Immunometabolites Drive Bacterial Adaptation to the Airway

Abstract

Pseudomonas aeruginosa and Staphylococcus aureus are both opportunistic pathogens that are frequently associated with chronic lung infections. While bacterial virulence determinants are critical in initiating infection, the metabolic flexibility of these bacteria promotes their persistence in the airway. Upon infection, these pathogens induce host immunometabolic reprogramming, resulting in an airway milieu replete with immune-signaling metabolites. These metabolites are often toxic to the bacteria and create a steep selection pressure for the emergence of bacterial isolates adapted for long-term survival in the inflamed lung. In this review, we discuss the main differences in the host immunometabolic response to P. aeruginosa and S. aureus, as well as how these pathogens alter their own metabolism to adapt to airway metabolites and cause persistent lung infections.

Staphylococcus aureus adaptive evolution: Recent insights on how immune evasion, immunometabolic subversion and host genetics impact vaccine development

“…A component of the TCA cycle generated by Acod1 or Irg1 , itaconate has a well-established role in modulating the proinflammatory response to LPS. Its importance in host defenses against S. aureus is being increasingly appreciated, as this is one of the major metabolites found in the airway in S. aureus pneumonia ( Tomlinson et al., 2021 ). Whilst itaconate suppresses inflammation in the host by inhibiting the NLRP3 inflammasome, glycolytic enzymes and succinate dehydrogenase (SDH/mitochondrial complex II) ( Lampropoulou et al., 2016 ; Qin et al., 2019 ; Hooftman et al., 2020 ), it has several bacterial targets.…”

“…Whilst itaconate suppresses inflammation in the host by inhibiting the NLRP3 inflammasome, glycolytic enzymes and succinate dehydrogenase (SDH/mitochondrial complex II) ( Lampropoulou et al., 2016 ; Qin et al., 2019 ; Hooftman et al., 2020 ), it has several bacterial targets. Itaconate inhibits the glyoxylate cycle of Salmonella typhimurium and Pseudomonas aeruginosa as well as glycolysis of S. aureus ( McFadden and Purohit, 1977 ; Hersch and Navarre, 2020 ; Tomlinson et al., 2021 ), crucial pathways for the survival of these pathogens. While the former two pathogens can degrade itaconate ( Sasikaran et al., 2014 ; Wang et al., 2019 ), S. aureus lacks these degradative enzymes, yet can tolerate it by actively altering its metabolic activity.…”

“…While the former two pathogens can degrade itaconate ( Sasikaran et al., 2014 ; Wang et al., 2019 ), S. aureus lacks these degradative enzymes, yet can tolerate it by actively altering its metabolic activity. It was recently shown that the inhibition of the staphylococcal glycolytic enzyme aldolase by itaconate led to redirecting of carbon flux to pathways that promote biofilm synthesis ( Figure 2 ) ( Tomlinson et al., 2021 ). Longitudinal isolates of S. aureus that have adapted to the itaconate-replete cystic fibrosis (CF) airway ( Riquelme et al., 2020 ) displayed enhanced biofilm forming capacity ( Tomlinson et al., 2021 ), a response that can be replicated by exposure of S. aureus to itaconate in vitro .…”

Itaconic acid facilitates inflammation abatement and alleviates liver ischemia-reperfusion injury by inhibiting NF-κB/NLRP3/caspase-1 inflammasome axis

“…With the development of metabolomics, research has revealed itaconic acid is not only present in microorganisms such as fungi but also widely present in mammalian immune cells (especially macrophages), and that it is produced in large quantities in response to external stimuli of inflammation (15). Recent years have also seen an explosion in the study of itaconic acid in macrophages (16)(17)(18)(19).…”

PmiR senses 2-methylisocitrate levels to regulate bacterial virulence in Pseudomonas aeruginosa

“…To survive in the host, P. aeruginosa has evolved multiple means of scavenging nutrients and adjusting its metabolism to maintain growth while also coping with stress ( 14 ). Furthermore, P. aeruginosa secretes an array of surface-associated and extracellular virulence factors to cause disease in the host and interfere with host defense ( 15 ).…”