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12 Apr 2022

Researchers discover how deadly, antibiotic resistant pathogen evades the immune system, laying the groundwork for better therapeutics to combat infection

Researchers at the Doherty institute and Columbia University have discovered that the deadly pathogen Klebsiella pneumoniae can change the metabolism of a host cell and override the immune response.

Klebsiella pneumoniae is a lethal pathogen in hospital settings that causes pulmonary infections, and one that is resistant to almost all antibiotics even those used as a last resort.

Until now, it was not understood how this deadly pathogen evaded detection by the immune system so that it was able to cause persistent infection.

New research published today in Cell Metabolism led by Dr Tania Wong, a Postdoctoral Research Fellow at Columbia University and her mentor, Professor Alice Prince, shows that much of the success of K. pneumoniae in hospital settings worldwide can be explained by the metabolic activities occurring in the infected host.

“We were able to show that the pathogen actually changes the metabolism of host cells and in doing so, supresses an effective immune response,” explained Dr Wong.

“By altering the host cell metabolism, K. pneumoniae is able to manipulate the nature of the immune response so that the host tolerates persistent infection, rather than trying to kill it.

These metabolic changes activated by the live bacteria led to an infection tolerance, overriding proinflammatory signals that would otherwise activate a brisk immune response.

K. pneumoniae is creating an environment where the immune system is disarmed, enabling it to run rampant,” said Dr Wong.

“We found that active K. pneumoniae stresses the host cells at a metabolic level, the same way that tumour cells scavenge nutrients in cancer patients.”

The team were inspired to apply this innovative and holistic approach, after seeing how successful it had been in cancer immunology and therapy.

“We thought we could leverage it and apply this perspective to the field of infectious diseases,” said Dr Wong.

As well as overriding the immune response, the pathogen was able to adapt when it sensed this metabolic change was occurring.

This marks the first time the metabolic changes occurring during K. pneumoniae pulmonary infection have been examined in such manner, with traditional research having focused so far on the antibiotic resistance mechanisms of the bacterium.

University of Melbourne Dr Abdou Hachani, a Senior Scientist in the groups of Professor Ben Howden and Tim Stinear at the Doherty Institute and collaborator in the study, explained that the work was also the first demonstration that K. pneumoniae deploys a mechanism called the Type Six Section system (T6SS) to survive in the harsh metabolic milieu within the host.

“To protect itself against airway oxidative stress, an antiseptic defence mechanism against dangerous bacteria, K. pneumoniae deploys the T6SS” said Dr Hachani.

“The T6SS resembles a molecular crossbow sported by bacterial pathogens. Our work shows it to be conserved in most of the K. pneumoniae strains belonging to the same lineage that causes serious illness worldwide.

The team hopes that this finding will lay the groundwork for the development of new therapeutic strategies to combat hospital-acquired infections with multidrug-resistant K. pneumoniae.

Peer review:
Funding: NHMRC, NIH