Pulmonary Pathogens Adapt to Immune Signaling Metabolites in the Airway

Abstract

A limited number of pulmonary pathogens are able to evade normal mucosal defenses to establish acute infection and then adapt to cause chronic pneumonias. Pathogens, such as Pseudomonas aeruginosa or Staphylococcus aureus, are typically associated with infection in patients with underlying pulmonary disease or damage, such as cystic fibrosis (CF) or chronic obstructive pulmonary disease (COPD). To establish infection, bacteria express a well-defined set of so-called virulence factors that facilitate colonization and activate an immune response, gene products that have been identified in murine models. Less well-understood are the adaptive changes that occur over time in vivo, enabling the organisms to evade innate and adaptive immune clearance mechanisms. These colonizers proliferate, generating a population sufficient to provide selection for mutants, such as small colony variants and mucoid variants, that are optimized for long term infection. Such host-adapted strains have evolved in response to selective pressure such as antibiotics and the recruitment of phagocytes at sites of infection and their release of signaling metabolites (e.g., succinate). These metabolites can potentially function as substrates for bacterial growth and but also generate oxidant stress. Whole genome sequencing and quantified expression of selected genes have helped to explain how P. aeruginosa and S. aureus adapt to the presence of these metabolites over the course of in vivo infection. The serial isolation of clonally related strains from patients with cystic fibrosis has provided the opportunity to identify bacterial metabolic pathways that are altered under this immune pressure, such as the anti-oxidant glyoxylate and pentose phosphate pathways, routes contributing to the generation of biofilms. These metabolic pathways and biofilm itself enable the organisms to dissipate oxidant stress, while providing protection from phagocytosis. Stimulation of host immune signaling metabolites by these pathogens drives bacterial adaptation and promotes their persistence in the airways. The inherent metabolic flexibility of P. aeruginosa and S. aureus is a major factor in their success as pulmonary pathogens.

Macrophage metabolic reprogramming during chronic lung disease

“…Itaconate exerts antimicrobial properties via inhibition of bacterial isocitrate lyase in the glyoxylate shunt 142 and to evade this mechanism P. Aeruginosa has developed a way to use itaconate as an energy source 143 . Similarly succinate, which is secreted in high levels during CF and especially during bacterial infection 144 , can be utilised by P. Aeruginosa and S. Aureus as a substrate to generate oxidative stress.…”

Airway immunometabolites fuel Pseudomonas aeruginosa infection

“…Opportunistic bacterial pathogens, such as Pseudomonas aeruginosa , Klebsiella pneumoniae and Staphylococcus aureus are frequently associated with persistent pulmonary infection [ 1 , 2 ]. These pathogens are a major cause of morbidity and mortality, especially in individuals with damaged airways, as occurs in ventilator associated pneumonia (VAP) [ 3 – 6 ], in subjects with antecedent viral infection [ 7 – 10 ], or in patients exhibiting airway inflammation, as in chronic obstructive pulmonary disease (COPD) [ 11 , 12 ] and in cystic fibrosis (CF) [ 13 – 16 ].…”

“…Antibiotic resistance is a common feature of these organisms, and may contribute to intractable infection, but even susceptible strains are able to cause chronic inflammation and eventual mortality, suggesting mechanisms other than drug resistance are involved in pulmonary pathogenesis. It is also curious that ex vivo, many of these bacteria are readily phagocytosed and killed by immune cells, suggesting that conditions within the airway itself, such as the complex metabolic milieu provided by inflammatory cells, may contribute to bacterial survival [ 1 , 2 ]. The ability of these major opportunists to form biofilms, which protect bacteria from antibodies, complement, phagocytosis, antibiotic penetrance and especially from oxidants is a common factor in their pathogenicity and clearly contributes to their shared ability to cause persistent pulmonary infection [ 11 , 17 , 18 ].…”

Consequences of Metabolic Interactions during Staphylococcus aureus Infection

“…Its ubiquity both as a component of the normal flora and as a pathogen reflects a substantial degree of metabolic flexibility, as well as the ability to elude immune clearance. Infection is associated with metabolic changes in both the host and microorganism: in the host to fuel an immune response [1] and in the bacteria to synthesize the gene products necessary to elude phagocytic clearance and to generate adenosine triphosphate (ATP) for protein synthesis and survival [2]. Over the course of infection, the metabolic activities of both host and pathogen are dynamically regulated, reflecting the requirements for an acute or a chronic infection.…”