Bosio Catharine M, Bielefeldt-Ohmann Helle, Belisle John T
Department of Microbiology, Immunology and Pathology, Colorado State University, Ft. Collins, CO 80523, USA.
J Immunol. 2007 Apr 1;178(7):4538-47. doi: 10.4049/jimmunol.178.7.4538.
Francisella tularensis is an obligate, intracellular bacterium that causes acute, lethal disease following inhalation. As an intracellular pathogen F. tularensis must invade cells, replicate, and disseminate while evading host immune responses. The mechanisms by which virulent type A strains of Francisella tularensis accomplish this evasion are not understood. Francisella tularensis has been shown to target multiple cell types in the lung following aerosol infection, including dendritic cells (DC) and macrophages. We demonstrate here that one mechanism used by a virulent type A strain of F. tularensis (Schu4) to evade early detection is by the induction of overwhelming immunosuppression at the site of infection, the lung. Following infection and replication in multiple pulmonary cell types, Schu4 failed to induce the production of proinflammatory cytokines or increase the expression of MHCII or CD86 on the surface of resident DC within the first few days of disease. However, Schu4 did induce early and transient production of TGF-beta, a potent immunosuppressive cytokine. The absence of DC activation following infection could not be attributed to the apoptosis of pulmonary cells, because there were minimal differences in either annexin or cleaved caspase-3 staining in infected mice compared with that in uninfected controls. Rather, we demonstrate that Schu4 actively suppressed in vivo responses to secondary stimuli (LPS), e.g., failure to recruit granulocytes/monocytes and stimulate resident DC. Thus, unlike attenuated strains of F. tularensis, Schu4 induced broad immunosuppression within the first few days after aerosol infection. This difference may explain the increased virulence of type A strains compared with their more attenuated counterparts.
土拉弗朗西斯菌是一种专性胞内细菌，吸入后会引发急性致命疾病。作为一种胞内病原体，土拉弗朗西斯菌必须侵入细胞、进行复制并扩散，同时逃避宿主的免疫反应。目前尚不清楚土拉弗朗西斯菌强毒力A型菌株实现这种逃避的机制。气溶胶感染后，土拉弗朗西斯菌已被证明可靶向肺内的多种细胞类型，包括树突状细胞（DC）和巨噬细胞。我们在此证明，土拉弗朗西斯菌强毒力A型菌株（Schu4）用于逃避早期检测的一种机制是在感染部位肺部诱导压倒性的免疫抑制。在多种肺细胞类型中感染并复制后，Schu4在疾病的最初几天未能诱导促炎细胞因子的产生，也未能增加驻留DC表面MHCII或CD86的表达。然而，Schu4确实诱导了早期且短暂的TGF-β产生，TGF-β是一种强效的免疫抑制细胞因子。感染后DC未被激活并非归因于肺细胞的凋亡，因为与未感染的对照相比，感染小鼠中膜联蛋白或裂解的半胱天冬酶-3染色的差异极小。相反，我们证明Schu4在体内积极抑制对二次刺激（LPS）的反应，例如未能募集粒细胞/单核细胞并刺激驻留DC。因此，与土拉弗朗西斯菌的减毒株不同，Schu4在气溶胶感染后的最初几天内诱导了广泛的免疫抑制。这种差异可能解释了A型菌株与其减毒程度更高的对应菌株相比毒力增加的原因。
