Antimicrobial therapy can prevent sepsis in pneumonia patients

Antimicrobial therapy that targets specific cells in the immune system could prevent sepsis and life-threatening disease in people with pneumonia, new research by Nottingham and Leicester scientists has shown.

Pneumonia is one of the leading causes of mortality by infectious disease and is more common in certain at-risk groups of people, such as the very young or the elderly.

This new discovery has identified how the bacterium that causes pneumonia replicates within our immune system during the initial stages of infection. Antimicrobial therapy kills or inhibits the growth of bacteria so the research could lead to better prevention of life-threatening infections like pneumococcal septicaemia. The research is published in Nature Microbiology.

The team of scientists from the University of Leicester’s Department of Genetics and Genome Biology worked with immunologist Dr Luisa Martinez-Pomares from the University of Nottingham’s School of Life Sciences.

They found that shortly after initial infection, the bacterium Streptococus pneumoniae (pneumococcus) replicates within a certain subset of immune cells in our bodies - a subset of splenic macrophages - before causing invasive and often fatal disease. This intracellular replication protects the bacterium from being killed by other immune cells and also from the activity of the most commonly used antibiotics, including those recommended for community acquired pneumonia in the UK.

The research also shows that antimicrobial therapy, specifically targeted to abort this phase of intracellular replication, can prevent the occurrence of pneumococcal septicaemia, which is common in many patients suffering from pneumonia.

Dr Martinez-Pomares said: “Having previously identified the spleen as a ‘hideout’ for the important pathogen Streptococcus pneumoniae, our group set to identify where within this organ the bacteria was located.

“Macrophages are immune cells essential for the fight against infection but, unwittingly, they can provide a safe environment for pathogens to evade killing. We observed S. pneumoniae replicating within a subset of splenic macrophages called ‘metallophilic macrophages’ in two different organisms. Based on these observations it appears that metallophilic macrophages, which are normally involved in promoting immunity, might represent the weak link in the fight against pneumococcal infection. Excitingly these results have important implications for the treatment of pneumococcal disease as antimicrobials targeting intracellular bacteria proved effective in preventing pneumococcal septicaemia.”

Leading the work, Professor Marco Oggioni from the University of Leicester and Leicester Hospitals, said: “Understanding infections is important in determining how best to treat an infection. Our work shows that we can treat potentially deadly infections more effectively using antibiotics that are already available.

“By discovering the mechanism of how and where bacteria initiate disease, we think we can give a strong message to the medical community to stimulate the revision of currently used therapies and this could potentially result in a reduction of disease burden and mortality in the UK and elsewhere.”

The team conducted its experiments on a variety of different organisms using confocal microscopy. This allowed them to tag and visualise different immune cells as well as the infecting bacteria.

As part of this work the team also developed a new model using the surplus spleens of pigs processed for food production.

This allowed for them to study infection in a model highly related to humans but without the need to infect a living animal.

The research, which was funded as part of a collaboration with the University of Oxford, involved Professor Peter Andrew from the University of Leicester’s Department of Infection, Immunity and Inflammation and Professor Chris Bayliss from the University of Leicester’s Department of Genetics and Genome Biology, the hepatobiliary and pancreatic surgeon Ashley Dennison from Leicester’s Hospitals, the immunologist Luisa Martinez-Pomares from the University of Nottingham and the expert in bacterial pathogenesis Richard Moxon from the University of Oxford.

The study was funded through a Medical Research Council grant: MR/M003078/1.

The paper, ‘’Intracellular replication of Streptococcus pneumoniae inside splenic macrophages serves as a reservoir for septicaemia’ will be published in the journal Nature Microbiology and is available here.