Intestinal infection was found to negatively affect the lung immune response in mice, according to authors of a study published in Open Forum Infectious Diseases. This finding further supports the existence of immunologic cross-talk in the lung-gut axis.

Given that the gastrointestinal and respiratory tracts have a common embryonic origin and that emerging data indicate cross-talk between these 2 sites in chronic inflammatory bowel disease and asthma, for example, it is important to better understand the immunologic mechanisms behind increased susceptibility to secondary respiratory infections, the authors wrote.

The investigators used mice pretreated with streptomycin, rendering them susceptible to intestinal infection with Salmonella enterica subspecies 1serovar Typhimurium (ST), which is similar to Salmonella subspecies found in the human colon. At 20 hours after streptomycin treatment, water and food were withdrawn for 4 hours, after which time some of the mice were inoculated with ST and the controls were given sterile phosphate-buffered saline. On day 6, both groups were inoculated with Klebsiella pneumoniae. A board-certified anatomic pathologist analyzed mouse lung samples in a blinded fashion.


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ST-infected mice had a survival rate of 0% to 30% at 120 hours after K pneumoniae infection compared with a 60% to 80% survival rate among mice infected without prior ST infection(P =.07). There was a significantly higher K pneumoniae bacterial burden in the lungs of mice with prior ST infection (n=19) compared with mice without prior ST infection (n=16; P =.05).

Histopathologic analysis in mice coinfected with ST and K pneumoniae revealed increased microabscess formation and marked polymorphonuclear neutrophil clustering. Additionally, lung tissue of mice infected with ST with or without coinfection with K pneumoniae exhibited microthrombi, which were absent in lung tissue of mice only infected with K pneumoniae.

When evaluating differences in cytokine production, K pneumoniae-challenged mice with prior ST infection (n=19) had higher levels of interferon-γ  and lower levels of granulocyte-macrophage colony-stimulating factor in the lungs compared with mice without prior ST infection (n=18; P <.01), but there was no significant difference in the presence of other lung defense cytokines.

Compared with mice without prior ST infection, those coinfected with ST and K pneumoniae had lower levels of lung neutrophils, which are essential for pulmonary clearance of bacterial infections like K pneumoniae. Following K pneumoniae challenge, monocyte-derived dendritic cells decreased and plasmacytoid dendritic cells increased in the lungs of mice with prior ST infection compared with mice without prior ST infection.

The study authors also found a significantly higher number of neutrophil extracellular traps in mice coinfected with ST and K pneumoniae compared with mice with K pneumoniae infection alone (P =.0006).

The investigators cited limitations of the study that included not evaluating serum levels of several cytokines and neutrophil chemokines, which would have added to their understanding of lung neutrophil trafficking after intestinal inflammation, and emphasized that this study lacked experiments to determine the mechanisms of increased lung pathology following intestinal infection.

The authors concluded that their study provides “novel findings that intestinal infection modulates neutrophil and cytokine responses in the lung, resulting in an increased susceptibility to a secondary pneumonia challenge.”

Disclosure: One study author declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 

Reference

Trivedi S, Grossmann AH, Jensen O, et al. Intestinal infection is associated with impaired lung innate immunity to secondary respiratory infection. Open Forum Infect Dis. Published online May 7, 2021. doi:10.1093/ofid/ofab237