Question

What sorts of adjustments would P. aeruginosa have to make in adapting successfully to the human lung?

Answer 1

Pseudomonas aeruginosa, a gram negative bacterium is opportunistic pathogen that can cause acute and chronic lung infections in immunocompromised lungs. P aeruginosa has a reservoir in upper respiratory tract where they reside in paranasal sinuses and nasopharynx. Adaptation in the upper respiratory tract is required for this organism to infect the lungs later on. The P. aeruginosa (PA) will adapt in the lungs by reducing production of virulence factors which results in reduced invasiveness. This allows the bacterium to persist in the lungs without being killed by immune cells. PA will evade host recognition of its flagellar antigens. Flagellin expression is reduced by elastase produced by neutrophils in the lung. The reduced expression of flagellin will therefore inhibit the type 3 secretion system (T3SS) in the bacteria, which is involved in activating inflammatory system in host. Thus, host recognition decreases and the bacterium can survive for longer duration in lung. T3SS is known to stimulate the innate immune cells by activating IL-18 secretion which later activates the NLRC4-inflammasome in host. The bacterium will reduce expression of proteins involved in this system to prevent inflammatory responses in the host. The bacterium reduces expression of type IV pilus, which is known to bind to host cell surface playing a role in T3SS toxicity. Loss of type IV pilus will cause reduce invasion and colonization.

There is increased secretion of Proteases by the bacterium that includes AprA, LasB and protease IV. These proteases cleave the inflammatory mediators such as chemokines, cytokines, immunoglobulins, antimicrobial proteins etc. Degradation of oxidative burst mediators by LasB will inhibit production of reactive oxygen species in alveolar macrophages, which can kill the bacteria. There will be reduced production of factors involved in complement activation, thereby inhibiting the humoral responses. Phagocytosis is inhibited due to degradation of SP-A and SP-D by LasB. Proteolytic degradation also reduces activation of inflammation. Bacterial proteases AprA and LasB are secreted by the bacterium that will cleave the flagellin. Alginate is primarily involved in reducing the producing of reactive oxygen species, thereby protecting the bacteria from oxidative damage in the lung.

Biofilms have to be formed by this bacterium in order to survive in the lungs. Extracellular polysaccharides alginate, Psl, and Pel are produced by the bacterium that causes biofilm formation. This allows the P. aeruginosa to adhere to the lung walls. As a result, the biofilms will lead to immune evasion of host responses. The polysaccharides also increase the tolerance of the biofilm for antibiotics, hinder opsonization and phagocytosis by neutrophils and prevent oxidative damage to the bacterium.

Lipopolysaccharides (LPS) are important constituents of the outer membrane of the gram negative bacterial cell wall. LPS acts as an endotoxin and helps in virulence. In chronic lung infection, lipid A of LPS is modified by the organism. Further, there is loss of O antigen, which is known to activate the humoral immune response against the bacterium.

All these evasive mechanism will allow the P. aeruginosa to survive and adapt to lung for longer duration causing long lasting infections.