Weinstein D L, O'Neill B L, Hone D M, Metcalf E S
Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814-4799, USA.
Infect Immun. 1998 May;66(5):2310-8. doi: 10.1128/IAI.66.5.2310-2318.1998.
Salmonella enterica serovar Typhi (hereafter referred to as S. typhi) is a host-restricted pathogen that adheres to and invades the distal ileum and subsequently disseminates to cause typhoid fever in humans. However, S. typhi appears to be avirulent in small animals. In contrast, other pathogenic salmonellae, such as S. enterica serovars Typhimurium and Dublin (S. typhimurium and S. dublin, respectively), typically cause localized gastroenteritis in humans but have been used as models for typhoid fever because these organisms cause a disease in susceptible rodents that resembles human typhoid. In vivo, S. typhi has been demonstrated to attach to and invade murine M cells but is rapidly cleared from the Peyer's patches without destruction of the M cells. In contrast, invasion of M cells by S. typhimurium is accompanied by destruction of these M cells and subsequently sloughing of the epithelium. These data have furthered our view that the early steps in the pathogenesis of typhoidal and nontyphoidal Salmonella serovars are distinct. To extend this concept, we have utilized an in vitro model to evaluate three parameters of initial host-pathogen interactions: adherence of three Salmonella serovars to human and murine small intestinal epithelial cell (IEC) lines, the capacity of these salmonellae to invade IECs, and the ability of the bacteria to induce interleukin-6 (IL-6) in these cell lines as a measure of host cell activation and the host acute-phase response. The results demonstrate that S. typhi adheres to and invades human small IECs better than either S. typhimurium or S. dublin. Interestingly, invA and invE null mutants of S. typhi are able neither to adhere to nor to invade IECs, unlike S. typhimurium invA and invE mutants, which adhere to but cannot invade IECs. S. typhi also induces significantly greater quantities of IL-6 in human small IEC lines than either of the other two Salmonella serovars. These findings suggest that differential host cytokine responses to bacterial pathogens may play an important role in the pathological sequelae that follow infection. Importantly, S. typhimurium did not induce IL-6 in murine IECs. Since S. typhimurium infection in mice is often used as a model of typhoid fever, these findings suggest that, at least in this case, the mouse model does not reflect the human disease. Taken together, our studies indicate that (i) marked differences occur in the initial steps of S. typhi, S. typhimurium, and S. dublin pathogenesis, and (ii) conclusions about S. typhi pathogenesis that have been drawn from the mouse model of typhoid fever should be interpreted conservatively.
伤寒沙门氏菌（以下简称伤寒杆菌）是一种宿主特异性病原体，它黏附并侵入回肠末端，随后扩散引发人类伤寒热。然而，伤寒杆菌在小动物中似乎无致病性。相比之下，其他致病性沙门氏菌，如鼠伤寒沙门氏菌和都柏林沙门氏菌（分别简称为鼠伤寒杆菌和都柏林杆菌），通常在人类中引起局部肠胃炎，但因其在易感啮齿动物中引发的疾病类似于人类伤寒，所以被用作伤寒热的模型。在体内，已证实伤寒杆菌可黏附并侵入鼠M细胞，但会迅速从派尔集合淋巴结中清除，而不会破坏M细胞。相反，鼠伤寒杆菌侵入M细胞时会伴随着这些M细胞的破坏以及随后上皮细胞的脱落。这些数据进一步强化了我们的观点，即伤寒和非伤寒沙门氏菌血清型发病机制的早期步骤是不同的。为了拓展这一概念，我们利用体外模型评估了宿主 - 病原体初始相互作用的三个参数：三种沙门氏菌血清型对人和鼠小肠上皮细胞（IEC）系的黏附、这些沙门氏菌侵入IEC的能力，以及细菌在这些细胞系中诱导白细胞介素 - 6（IL - 6）的能力，以此作为宿主细胞激活和宿主急性期反应的指标。结果表明，伤寒杆菌对人小肠IEC的黏附和侵入能力优于鼠伤寒杆菌和都柏林杆菌。有趣的是，伤寒杆菌的invA和invE基因缺失突变体既不能黏附也不能侵入IEC，这与鼠伤寒杆菌的invA和invE突变体不同，后者能黏附但不能侵入IEC。伤寒杆菌在人小肠IEC系中诱导产生的IL - 6量也明显多于其他两种沙门氏菌血清型。这些发现表明，宿主对细菌病原体的不同细胞因子反应可能在感染后的病理后遗症中起重要作用。重要的是，鼠伤寒杆菌在鼠IEC中不诱导IL - 6产生。由于小鼠中的鼠伤寒杆菌感染常被用作伤寒热的模型，这些发现表明，至少在这种情况下，小鼠模型不能反映人类疾病。综上所述，我们的研究表明：（i）伤寒杆菌、鼠伤寒杆菌和都柏林杆菌发病机制的初始步骤存在显著差异；（ii）从伤寒热小鼠模型得出的关于伤寒杆菌发病机制的结论应谨慎解读。
