Development of tolerogenic dendritic cells and regulatory T cells favors exponential bacterial growth and survival during early respiratory tularemia

Journal of Leukocyte Biology

Anju Singh¹  Tabassum Rahman¹  Timothy J. Sellati¹  Giang H. Pham¹  Bikash Sahay¹  Edmund J. Gosselin and¹  Sivakumar Periasamy¹  Paul J. Feustel¹ 

[1] Centers for Immunology and Microbial Disease and  Neuropharmacology and Neuroscience, Albany Medical College, Albany, New York, USA

关键词: NF-κB;    lipopolysaccharide;    neutrophils;    Francisella tularensis;    IL-10;    TGF-β;   

DOI  :  10.1189/jlb.0411197

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Tularemia is a vector-borne zoonosis caused by Ft, a Gram-negative, facultative intracellular bacterium. Ft exists in two clinically relevant forms, the European biovar B (holarctica), which produces acute, although mild, self-limiting infections, and the more virulent United States biovar A (tularensis), which is often associated with pneumonic tularemia and more severe disease. In a mouse model of tularemia, respiratory infection with the virulence-attenuated Type B (LVS) or highly virulent Type A (SchuS4) strain engenders peribronchiolar and perivascular inflammation. Paradoxically, despite an intense neutrophilic infiltrate and high bacterial burden, Th1-type proinflammatory cytokines (e.g., TNF, IL-1β, IL-6, and IL-12) are absent within the first ∼72 h of pulmonary infection. It has been suggested that the bacterium has the capacity to actively suppress or block NF-κB signaling, thus causing an initial delay in up-regulation of inflammatory mediators. However, our previously published findings and those presented herein contradict this paradigm and instead, strongly support an alternative hypothesis. Rather than blocking NF-κB, Ft actually triggers TLR2-dependent NF-κB signaling, resulting in the development and activation of tDCs and the release of anti-inflammatory cytokines (e.g., IL-10 and TGF-β). In turn, these cytokines stimulate development and proliferation of Tregs that may restrain Th1-type proinflammatory cytokine release early during tularemic infection. The highly regulated and overall anti-inflammatory milieu established in the lung is permissive for unfettered growth and survival of Ft. The capacity of Ft to evoke such a response represents an important immune-evasive strategy.

【 授权许可】

Unknown