Control of Systemic Pathogen Dissemination by Nutritional Immunity

Seminar Details
Wednesday, April 5, 2017 - 9:00am to 10:00am


Kei Sakamoto, M.D., Ph.D.
Research Fellow - Nunez Lab
Department of Pathology


5623 Med. Sci. II  (Wheeler Seminar Room)

Iron is an essential nutrient for multicellular organisms and nearly all microorganisms including pathogenic bacteria. In mammals, the majority of iron is found in erythrocytes where is bound to heme moieties in hemoglobin. Given the strict requirement for iron by practically all pathogenic bacteria, the host immune system has developed several strategies to limit iron availability to bacteria. However, the mechanisms by which the immune system limits the availability of heme, the major source of iron in the body, to restrict bacterial growth in vivo remain unclear. We report here that interleukin-22 (IL-22), a cytokine that promotes early host defense and epithelial barrier function at mucosal surfaces, suppresses the systemic growth of the enteric pathogen Citrobacter rodentium and Escherichia coli, a major cause of bacteremia and sepsis in humans. Using an unbiased proteomic approach, we found that upon infection IL-22 induces the production in plasma of hemopexin and haptoglobin that bind with high affinity to heme and hemoglobin, respectively. In contrast, α- and β-globin and heme release triggered by infection was enhanced in the absence of IL-22. Erythrocyte lysis resulting in heme release required EspB, a type III secretion system translocator protein that can pores in the eukaryotic cell membrane. Biochemical and functional analyses revealed that the ability of IL-22 to limit bacterial growth required hemopexin, but haptoglobin was dispensable. The impairment of Il22-/- mice to control pathogen growth in vivo was rescued by hemopexin administration. Moreover, deficiency in hemopexin, but not haptoglobin, was associated with increased pathogen loads in vivo. These studies reveal a previously unrecognized host defense mechanism regulated by IL-22 in which hemopexin scavengers heme limiting iron availability to bacteria during systemic infection.

Sponsored by the Host Microbiome Initiative