Abstract
Cystic fibrosis (CF) is a hereditary disease due to mutations in the CFTR gene and causes mortality in humans mainly due to respiratory infections caused by Pseudomonas aeruginosa. In a previous work we used phage therapy, which is a treatment with a mix of phages, to actively counteract acute P. aeruginosa infections in mice and Galleria mellonella larvae. In this work we apply phage therapy to the treatment of P. aeruginosa PAO1 infections in a CF zebrafish model. The structure of the CFTR channel is evolutionary conserved between fish and mammals and cftr-loss-of-function zebrafish embryos show a phenotype that recapitulates the human disease, in particular with destruction of the pancreas. We show that phage therapy is able to decrease lethality, bacterial burden, and the pro-inflammatory response caused by PAO1 infection. In addition, phage administration relieves the constitutive inflammatory state of CF embryos. To our knowledge, this is the first time that phage therapy is used to cure P. aeruginosa infections in a CF animal model. We also find that the curative effect against PAO1 infections is improved by combining phages and antibiotic treatments, opening a useful therapeutic approach that could reduce antibiotic doses and time of administration.
Highlights
One of the most serious health emergencies in the last decades is the reappearance of bacterial infections[1,2]
The distribution of fluorescent bacteria within the embryos was followed by microscopy: as reported in Fig. 1a, at 20 hpi bacteria could be visualized in different organs of the embryos, indicating that bacterial infection can spread in the whole embryo
We demonstrated that phage therapy is able to fight P. aeruginosa infections in zebrafish embryos
Summary
One of the most serious health emergencies in the last decades is the reappearance of bacterial infections[1,2]. This serious fallout is a consequence of the rapid spread of resistance towards currently in use antibiotics among pathogenic bacteria together with the difficulty in discovering new effective antibiotics. An increasing number of reports on the effectiveness of phage therapy in controlling bacterial infections have been provided, ranging from Klebsiella pneumoniae pulmonary infections[11], Pseudomonas aeruginosa keratitis[12], or P. aeruginosa infected mice[4,13,14]. Of a single phage[15,16], a likely consequence of the enlargement of the host range and of the reduced frequency of bacteria resistant to phages, as reported by Chadha et al.[17]
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