Respiratory Syncytial Virus (RSV) is the commonest cause of severe respiratory infection in infants, leading to over 3 million hospitalizations and around 66,000 deaths worldwide each year. RSV bronchiolitis predominantly strikes apparently healthy infants, with age as the principal risk factor for severe disease. The differences in the immune response to RSV in the very young are likely to be key to determining the clinical outcome of this common infection. Remarkable age-related differences in innate cytokine responses follow recognition of RSV by numerous pattern recognition receptors, and the importance of this early response is supported by polymorphisms in many early innate genes, which associate with bronchiolitis. In the absence of strong, Th1 polarizing signals, infants develop T cell responses that can be biased away from protective Th1 and cytotoxic T cell immunity toward dysregulated, Th2 and Th17 polarization. This may contribute not only to the initial inflammation in bronchiolitis, but also to the long-term increased risk of developing wheeze and asthma later in life. An early-life vaccine for RSV will need to overcome the difficulties of generating a protective response in infants, and the proven risks associated with generating an inappropriate response. Infantile T follicular helper and B cell responses are immature, but maternal antibodies can afford some protection. Thus, maternal vaccination is a promising alternative approach. However, even in adults adaptive immunity following natural infection is poorly protective, allowing re-infection even with the same strain of RSV. This gives us few clues as to how effective vaccination could be achieved. Challenges remain in understanding how respiratory immunity matures with age, and the external factors influencing its development. Determining why some infants develop bronchiolitis should lead to new therapies to lessen the clinical impact of RSV and aid the rational design of protective vaccines.

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SummaryWe investigated the role of commensals at the peak of infection with the colonic mouse pathogen Citrobacter rodentium. Bioluminescent and kanamycin (Kan)-resistant C. rodentium persisted avirulently in the cecal lumen of mice continuously treated with Kan. A single Kan treatment was sufficient to displace C. rodentium from the colonic mucosa, a phenomenon not observed following treatment with vancomycin (Van) or metronidazole (Met). Kan, Van, and Met induce distinct dysbiosis, suggesting C. rodentium relies on specific commensals for colonic colonization. Expression of the master virulence regulator ler is induced in germ-free mice, yet C. rodentium is only seen in the cecal lumen. Moreover, in conventional mice, a single Kan treatment was sufficient to displace C. rodentium constitutively expressing Ler from the colonic mucosa. These results show that expression of virulence genes is not sufficient for colonization of the colonic mucosa and that commensals are essential for a physiological infection course.

Salmonella enterica (e.g., serovars Typhi and Typhimurium) relies on translocation of effectors via type III secretion systems (T3SS). Specialization of typhoidal serovars is thought to be mediated via pseudogenesis. Here, we show that the Salmonella Typhi STY1076/t1865 protein, named StoD, a homologue of the enteropathogenic Escherichia coli/enterohemorrhagic E. coli/Citrobacter rodentium NleG, is a T3SS effector. The StoD C terminus (StoD-C) is a U-box E3 ubiquitin ligase, capable of autoubiquitination in the presence of multiple E2s. The crystal structure of the StoD N terminus (StoD-N) at 2.5 Å resolution revealed a ubiquitin-like fold. In HeLa cells expressing StoD, ubiquitin is redistributed into puncta that colocalize with StoD. Binding assays showed that StoD-N and StoD-C bind the same exposed surface of the β-sheet of ubiquitin, suggesting that StoD could simultaneously interact with two ubiquitin molecules. Consistently, StoD interacted with both K63- (KD = 5.6 ± 1 μM) and K48-linked diubiquitin (KD = 15 ± 4 μM). Accordingly, we report the first S. Typhi–specific T3SS effector. We suggest that StoD recognizes and ubiquitinates pre-ubiquitinated targets, thus subverting intracellular signaling by functioning as an E4 enzyme.

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