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The Achromobacter xylosoxidans type VI secretion system 2 (T6SS): from clinical to molecular evidences of its 3 implication in cystic fibrosis

ABSTRACT: Bacteria of the genus Achromobacter are environmental germs, with an unknown reservoir, which can become opportunistic pathogens in immunocompromised patients, and be responsible for bacteremia, meningitis, pneumonia and peritonitis. Achromobacter xylosoxidans is an emerging pathogenic bacterium frequently isolated in the context of cystic fibrosis (CF). Recent studies show that A. xylosoxidans is involved in the degradation of the respiratory function of CF patients. The respiratory ecosystem of CF patients is colonized by bacterial species that constantly fight for space and access to nutrients. In particular, these bacteria use an antagonism system, a type VI secretion nanomachine (T6SS), which represents a virulence factor in many pathogenic bacteria. This study aimed to investigate the prevalence of the T6SS genes in Achromobacter xylosoxidans isolated in cystic fibrosis patient. We also evaluated clinical and molecular characteristics of T6SS-positive A. xylosoxidans strains. We have shown that A. xylosoxidans possesses a T6SS-encoded gene cluster and that some environmental and clinical isolates assemble a functional T6SS nanomachine. The A. xylosoxidans T6SS is used to target competitor bacteria, including other CF-specific pathogens. We gathered some evidences pointing toward a role of T6SS in CF-lung colonization: i, CF mimicking conditions trigger the activation of A. xylosoxidans T6SS; ii, we detected Hcp in the sputum of CF patient and iii, the T6SS helps internalization of A. xylosoxidans in lung epithelial cells. Our study highlights a new clinical determinant of the virulence of A. xylosoxidans as well as new diagnostic and therapeutic options in cystic fibrosis.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Achromobacter Xylosoxidans A8

TISSUE(S): Saliva

SUBMITTER: Regine Lebrun

LAB HEAD: Régine Lebrun

PROVIDER: PXD031682 | Pride | 2024-02-01

REPOSITORIES: Pride

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			Action	DRS
	20201116_02_054_ED_ref.msf	Msf
	20201116_02_054_ED_ref.raw	Raw
	20201116_11_054_ED_Ax_4.msf	Msf
	20201116_11_054_ED_Ax_4.raw	Raw
	20201116_17_054_ED_Ax_6.msf	Msf

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Project description:Dysfunction of the cystic fibrosis transmembrane regulator (CFTR) in cystic fibrosis (CF) results in exaggerated and chronic inflammation as well as increased susceptibility to chronic pulmonary infections, in particular with Pseudomonas aeruginosa. Based on the concept that host immune responses do not seem to be adequate to eradicate P.aeruginosa from the lungs of CF patients and that dendritic cells (DC) play an important role in initiating and shaping adaptive immune responses, this study analyzed the role of CFTR in bone marrow-derived murine DC from CFTR knockout (CF) mice with and without exposure to P.aeruginosa. DC expressed CFTR mRNA and protein, although at much lower levels compared to whole lung. Microarray analysis of gene expression levels in DC generated from CF and wild type (WT) mice revealed significantly different expression of 16 genes in CF DC compared to WT DC. Among the genes with lower expression in CF DC was Caveolin-1, a membrane lipid raft protein. Messenger RNA and protein levels of Caveolin-1 were decreased in the CF DC compared to WT DC. Consistently, the active form of sterol-responsive element binding protein (SREBP), a negative regulator of Caveolin-1 expression, was increased in CF DC. Following exposure to P.aeruginosa, gene expression levels in CF and WT DC changed for 912 genes involved in inflammation, chemotaxis, signaling, cell cycling and apoptosis more than 1.5-fold. Among the genes that showed a different response between WT and CF DC infected with P.aeruginosa, were 3Î²-hydroxysterol-Î7 reductase (Dhcr7) and stearoyl-CoA desaturase 2 (Scd2), two enzymes involved in the lipid metabolism that are also regulated by SREBP. These results suggest that CFTR dysfunction in non-epithelial cells results in changes in the expression of genes encoding factors involved in membrane structure and lipid-metabolism. These membrane alterations in immune cells may contribute to the abnormal inflammatory and immune response characteristic of CF. Experiment Overall Design: comparison of gene expression in dendritic cells of cystic fibrosis mice without or with Pseudosmonas aeruginosa infection vs wild type dendritic cell controls

Project description:The airways of cystic fibrosis patients are chronically colonized by a diverse range of microbial pathogens, the composition of which changes throughout life Alteration to the pulmonary environment caused by inter-microbial interactions and pathogen-host interactions influence the type of microbes that can engage in sustained infection. The opportunistic bacterial pathogen Pseudomonas aeruginosa is the primary cause of morbidity and mortality amongst individuals with cystic fibrosis and it is estimated that 60 – 80 % of cystic fibrosis patients experience chronic P. aeruginosa infection by the age of 20 years Aspergillus fumigatus is the most prevalent fungal pathogen isolated from cystic fibrosis airways, affecting up to 58% of patients. It is the causative agent of allergic bronchopulmonary aspergillosis (ABPA), a hypersensitivity disorder resulting from the inhalation of fungal conidia. Although co-colonization of the cystic fibrosis airways by P. aeruginosa and A. fumigatus is rare (3.1 – 15.8 %) disease prognosis is poor when both are present. However, sequential infection is more common. It has recently been suggested that A. fumigatus is more prevalent in juvenile cystic fibrosis patients that has been initially reported due to inconsistencies in the culture methods used to detect A. fumigatus. Despite the prevalence and persistence of A. fumigatus, P. aeruginosa predominates as the primary pathogen in the cystic fibrosis lung, suggesting that interactions with other pathogens such as A. fumigatus may influence the pathogenicity of P. aeruginosa by altering its virulence. We report here an investigation of the effect of culturing P. aeruginosa in the presence of A. fumigatus by measuring differences in growth rate and the overall proteome of the bacteria. It was hypothesized that A. fumigatus creates an environment that promotes a metabolic-driven increase in P. aeruginosa that results in it outcompeting the fungus. The molecular basis of this increased proliferation was investigated further using Label-free quantitative (LFQ) proteomics to characterise the proteome changes in P. aeruginosa when exposed to the supernatant of i) A. fumigatus alone ii) the supernatant of an A. fumigatus/P. aeruginosa co-culture and iii) P. aeruginosa alone. LFQ proteomics involves the simultaneous identification and quantification of thousands of proteins (the ultimate determinants of phenotype) from a single sample has recently been employed to characterise the P. aeruginosa proteome in response to iron limiting conditions, resolving how how the bacteria survives and proliferates in such environments.

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The Achromobacter xylosoxidans type VI secretion system 2 (T6SS): from clinical to molecular evidences of its 3 implication in cystic fibrosis

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