Chronic Infection by Mucoid Pseudomonas aeruginosa Associated with Dysregulation in T-Cell Immunity to Outer Membrane Porin F

Abstract

Rationale: Pseudomonas aeruginosa (PA) is an environmental pathogen that commonly infects individuals with cystic fibrosis (CF) and non-CF bronchiectasis, impacting morbidity and mortality. To understand the pathobiology of interactions between the bacterium and host adaptive immunity and to inform rational vaccine design, it is important to understand the adaptive immune correlates of disease.Objectives: To characterize T-cell immunity to the PA antigen outer membrane porin F (OprF) by analyzing immunodominant epitopes in relation to infection status.Methods: Patients with non-CF bronchiectasis were stratified by frequency of PA isolation. T-cell IFN-g immunity to OprF and its immunodominant epitopes was characterized. Patterns of human leukocyte antigen (HLA) restriction of immunodominant epitopes were defined using HLA class II transgenic mice. Immunity was characterized with respect to cytokine and chemokine secretion, antibody response, and T-cell activation transcripts. Measurements and Main Results:Patients were stratified according to whether PA was never, sometimes (,50%), or frequently (>50%) isolated from sputum. Patients with frequent PA sputumpositive isolates were more likely to be infected by mucoid PA, and they showed a narrow T-cell epitope response and a relative reduction in Th1 polarizing transcription factors but enhanced immunity with respect to antibody production, innate cytokines, and chemokines. Conclusions:We have defined the immunodominant, HLArestricted T-cell epitopes of OprF. Our observation that chronic infection is associated with a response of narrowed specificity, despite strong innate and antibody immunity, may help to explain susceptibility in these individuals and pave the way for better vaccine design to achieve protective immunity.

Infection with Burkholderia pseudomallei – immune correlates of survival in acute melioidosis

“…Although the Bp immunome is clearly large and complex, the definition of highly immunodominant, common, peptide-HLA complexes offers the potential for developments in future immune monitoring of immune status 12 – 14 , 22 , 23 . A new tool developed from analysis of Bp pMHC and Pseudomonas aerguniosa 24 pMHC complexes in responder datasets is BIITE, a means of elucidating likely pMHC combinations out of bulk PBMC responses in HLA-heterozygous individuals who will be expressing multiple HLA class II heterodimers to present peptide 23 . AhpC, and specifically, the p6 epitope from this antigen, stand out as a part of the Bp immunome that is highly visible to the T cell repertoire.…”

BIITE: A Tool to Determine HLA Class II Epitopes from T Cell ELISpot Data

“…The bacterium Pseudomonas Aeruginosa (PA) is an environmental organism that can cause infection in damaged lung or the immune compromised host. PBMCs from a small cohort (N = 58) of patients with a chronic lung disease associated with recurrent lung infection and progressive lung damage, called bronchiectasis, were used to test 34 overlapping 20-mers of the OprF protein using IFNγ ELISpot assays [ 15 ]. We used a cut-off of 2SD above the mean of medium only control to decide whether a particular ELISpot result for an individual was positive or negative.…”

“…Analogously to the Burkholderia dataset, we had access to a immunogenicity data derived from transgenic mouse models and binding data from peptide-binding assays [ 15 ]. Transgenic mouse models were available for DRB1*01 , DRB1*04 and DRB1*15 ; binding data was available for 7 HLA-DRB1 alleles.…”

Early increase of VEGF‐A is associated with resolution of ventilator‐associated pneumonia: Clinical and experimental evidence

“…When the infection was eradicated after treatment with colistin, VEGF‐A levels further increased supporting a role of VEGF‐A in the healing process of the lung. Although a chronic P. aeruginosa lung infection is associated with IFNγ responses from T‐lymphocytes, the animal data in this study showed unchanged concentrations in lung tissue over time, indicating innate immunity as the site of IFNγ production.…”