus limiting the variety of isolates.Methodology/Principal findings: T.b. gambiense parasites were outgrown directly from the cerebrospinal fluid of infected patients by in vitro culture and analyzed for their molecular polymorphisms. Experimental murine infections showed that these isolates could be clustered into three groups with different characteristics regarding their in vivo infection properties, immune response and capacity for brain invasion. The first isolate induced a classical chronic infection with a fluctuating blood parasitaemia, an invasion of the central nervous system (CNS), a trypanosome specific-antibody response and death of the animals within 6 -8 months. The second group induced a sub-chronic infection resulting in a single wave of parasitaemia after infection, followed by a low parasitaemia with no parasites detected by microscope observations of blood but detected by PCR, and the presence of a specific antibody response. The third isolate induced a silent infection characterised by the absence of microscopically detectable parasites throughout, but infection was detectable by PCR during the whole course of infection. Additionally, specific antibodies were barely detectable when mice were infected with a low number of this group of parasites. In both sub-chronic and chronic infections, most of the mice survived more than one year without major clinical symptoms despite an early dissemination and growth of the parasites in different organs including the CNS, as demonstrated by bioluminescent imaging.Conclusions/Significance: Whereas trypanosome characterisation assigned all these isolates to the homogeneous Group I of T.b. gambiense, they clearly induce very different infections in mice thus mimicking the broad clinical diversity observed in HAT due to T.b. gambiense. Therefore, these murine models will be very useful for the understanding of different aspects of the physiopathology of HAT and for the development of new diagnostic tools and drugs.