The Innate Immune Glycoprotein Lactoferrin Represses the Helicobacter pylori cag Type IV Secretion System

• Published in: Chembiochem : a European journal of chemical biology 2021-09, Vol.22 (18), p.2783-2790
• Main Authors: Lu, Jacky, Haley, Kathryn P., Francis, Jamisha D., Guevara, Miriam A., Doster, Ryan S., Craft, Kelly M., Moore, Rebecca E., Chambers, Schuyler A., Delgado, Alberto G., Piazuelo, Maria Blanca, Damo, Steven M., Townsend, Steven D., Gaddy, Jennifer A.
• Format: Article
• Language: English
• Subjects: Animals; Antiinfectives and antibacterials; antimicrobial; Antimicrobial activity; Antimicrobial agents; bacterial pathogenesis; Biosynthesis; Carcinogens; Cell culture; Chronic infection; Disease Models, Animal; Electron microscopy; Epithelial cells; Epithelial Cells - cytology; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelium; Gastric cancer; Gastric Mucosa - cytology; Gastric Mucosa - metabolism; Gerbillinae; glycobiology; Glycoproteins; Helicobacter Infections - drug therapy; Helicobacter Infections - microbiology; Helicobacter pylori; Helicobacter pylori - drug effects; Helicobacter pylori - metabolism; host-pathogen interactions; Immune response; Immune system; Immunity, Innate; Infections; Inflammation; innate immunity; Interleukin-8 - metabolism; Iron; Iron - metabolism; iron homeostasis; Lactoferrin; Lactoferrin - chemistry; Lactoferrin - metabolism; Lactoferrin - pharmacology; Lactoferrin - therapeutic use; Nutrient sources; Pili; Protein Isoforms - chemistry; Protein Isoforms - metabolism; Protein Isoforms - pharmacology; Protein Isoforms - therapeutic use; toxin secretion; Trinucleotide repeats; Type IV Secretion Systems - antagonists & inhibitors; Type IV Secretion Systems - metabolism; virulence
• ISSN: 1439-4227; 1439-7633
• DOI: 10.1002/cbic.202100249

Chronic infection with Helicobacter pylori increases risk of gastric diseases including gastric cancer. Despite development of a robust immune response, H. pylori persists in the gastric niche. Progression of gastric inflammation to serious disease outcomes is associated with infection with H. pylori strains which encode the cag Type IV Secretion System (cag T4SS). The cag T4SS 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 to H. pylori infection, the host produces a variety of antimicrobial molecules, including the iron‐binding glycoprotein, lactoferrin. Our work shows that apo‐lactoferrin exerts antimicrobial activity against H. pylori under iron‐limited conditions, while holo‐lactoferrin enhances bacterial growth. Culturing H. pylori in the presence of holo‐lactoferrin prior to co‐culture with gastric epithelial cells, results in repression of the cag T4SS activity. Concomitantly, a decrease in biogenesis of cag 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 of H. pylori‐related disease. Helicobacter pylori infection results in enhanced host production of lactoferrin which participates in nutritional immunity and can also serve as a source of nutrient iron for this pathogen, which can repress a major oncogenic virulence factor, the cag T4SS.