Dysregulation of stress erythropoiesis and enhanced susceptibility to Salmonella Typhimurium infection in AhR-deficient mice

• Published in: The Journal of infectious diseases 2024-06
• Main Authors: Mayer, Michelle, Cengiz-Dartenne, Sevgi Can, Thiem, Manja, Hatzfeld, Philip, Semeniuk, Adrian, Wang, Nancy, Strugnell, Richard A, Förster, Irmgard, Weighardt, Heike
• Format: Article
• Language: English
• ISSN: 1537-6613
• DOI: 10.1093/infdis/jiae304

By acting as an environmental sensor, the ligand-induced transcription factor aryl hydrocarbon receptor (AhR) regulates acute innate and adaptive immune responses against pathogens. Here, we analyzed the function of AhR in a model for chronic systemic infection with attenuated Salmonella Typhimurium (STM). WT and AhR-deficient mice were infected with the attenuated STM strain TAS2010 and analyzed for bacterial burden, host defense functions and inflammatory stress erythropoiesis. AhR-deficient mice were highly susceptible to TAS2010 infection compared with WT mice demonstrated by reduced bacterial clearance and increased mortality. STM infection resulted in macrocytic anemia and enhanced splenomegaly along with destruction of the splenic architecture in AhR-deficient mice. In addition, AhR-deficient mice displayed a major expansion of splenic immature red blood cells, indicative of infection-induced stress erythropoiesis. Elevated serum levels of erythropoietin and interleukin-6 upon infection as well as increased numbers of splenic stress erythroid progenitors already in steady state probably drive this effect and might cause the alterations in splenic immune cell compartments, thereby preventing an effective host defense against STM in AhR-deficient mice. AhR-deficient mice fail to clear chronic TAS2010 infection due to enhanced stress erythropoiesis in the spleen and accompanying destruction of the splenic architecture.