SUMMARY Amyloid-β peptide (Aβ) fibrilization and deposition as β-amyloid are hallmarks of Alzheimer’s disease (AD) pathology. We recently reported Aβ is an innate immune protein that protects against fungal and bacterial infections. Fibrilization pathways mediate Aβ antimicrobial activities. Thus, infection can seed and dramatically accelerate β-amyloid deposition. Here, we show Aβ oligomers bind herpesvirus surface glycoproteins, accelerating β-amyloid deposition and leading to protective viral entrapment activity in 5XFAD mouse and 3D human neural cell culture infection models against neurotropic herpes simplex virus 1 (HSV1) and human herpesvirus 6A and B. Herpesviridae are linked to AD, but it has been unclear how viruses may induce β-amyloidosis in brain. These data support the notion that Aβ might play a protective role in CNS innate immunity, and suggest an AD etiological mechanism in which herpesviridae infection may directly promote Aβ amyloidosis.

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Orally administrated iron is suspected to increase susceptibility to enteric infections among children in infection endemic regions. Here we investigated the effect of dietary iron on the pathology and local immune responses in intestinal infection models. Mice were held on iron-deficient, normal-iron, or high-iron diets and after two weeks they were orally challenged with the pathogen Citrobacter rodentium. Microbiome analysis by pyrosequencing revealed profound iron- and infection-induced shifts in microbiota composition. Fecal levels of the innate defensive molecules and markers of inflammation lipocalin-2 and calprotectin were not influenced by dietary iron intervention alone, but were markedly lower in mice on the iron-deficient diet after infection. Next, mice on the iron-deficient diet tended to gain more weight and to have a lower grade of colon pathology. Furthermore, survival of the nematode Caenorhabditis elegans infected with Salmonella enterica serovar Typhimurium was prolonged after iron-deprivation. Together, these data show that iron limitation restricts disease pathology upon bacterial infection. However, our data also showed decreased intestinal inflammatory responses of mice fed on high-iron diets. Thus additionally, our study indicates that the effects of iron on processes at the intestinal host-pathogen interface may highly depend on host iron status, immune status and gut microbiota composition.

The liver hormone hepcidin is the central regulator of systemic iron metabolism. Its increased expression in inflammatory states leads to hypoferremia and anemia. Elucidation of the mechanisms that up-regulate hepcidin during inflammation is essential for developing rational therapies for this anemia. Using mouse models of inflammatory bowel disease, we have shown previously that colitis-associated hepcidin induction is influenced by intestinal microbiota composition. Here we investigate how two commensal bacteria, Bifidobacterium longum and Bacteroides fragilis, representative members of the gut microbiota, affect hepcidin expression. We found that supernatants of a human macrophage cell line infected with either of the bacteria up-regulated hepcidin when added to a human hepatocyte cell line. This activity was abrogated by neutralization of IL-1␤. Moreover, purified IL-1␤ increased hepcidin expression when added to the hepatocyte line or primary human hepatocytes and when injected into mice. IL-1␤ activated the bone morphogenetic protein (BMP) signaling pathway in hepatocytes and in mouse liver, as indicated by increased phosphorylation of small mothers against decapentaplegic proteins. Activation of BMP signaling correlated with IL-1␤-induced expression of BMP2 in human hepatocytes and activin B in mouse liver. Treatment of hepatocytes with two different chemical inhibitors of BMP signaling or with a neutralizing antibody to BMP2 prevented IL-1␤-induced up-regulation of hepcidin. Our results clarify how commensal bacteria affect hepcidin expression and reveal a novel connection between IL-1␤ and activation of BMP signaling. They also suggest that there may be differences between mice and humans with respect to the mechanism by which IL-1␤ up-regulates hepcidin.Hepcidin is a 25-amino acid peptide hormone that is secreted by the liver and functions as the key regulator of systemic iron homeostasis (1). Its expression in hepatocytes is regulated exclusively at the level of transcription and is sensitive to a number of inputs, including tissue and plasma iron concentrations. Although the exact mechanism by which tissue iron concentrations are detected is not clear, it is known that elevated hepatic iron concentrations lead to increased expression of bone morphogenetic protein 6 (BMP6) (2). BMP6 acts on the BMP 3 receptor and its co-receptor hemojuvelin on the hepatocyte surface to activate signals that lead to phosphorylation of the receptor-associated proteins small mothers against decapentaplegic (SMAD) 1, 5, and 8, which then interact with SMAD4. The complex of SMAD4 and the phosphorylated receptor-associated SMAD translocates to the nucleus, binds to specific sites in the hepcidin promoter, and increases transcription (3, 4). Circulating iron levels are sensed by a mechanism involving interactions between the type II transferrin receptor and the hemochromatosis protein HFE, both of which are expressed on the hepatocyte plasma membrane (5). Elevated plasma iron induces the two proteins to associate, leading to...