<i>Salmonella</i> effector SpvB interferes with intracellular iron homeostasis <i>via</i> regulation of transcription factor NRF2

Abstract

Iron is a necessary nutrient for humans and nearly all bacterial species. During <i>Salmonella</i> infection, macrophages limit the availability of iron to intracellular pathogens in one of the central components of nutritional immunity. However, <i>Salmonella</i> also have mechanisms to interfere with the antimicrobial effect of host iron withdrawal and meet their own nutrient requirements by scavenging iron from the host. Here, we provide what is, to our knowledge, the first report that SpvB, a pSLT-encoded cytotoxic protein whose function is associated with the intracellular stage of salmonellosis, perturbs macrophage iron metabolism, thereby facilitating <i>Salmonella</i> survival and intracellular replication. In investigating the underlying mechanism, we observed that the <i>Salmonella</i> effector SpvB down-regulated nuclear factor erythroid-derived 2-related factor 2 (NRF2), and its C-terminal domain was necessary and sufficient for NRF2 degradation <i>via</i> the proteasome pathway. Decreased NRF2 expression in the nucleus resulted in a decrease in its transcriptional target ferroportin, encoding the sole macrophage iron exporter, thus ultimately decreasing iron efflux and increasing the intracellular iron content. Additionally, SpvB contributes to the pathogenesis of <i>Salmonella</i> including severe serum hypoferremia, increased splenic and hepatic bacterial burden, and inflammatory injury <i>in vivo</i>. Together, our observations uncovered a novel contribution of SpvB to <i>Salmonella</i> pathology <i>via</i> interference with host intracellular iron metabolism.-Yang, S., Deng, Q., Sun, L., Dong, K., Li, Y., Wu, S., Huang, R. <i>Salmonella</i> effector SpvB interferes with intracellular iron homeostasis <i>via</i> regulation of transcription factor NRF2.