title: Development of tolerogenic dendritic cells and regulatory T cells favors exponential bacterial growth and survival during early respiratory tularemia.
abstract: 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, T(h)1-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 T(regs) that may restrain T(h)1-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.
authors: Albany Medical College, Albany, NY 12208-3479, USA.
authors: Sivakumar
authors: S
authors: Periasamy
authors: Anju
authors: A
authors: Singh
authors: Bikash
authors: B
authors: Sahay
authors: Tabassum
authors: T
authors: Rahman
authors: Paul J
authors: PJ
authors: Feustel
authors: Giang H
authors: GH
authors: Pham
authors: Edmund J
authors: EJ
authors: Gosselin
authors: Timothy J
authors: TJ
authors: Sellati
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005604:Francisella tularensis / Q000254:growth & development* / Q000472:pathogenicity*; D007113:Immunity, Innate; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050826:Suppressor of Cytokine Signaling Proteins; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000502:physiology; D014406:Tularemia / Q000276:immunology* / Q000382:microbiology / Q000473:pathology
chemical_list: D016207:Cytokines; D050826:Suppressor of Cytokine Signaling Proteins; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2