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

Abstract

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.

Lactoferrin: A glycoprotein that plays an active role in human health

“…A study of 48 term and preterm infants found that the number of fecal bifidobacteria and lactobacilli correlates significantly with fecal Lf concentrations 3 days after delivery, suggesting that Lf may promote the growth of beneficial intestinal microbiota ( 52 ). Although Lf inhibits the growth of harmful bacteria, some researchers have found large amounts of Lf in the resected stomachs of patients with gastritis, speculating that H. pylori takes up iron through specific Lf receptors, and more importantly, Lf may play a major role in the virulent effects of H. pylori infection ( 53 ).…”

Antibiofilm Activity of Human Milk Oligosaccharides against Multidrug Resistant and Susceptible Isolates of Acinetobacter baumannii

“…29−36 Human milk harbors a variety of antimicrobial molecules that can inhibit the growth and viability of a variety of pathogenic microbes as well as immune-modulating molecules that influence inflammation responses to invading pathogens. 34 Our recent work and the work of others has demonstrated that the human milk glycoprotein lactoferrin has antimicrobial and antibiofilm activities against A. baumannii and other bacteria, including S. agalactiae, S. aureus, and Pseudomonas aeruginosa. 35−39 In addition to the proteinaceous components of milk, the human milk glycome is also of particular interest, as components within this population of molecules have been associated with strong protection against infection by enteric pathogens.…”

“…The utility of human milk as a prebiotic that can protect against a variety of infections has been well demonstrated in the literature. ,, Infants whose primary source of nutrition, which is derived from human breast milk, have enhanced protection against diarrhea, respiratory infection, urinary tract infection, ear infection, necrotizing enterocolitis (NEC), and specifically, infection with Escherichia coli , Clostridioides difficile , and Campylobacter jejuni . − Human milk harbors a variety of antimicrobial molecules that can inhibit the growth and viability of a variety of pathogenic microbes as well as immune-modulating molecules that influence inflammation responses to invading pathogens . Our recent work and the work of others has demonstrated that the human milk glycoprotein lactoferrin has antimicrobial and antibiofilm activities against A. baumannii and other bacteria, including S. agalactiae , S. aureus , and Pseudomonas aeruginosa . − In addition to the proteinaceous components of milk, the human milk glycome is also of particular interest, as components within this population of molecules have been associated with strong protection against infection by enteric pathogens …”

Antimicrobial Effects of Lactoferrin against Helicobacter pylori Infection

“…Lu et al's subsequent report showed that the increased levels of LF in gastric tissue were caused by H. pylori colonization, as demonstrated by the Mongolian gerbil's model [48]. The Mongolian gerbil is a rodent model that recapitulates many features of H. pyloriinduced gastric disease in humans [49].…”