Innate Nutritional Immunity

Abstract

Iron (Fe) is an essential micronutrient for both microbes and their hosts. The biologic importance of Fe derives from its inherent ability to act as a universal redox catalyst, co-opted in a variety of biochemical processes critical to maintain life. Animals evolved several mechanisms to retain and limit Fe availability to pathogenic microbes, a resistance mechanism termed "nutritional immunity." Likewise, pathogenic microbes coevolved to deploy diverse and efficient mechanisms to acquire Fe from their hosts and in doing so overcome nutritional immunity. In this review, we discuss how the innate immune system regulates Fe metabolism to withhold Fe from pathogenic microbes and how strategies used by pathogens to acquire Fe circumvent these resistance mechanisms.

Figure 1. Microbial manipulation of heme-Fe metabolism

EM are generated via a lineage-specific genetic program controlled by the heme-responsive transcription factor SPI-C (100, 101). SPI-C regulates the expression of several effector genes coupling RBC sensing and engulfment with the breakdown of Hb and other RBC components, while sparing heme, which is transported to the cytosol by HRG1 (101, 102). Heme is degraded by heme oxygenase-1 (HMOX1/HO-1), an inducible heme catabolizing enzyme constitutively expressed by EM (15). This allows for Fe extraction from heme and Fe transport via the cellular Fe exporter solute carrier family 40 member 1 (SLC40A1/ferroportin) (–105). Once secreted, Fe is captured in plasma by transferrin (TF) and delivered via the transferrin receptor-1 (TFR), to erythroblasts in the bone marrow, where Fe is used in the last step of heme biosynthesis and incorporated into nascent Hb (15). Pathogenic microbes evolved several mechanisms that subvert these regulatory mechanisms of Fe metabolism. They can for example invade EM to access their heme-Fe content, use siderophores to capture Fe from plasma, acquire Fe bound to TF via microbial transferrin receptors (mTFR), or access heme-Fe by invading RBC. Pathogens can also lyse RBC via hemolysins to access their heme-Fe, or acquire Fe from extracellular Hb or from heme, using microbial Hb and heme receptors, respectively.

Figure 2. Heme-based nutritional immunity

Microbial sensing via PRRs (PRR), expressed by innate immune cells triggers the secretion of cytokines such as IL-6 or IL-22, which induce the expression of haptoglobin (HP) or hemopexin (HPX) in the liver. Haptoglobin is an acute phase glycoprotein which display high affinity for Hb dimers (K_D≈10⁻¹²M) (–108) and prevents heme release from Hb dimers (109, 110). HPX is also an acute phase glycoprotein, which displays high affinity for heme (K_D<10⁻¹²M). Albumin, the most abundant heme binding protein in the plasma displays affinity towards heme (K_D<10⁻⁸ M) (111) and is thought to play a key role in heme scavenging, transferring labile heme in plasma to HPX (112). While HPX was thought to act essentially to prevent the pathogenic effects of labile heme (79) it also acts as a host defense strategy against invasion by pathogenic and commensal bacteria (81). Hb-haptoglobin complexes are recognized by CD163 expressed in macrophages while HPX-heme complex are recognized by the low-density lipoprotein receptor-related protein (LRP)/CD91 expressed in macrophages but also in hepatocytes (113). Upon binding to CD163, Hb-haptoglobin complexes undergo endocytosis and are targeted for lysosomal proteolysis, a process coupled to heme transport into the cytosol, and subsequent targeting of heme for catabolism by HO-1. Upon recognition by CD91 in hepatocytes, hemopexin-heme complexes undergo endocytosis (113) and HPX is recycled, while heme is catabolized by HO-1 (113). In both cases, the Fe released via heme catabolism by HO-1 is stored by ferritin, away from microbial pathogens. While RBC lysis by microbial bacteria is thought to act essentially as a Fe-acquisition strategy (6), labile heme generated through this process can disrupt the cytoskeleton dynamics of innate immune cells impairing bacterial phagocytosis via a mechanism involving dedicator of cytokinesis 8 (DOCK8) (114). Similar mechanisms are likely to operate in the context of malaria to impair Plasmodium-infected RBC clearance

Figure 3. Integration of nutritional immunity as an innate resistance mechanism

Pathogen sensing via PRR signaling (S₁) activates the expression of effector genes conferring resistance to pathogens. These encode molecules (E₁) such as NOX2 and NOS2 that induce intrinsic microbicidal activity via ROS and RNS (A), as well as molecules (E₂) withholding heme-Fe from pathogens, such as ferroportin (15) (B). ROS and RNS can regulate ferroportin and nutritional immunity via activation of the transcription factor Nrf2 (E₃) to optimize resistance to infections (C).