Intestinal infection results in impaired lung innate immunity to secondary respiratory infection

Shubhanshi Trivedi, Allie H. Grossmann, Owen Jensen, Mark J. Cody, Kristi J. Warren, Christian C. Yost, Daniel T. Leung

Preprint posted on 4 August 2020

Article now published in Open Forum Infectious Diseases at

Double trouble: Prior intestinal infection worsens subsequent lung infection

Selected by Josie Gibson

Categories: immunology, microbiology


Diarrhoea and pneumonia are associated infections, where diarrhoea is linked to increased likelihood of pneumonia. These types of connected infections have high mortality rates; over a million deaths are caused by linked gut and lung infections in children worldwide. The mechanism by which prior diarrhoea increases the risk of subsequent lung infection is unknown. The aim of this study is to examine how intestinal infection may alter immune responses in the lung. This is done using sequential murine infections, where the impact of a prior gut infection (using Salmonella enterica serovar Typhimurium (S. Typhimurium)), is assessed in a subsequent lung infection (using Klebsiella pneumoniae).

Key findings:

The key finding of this study is that a prior gut infection with S. Typhimurium leads to increased susceptibility to K. pneumoniae infection in the lung, and that this is associated with altered neutrophil immune responses.

The first results show that following initial intestinal infection with S. Typhimurium, mice had increased susceptibility to lung infection with K. pneumoniae, specifically higher bacterial burden, worse sickness, and higher mortality. Lung inflammation was next examined histologically. In dual infected mice a higher inflammatory response was observed, with neutrophils recruited, but also higher levels of damaged and necrotic neutrophils, as well as bacterial microabscess formation. The authors also observed lung cytokine alterations, mice infected with S. Typhimurium alone had higher levels of some pro-inflammatory cytokines, indicating that gut infection was altering the lung cytokine profile. Furthermore, mice with prior gut infection and K. pneumoniae infection, had higher levels of pro-inflammatory IFN-γ in the lung. The authors next determined that mice with both gut and lung infections had reduced neutrophil recruitment, but higher (plasmacytoid) dendritic cell counts at the lung infection site compared to mice with lung infections only. This indicates that intestinal infection changes cytokine profiles and immune cell numbers at a distal site in the lung.

Finally, neutrophil extracellular traps (NETs) were examined due to their known role in tissue damage. NETs were observed much more frequently in the lungs of dual S. Typhimurium and K. pneumoniae infected mice. The authors suggest that these NETs may be a cause of tissue damage leading to lung infection susceptibility, and that the higher levels of IFN-γ in the dual infected mice lungs (described above) may promote NET formation.

Why I chose this Preprint:

I selected this preprint because I think it is fascinating that a secondary infection can be affected by a prior infection at a separate and distant site in the host. This paper furthers our understanding of how the immune system can be altered at multiple sites in the host, resulting in susceptibility to separate infections. The authors show how prior intestinal infection affects lung immune responses, highlighting neutrophil dysfunction, which may be responsible for an increased likelihood of secondary pneumonia.

Questions to the authors:

  1. The study determines a key role of neutrophil dysfunction in the lung after an initial gut infection. Have you examined whether the association of lung and gut infections is lost in mice deficient in neutrophils?
  2. You identified neutrophils, IFN-γ and NETs to be involved in the link between gut infection and lung susceptibility to infection. Do you think targeting these may be useful as a prophylactic treatment following diarrhoea to prevent lung infection?



Posted on: 30 September 2020 , updated on: 25 March 2021


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Author's response

Daniel Leung shared

Answer 1: The next step to look into this is to look at mice that are depleted of neutrophils. We believe that in secondary infections, neutrophil response and NET production requires a fine balance: underactivity can lead to risk for increased pathogen replication and invasion, whereas over-activity can result in excessive inflammation and tissue damage.

Answer 2: Yes, our work suggests that treatments, or biomarkers, associated with these factors have the potential to have clinical relevance in the management of infectious diarrhoea. However, translation to therapeutics is still far away and much more research is needed in understanding these mechanisms.

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