Nuclear factor kappa B-dependent persistence of Typhi and Paratyphi in human macrophages.

Unlabelled: serovars Typhi and Paratyphi cause a prolonged illness known as enteric fever, whereas other serovars cause acute gastroenteritis. Mechanisms responsible for the divergent clinical manifestations of nontyphoidal and enteric fever infections have remained elusive. Here, we show that . Typhi and . Paratyphi A can persist within human macrophages, whereas . Typhimurium rapidly induces apoptotic macrophage cell death that is dependent on pathogenicity island 2 (SPI2). . Typhi and . Paratyphi A lack 12 specific SPI2 effectors with pro-apoptotic functions, including nine that target nuclear factor κB (NF-κB). Pharmacologic inhibition of NF-κB or heterologous expression of the SPI2 effectors GogA or GtgA restores apoptosis of . Typhi-infected macrophages. In addition, the absence of the SPI2 effector SarA results in deficient signal transducer and activator of transcription 1 (STAT1) activation and interleukin 12 production, leading to impaired T1 responses in macrophages and humanized mice. The absence of specific nontyphoidal SPI2 effectors may allow . Typhi and . Paratyphi A to cause chronic infections.

Importance: Salmonella enterica is a common cause of gastrointestinal infections worldwide. The serovars Typhi and Paratyphi A cause a distinctive systemic illness called enteric fever, whose pathogenesis is incompletely understood. Here, we show that enteric fever serovars lack 12 specific virulence factors possessed by nontyphoidal serovars, which allow the enteric fever serovars to persist within human macrophages. We propose that this fundamental difference in the interaction of with human macrophages is responsible for the chronicity of typhoid and paratyphoid fever, suggesting that targeting the nuclear factor κB (NF-κB) complex responsible for macrophage survival could facilitate the clearance of persistent bacterial infections.