Abstract
Pneumonia and diarrhea are among the leading causes of death worldwide, and epidemiological studies have demonstrated that diarrhea is associated with an increased risk of subsequent pneumonia. Our aim was to determine the impact of intestinal infection on innate immune responses in the lung. Using a mouse model of intestinal infection by Salmonella enterica serovar Typhimurium (S. Typhimurium), we investigated how infection in the gut compartment can modulate immunity in the lungs and impact susceptibility to bacterial (Klebsiella pneumoniae) challenge. We found alterations in frequencies of innate immune cells in lungs of intestinally-infected mice compared to uninfected mice. On subsequent challenge with K. pneumoniae we found that mice with prior intestinal infection have higher lung bacterial burden and inflammation, increased neutrophil margination, and neutrophil extracellular traps (NETs), but lower overall numbers of neutrophils, compared to mice without prior intestinal infection. Together, these results suggest that intestinal infection impacts lung innate immune responses, most notably neutrophil characteristics, potentially resulting in increased susceptibility to secondary pneumonia.
Author summary Infections of the lung and gut are among the leading causes of death worldwide. Human studies have shown that children with diarrhea are at higher risk of subsequent lung infection. How intestinal infections impact lung immunity is not well known. In the present study, we reveal that bacterial infection of the intestinal mucosa may compromise lung immunity, offering new insights into increased susceptibility to respiratory infections. We found that upon respiratory infection, mice with prior intestinal infection are more moribund and despite having higher bacterial burden, they show reduced numbers of neutrophils in the lung compared to mice without prior intestinal infection. We also found excessive neutrophil extracellular traps formation in the lungs of mice with prior intestinal infection, providing evidence of increased pulmonary tissue damage. Collectively, these data identify a direct link between pulmonary and enteric infection and suggests gut infections impair neutrophils responses in the lungs.
Competing Interest Statement
The authors have declared no competing interest.
