Genetic adaptation by Pseudomonas aeruginosa to the airways of cystic fibrosis patients

Abstract

In many human infections, hosts and pathogens coexist for years or decades. Important examples include HIV, herpes viruses, tuberculosis, leprosy, and malaria. With the exception of intensively studied viral infections such as HIV/AIDs, little is known about the extent to which the clonal expansion that occurs during long-term infection by pathogens involves important genetic adaptations. We report here a detailed, whole-genome analysis of one such infection, that of a cystic fibrosis (CF) patient by the opportunistic bacterial pathogen Pseudomonas aeruginosa. The bacteria underwent numerous genetic adaptations during 8 years of infection, as evidenced by a positive-selection signal across the genome and an overwhelming signal in specific genes, several of which are mutated during the course of most CF infections. Of particular interest is our finding that virulence factors that are required for the initiation of acute infections are often selected against during chronic infections. It is apparent that the genotypes of the P. aeruginosa strains present in advanced CF infections differ systematically from those of "wild-type" P. aeruginosa and that these differences may offer new opportunities for treatment of this chronic disease.

Fig. 1.

Tree showing mutations that occurred in patient 1 isolates during chronic airways infection. Isolates are numbered 1–35 in black type. Isolates 1 and 35, both circled, are the respective 6- and 96-month isolates whose genomes were sequenced. Mutations are shown in red italic type; mutations present in the 96-month isolate are numbered m1–m68, and mutations present only in intermediate isolates are numbered s1–s17. Mutations s9 and m52 are both in the same highly mutable repeat and appear to have occurred consecutively during the infection. Refer to Tables 4 and 5 for more information on individual mutations.