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Abstract Perinatal infection with Streptococcus agalactiae , or Group B Streptococcus (GBS), is associated with preterm birth, neonatal sepsis, and stillbirth. Here, we study the interactions of GBS with macrophages, essential sentinel immune cells that defend the gravid reproductive tract. Transcriptional analyses of GBS-macrophage co-cultures reveal enhanced expression of a gene encoding a putative metal resistance determinant, cadD . Deletion of cadD reduces GBS survival in macrophages, metal efflux, and resistance to metal toxicity. In a mouse model of ascending infection during pregnancy, the ΔcadD strain displays attenuated bacterial burden, inflammation, and cytokine production in gestational tissues. Furthermore, depletion of host macrophages alters cytokine expression and decreases GBS invasion in a cadD -dependent fashion. Our results indicate that GBS cadD plays an important role in metal detoxification, which promotes immune evasion and bacterial proliferation in the pregnant host. 

Calgranulin proteins are an important class of molecules involved in innate immunity. These members of the S100 class of the EF-hand family of calcium-binding proteins have numerous cellular and antimicrobial functions. One protein in particular, S100A12 (also called EN-RAGE or calgranulin C), is highly abundant in neutrophils during acute inflammation and has been implicated in immune regulation. Structure-function analyses reveal that S100A12 has the capacity to bind calcium, zinc, and copper, processes that contribute to nutritional immunity against invading microbial pathogens. S100A12 is a ligand for the receptor for advanced glycation end products (RAGE), toll-like receptor 4 (TLR4), and CD36, which promote cellular and immunological pathways to alter inflammation. We conducted a scoping review of the existing literature to define what is known about the association of S100A12 with digestive disease and health. Results suggest that S100A12 is implicated in gastroenteritis, necrotizing enterocolitis, gastritis, gastric cancer, Crohn’s disease, irritable bowel syndrome, inflammatory bowel disease, and digestive tract cancers. Together, these results reveal S100A12 is an important molecule broadly associated with the pathogenesis of digestive diseases. 

Chronic infection withHelicobacter pyloriincreases risk of gastric diseases including gastric cancer. Despite development of a robust immune response,H. pyloripersists in the gastric niche. Progression of gastric inflammation to serious disease outcomes is associated with infection withH. pyloristrains which encode thecagType IV Secretion System (cag T4SS). ThecagT4SS is responsible for translocating the oncogenic protein CagA into host cells and inducing pro‐inflammatory and carcinogenic signaling cascades. Our previous work demonstrated that nutrient iron modulates the activity of the T4SS and biogenesis of T4SS pili. In response toH. pyloriinfection, the host produces a variety of antimicrobial molecules, including the iron‐binding glycoprotein, lactoferrin. Our work shows that apo‐lactoferrin exerts antimicrobial activity againstH. pyloriunder iron‐limited conditions, while holo‐lactoferrin enhances bacterial growth. CulturingH. pyloriin the presence of holo‐lactoferrin prior to co‐culture with gastric epithelial cells, results in repression of thecag T4SS activity. Concomitantly, a decrease in biogenesis ofcag T4SS pili at the host‐pathogen interface was observed under these culture conditions by high‐resolution electron microscopy analyses. Taken together, these results indicate that acquisition of alternate sources of nutrient iron plays a role in regulating the pro‐inflammatory activity of a bacterial secretion system and present novel therapeutic targets for the treatment ofH. pylori‐related disease.