Melby P C, Tryon V V, Chandrasekar B, Freeman G L
Department of Veterans Affairs Medical Center, and Department of Medicine, The University of Texas Health Science Center, San Antonio 78284-7881, USA.
Infect Immun. 1998 May;66(5):2135-42. doi: 10.1128/IAI.66.5.2135-2142.1998.
The Syrian golden hamster (Mesocricetus auratus) is uniquely susceptible to a variety of intracellular pathogens and is an excellent model for a number of human infectious diseases. The molecular basis for this high level of susceptibility is unknown, and immunological studies related to this model have been limited by the lack of available reagents. In this report we describe the cloning and sequence analysis of portions of the Syrian hamster interleukin 2 (IL-2), IL-4, gamma interferon (IFN-gamma), tumor necrosis factor alpha, IL-10, IL-12p40, and transforming growth factor beta cDNAs. In addition, we examined the cytokine response to infection with the intracellular protozoan Leishmania donovani in this animal model. Sequence analysis of the hamster cytokines revealed 69 to 93% homology with the corresponding mouse, rat, and human nucleotide sequences and 48 to 100% homology with the deduced amino acid sequences. The hamster IFN-gamma, compared with the mouse and rat homologs, had an additional 17 amino acids at the C terminus that could decrease the biological activity of this molecule and thus contribute to the extreme susceptibility of this animal to intracellular pathogens. The splenic expression of these genes in response to infection with L. donovani, the cause of visceral leishmaniasis (VL), was determined by Northern blotting. VL in the hamster is a progressive, lethal disease which very closely mimics active human disease. In this model there was pronounced expression of the Th1 cytokine mRNAs, with transcripts being detected as early as 1 week postinfection. Basal expression of IL-4 in uninfected hamsters was prominent but did not increase in response to infection with L. donovani. IL-12 transcript expression was detected at low levels in infected animals and paralleled the expression of IFN-gamma. Expression of IL-10, a potent macrophage deactivator, increased throughout the course of infection and could contribute to the progressive nature of this infection. These initial studies are the first to examine the molecular immunopathogenesis of a hamster model of VL infection and indicate that progressive disease in this model of VL is not associated with early polarization of the splenic cellular immune response toward a Th2 phenotype and away from a Th1 phenotype.
叙利亚金黄地鼠（Mesocricetus auratus）对多种细胞内病原体具有独特的易感性，是多种人类传染病的优秀模型。这种高度易感性的分子基础尚不清楚，与该模型相关的免疫学研究因缺乏可用试剂而受到限制。在本报告中，我们描述了叙利亚仓鼠白细胞介素2（IL-2）、IL-4、γ干扰素（IFN-γ）、肿瘤坏死因子α、IL-10、IL-12p40和转化生长因子β cDNA部分的克隆和序列分析。此外，我们在这个动物模型中研究了细胞内原生动物杜氏利什曼原虫感染后的细胞因子反应。仓鼠细胞因子的序列分析显示，与相应的小鼠、大鼠和人类核苷酸序列有69%至93%的同源性，与推导的氨基酸序列有48%至100%的同源性。与小鼠和大鼠的同源物相比，仓鼠IFN-γ在C末端有额外的17个氨基酸，这可能会降低该分子的生物学活性，从而导致这种动物对细胞内病原体的极度易感性。通过Northern印迹法测定了这些基因在脾脏中对内脏利什曼病（VL）病原体杜氏利什曼原虫感染的表达。仓鼠的VL是一种进行性致死疾病，与活跃的人类疾病非常相似。在这个模型中，Th1细胞因子mRNA有明显表达，早在感染后1周就检测到转录本。未感染仓鼠中IL-4的基础表达很突出，但对杜氏利什曼原虫感染没有增加。在感染动物中检测到IL-12转录本表达水平较低，与IFN-γ的表达平行。IL-10是一种有效的巨噬细胞失活剂，其表达在感染过程中增加，可能导致这种感染的进行性发展。这些初步研究首次探讨了VL感染仓鼠模型的分子免疫发病机制，表明该VL模型中的进行性疾病与脾脏细胞免疫反应早期向Th2表型极化并远离Th1表型无关。
