Conditional deletion of HIF-1α provides new insight regarding the murine response to gastrointestinal infection with Salmonella Typhimurium

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Abstract The hypoxia-inducible transcription factor 1 (HIF-1) has been shown to ameliorate different bacterial infections through enhancement of microbial killing. While the impact of HIF-1 on inflammatory diseases of the gut has been studied intensively, its function in bacterial infections of the intestine remains largely elusive. With the help of a publicly available gene expression data set, we could infer significant activation of the HIF-1 transcription factor after oral infection of mice with Salmonella Typhimurium. This prompted us to apply lineage-restricted deletion of the Hif1a locus in mice to examine cell type-specific functions of HIF-1 in this model. We show hypoxia-independent induction of HIF-1 activity upon Salmonella infection in the intestinal epithelium as well as in macrophages. Surprisingly, Hif1a deletion in intestinal epithelial cells impacted neither disease outcome nor inflammatory activity. The conditional knockout of Hif1a in myeloid cells enhanced the mRNA expression of the largely pro-inflammatory chemokine Cxcl2 , revealing a potentially inflammatory effect of HIF-1 deficiency in myeloid cells in the gut in vivo . Again, the disease outcome was not affected. In vitro HIF-1-deficient macrophages showed an overall impaired transcription of pro-inflammatory factors, however, Salmonella bypassed direct intracellular, bactericidal HIF-1-dependent mechanisms in a Salmonella pathogenicity island (SPI)-2 independent manner. Taken together, our data suggest that HIF-1 in intestinal epithelial and myeloid cells is either dispensable or compensable in the immune defense against Salmonella Typhimurium.

Authors 11

1. Laura Robrahn Aachen Department of General, Visceral and Transplantation Surgery

   RWTH Aachen University · Universitätsklinikum Aachen

   Affiliation as printed

   Department of General, Visceral and Transplantation Surgery, RWTH University Hospital, Pauwelsstraße 30, 52074 Aachen, Germany

2. Aline Dupont Aachen Institute of Medical Microbiology

   RWTH Aachen University · Universitätsklinikum Aachen

   Affiliation as printed

   Institute of Medical Microbiology, RWTH University Hospital, Pauwelsstraße 30, 52074 Aachen, Germany

3. Sandra Jumpertz Aachen Department of General, Visceral and Transplantation Surgery

   RWTH Aachen University · Universitätsklinikum Aachen

   Affiliation as printed

   Department of General, Visceral and Transplantation Surgery, RWTH University Hospital, Pauwelsstraße 30, 52074 Aachen, Germany

4. Kaiyi Zhang Aachen Institute of Medical Microbiology

   RWTH Aachen University · Universitätsklinikum Aachen

   Affiliation as printed

   Institute of Medical Microbiology, RWTH University Hospital, Pauwelsstraße 30, 52074 Aachen, Germany

5. Christian H. Holland Aachen Joint Research Center for Computational Biomedicine

   RWTH Aachen University · Universitätsklinikum Aachen · Heidelberg University · University Hospital Heidelberg

   Affiliation as printed

   Institute for Computational Biomedicine, Faculty of Medicine, Heidelberg University, and Heidelberg University Hospital, Bioquant, Heidelberg, Germany

   Joint Research Center for Computational Biomedicine, RWTH Aachen University Hospital, Aachen, Germany

6. Joël Guillaume Aachen Institute of Molecular Medicine

   RWTH Aachen University · Universitätsklinikum Aachen

   Affiliation as printed

   Institute of Molecular Medicine, RWTH University Hospital, Aachen, Germany

7. Sabrina Rappold Aachen Department of General, Visceral and Transplantation Surgery

   RWTH Aachen University · Universitätsklinikum Aachen

   Affiliation as printed

   Department of General, Visceral and Transplantation Surgery, RWTH University Hospital, Pauwelsstraße 30, 52074 Aachen, Germany

8. Vuk Cerovic Aachen Institute of Molecular Medicine

   RWTH Aachen University · Universitätsklinikum Aachen

   Affiliation as printed

   Institute of Molecular Medicine, RWTH University Hospital, Aachen, Germany

9. Julio Sáez-Rodríguez Aachen Joint Research Center for Computational Biomedicine

   RWTH Aachen University · Universitätsklinikum Aachen · Heidelberg University · University Hospital Heidelberg

   Affiliation as printed

   Institute for Computational Biomedicine, Faculty of Medicine, Heidelberg University, and Heidelberg University Hospital, Bioquant, Heidelberg, Germany

   Joint Research Center for Computational Biomedicine, RWTH Aachen University Hospital, Aachen, Germany

10. Mathias Walter Hornef corresponding Aachen Institute of Medical Microbiology

    RWTH Aachen University · Universitätsklinikum Aachen

    Affiliation as printed

    Institute of Medical Microbiology, RWTH University Hospital, Pauwelsstraße 30, 52074 Aachen, Germany

11. Thorsten Cramer corresponding Aachen Department of General, Visceral and Transplantation Surgery

    RWTH Aachen University · Universitätsklinikum Aachen · Maastricht University · Maastricht University Medical Centre

    Affiliation as printed

    Department of General, Visceral and Transplantation Surgery, RWTH University Hospital, Pauwelsstraße 30, 52074 Aachen, Germany

    Department of Surgery, Maastricht University Medical Center, Maastricht, The Netherlands

    ESCAM – European Surgery Center Aachen Maastricht, Germany and The Netherlands

    NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands