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- Carey, Alison J., et al.
(författare)
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Uropathogenic Escherichia coli engages CD14-dependent signaling to enable bladder-macrophage-dependent control of acute urinary tract infection
- 2016
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Ingår i: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 0022-1899 .- 1537-6613. ; 213:4, s. 659-668
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Tidskriftsartikel (refereegranskat)abstract
- Background. CD14, a coreceptor for several pattern recognition receptors and a widely used monocyte/macrophage marker, plays a key role in host responses to gram-negative bacteria. Despite the central role of CD14 in the inflammatory response to lipopolysaccharide and other microbial products and in the dissemination of bacteria in some infections, the signaling networks controlled by CD14 during urinary tract infection (UTI) are unknown. Methods. We used uropathogenic Escherichia coli (UPEC) infection of wild-type (WT) C57BL/6 and Cd14-/- mice and RNA sequencing to define the CD14-dependent transcriptional signature and the role of CD14 in host defense against UTI in the bladder. Results. UPEC induced the upregulation of Cd14 and the monocyte/macrophage-related genes Emr1/F4/80 and Csf1r/c-fms, which was associated with lower UPEC burdens in WT mice, compared with Cd14-/- mice. Exacerbation of infection in Cd14-/- mice was associated with the absence of a 491-gene transcriptional signature in the bladder that encompassed multiple host networks not previously associated with this receptor. CD14-dependent pathways included immune cell trafficking, differential cytokine production in macrophages, and interleukin 17 signaling. Depletion of monocytes/macrophages in the bladder by administration of liposomal clodronate led to higher UPEC burdens. Conclusions. This study identifies new host protective and signaling roles for CD14 in the bladder during UPEC UTI.
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- Wilkinson, Tom M. A., et al.
(författare)
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Non-typeable Haemophilus influenzae protein vaccine in adults with COPD : A phase 2 clinical trial
- 2019
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Ingår i: Vaccine. - : Elsevier BV. - 0264-410X .- 1873-2518. ; 37:41, s. 6102-6111
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Tidskriftsartikel (refereegranskat)abstract
- Loss of airway microbial diversity is associated with non-typeable Haemophilus influenzae (NTHi) infection and increased risk of exacerbation in chronic obstructive pulmonary disease (COPD). We assessed the safety and immunogenicity of an investigational vaccine containing NTHi antigens, recombinant protein D (PD) and combined protein E and Pilin A (PE-PilA), and AS01 adjuvant in adults with moderate/-severe COPD and prior exacerbations. In this phase 2, observer-blind, controlled trial (NCT02075541), 145 COPD patients aged 40-80 years randomly (1:1) received two doses of NTHi vaccine or placebo 60 days apart, on top of standard care. Reactogenicity in the 7-day post-vaccination period was higher following NTHi vaccine than placebo. Most solicited adverse events (AEs) were mild/moderate. At least one unsolicited AE was reported during the 30-day post-vaccination period by 54.8% of NTHi vaccine and 51.4% of placebo recipients. One serious AE (placebo group) was assessed by the investigator as vaccine-related. Anti-PD, anti-PE and anti-PiIA geometric mean antibody concentrations increased up to 30 days after each NTHi vaccine dose, waned thereafter, but remained higher than baseline (non-overlapping confidence intervals) up to 13 months post-dose 2. The frequency of specific CD4(+) T cells increased following two doses of NTHi vaccine and remained higher than baseline. Exploratory analysis showed a statistically non-significant lower yearly rate of moderate/severe exacerbations in the NTHi vaccine group than following placebo (1.49 versus 1.73) in the one-year period post-dose 2, with estimated vaccine efficacy of 13.3% (95% confidence interval -24.2 to 39.5; p = 0.44). The NTHi vaccine had an acceptable safety and reactogenicity profile and good immunogenicity in adults with COPD.
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