RESUMO
Hypermutator lineages of Pseudomonas aeruginosa arise frequently during the years of airway infection experienced by patients with cystic fibrosis and bronchiectasis but are rare in the absence of chronic infection and structural lung disease. Since the onset of the COVID-19 pandemic, large numbers of patients have remained mechanically ventilated for extended periods of time. These patients are prone to acquire bacterial pathogens that persist for many weeks and have the opportunity to evolve within the pulmonary environment. However, little is known about what types of adaptations occur in these bacteria and whether these adaptations mimic those observed in chronic infections. We describe a COVID-19 patient with a secondary P. aeruginosa lung infection in whom the causative bacterium persisted for >50 days. Over the course of this infection, a hypermutator lineage of P. aeruginosa emerged and co-existed with a non-hypermutator lineage. Compared to the parental lineage, the hypermutator lineage evolved to be less cytotoxic and less virulent. Genomic analyses of the hypermutator lineage identified numerous mutations, including in the mismatch repair gene mutL and other genes frequently mutated in individuals with cystic fibrosis. Together, these findings demonstrate that hypermutator lineages can emerge when P. aeruginosa persists following acute infections such as ventilator-associated pneumonia and that these lineages have the potential to affect patient outcomes.IMPORTANCEPseudomonas aeruginosa may evolve to accumulate large numbers of mutations in the context of chronic infections such as those that occur in individuals with cystic fibrosis. However, these "hypermutator" lineages are rare following acute infections. Here, we describe a non-cystic fibrosis patient with COVID-19 pneumonia who remained mechanically ventilated for months. The patient became infected with a strain of P. aeruginosa that evolved to become a hypermutator. We demonstrate that hypermutation led to changes in cytotoxicity and virulence. These findings are important because they demonstrate that P. aeruginosa hypermutators can emerge following acute infections and that they have the potential to affect patient outcomes in this setting.
Assuntos
COVID-19 , Fibrose Cística , Infecções por Pseudomonas , Humanos , Fibrose Cística/complicações , Pseudomonas aeruginosa/genética , Respiração Artificial/efeitos adversos , Infecção Persistente , Pandemias , Infecções por Pseudomonas/complicações , Fenótipo , COVID-19/complicaçõesRESUMO
Klebsiella pneumoniae has been classified into two types, classical K. pneumoniae (cKP) and hypervirulent K. pneumoniae (hvKP). cKP isolates are highly diverse and important causes of nosocomial infections; they include globally disseminated antibiotic-resistant clones. hvKP isolates are sensitive to most antibiotics but are highly virulent, causing community-acquired infections in healthy individuals. The virulence phenotype of hvKP is associated with pathogenicity loci responsible for siderophore and hypermucoid capsule production. Recently, convergent strains of K. pneumoniae, which possess features of both cKP and hvKP, have emerged and are cause of much concern. Here, we screen the genomes of 2,608 multidrug-resistant K. pneumoniae isolates from the United States and identify 47 convergent isolates. We perform phenotypic and genomic characterization of 12 representative isolates. These 12 convergent isolates contain a variety of antimicrobial resistance plasmids and virulence plasmids. Most convergent isolates contain aerobactin biosynthesis genes and produce more siderophores than cKP isolates but not more capsule. Unexpectedly, only 1 of the 12 tested convergent isolates has a level of virulence consistent with hvKP isolates in a murine pneumonia model. These findings suggest that additional studies should be performed to clarify whether convergent strains are indeed more virulent than cKP in mouse and human infections.
Assuntos
Klebsiella pneumoniae , Fatores de Virulência , Humanos , Animais , Camundongos , Virulência/genética , Fatores de Virulência/genética , Antibacterianos/farmacologia , Plasmídeos , SideróforosRESUMO
M and M-like proteins are major virulence factors of the widespread and potentially deadly bacterial pathogen Streptococcus pyogenes. These proteins confer resistance against innate and adaptive immune responses by recruiting specific human proteins to the streptococcal surface. Nonimmune recruitment of immunoglobulins G (IgG) and A (IgA) through their fragment crystallizable (Fc) domains by M and M-like proteins was described almost 40 years ago, but its impact on virulence remains unresolved. These interactions have been suggested to be consequential under immune conditions at mucosal surfaces and in secretions but not in plasma, while other evidence suggests importance in evading phagocytic killing in nonimmune blood. Recently, an indirect effect of Fc-binding through ligand-induced stabilization of an M-like protein was shown to increase virulence. Nonimmune recruitment has also been seen to contribute to tissue damage in animal models of autoimmune diseases triggered by S. pyogenes infection. The damage was treatable by targeting Fc-binding. This and other potential therapeutic applications warrant renewed attention to Fc-binding by M and M-like proteins.