Variants in Autophagy Genes Affect Susceptibility to Both Crohn's Disease and Helicobacter pylori Infection

Abstract

See “Vacuolating cytotoxin and variants in Atg16L1 that disrupt autophagy promote Helicobacter pylori infection in humans” by Raju D, Hussey S, Ang M, et al, on page 1160.Helicobacter pylori (H pylori) is a Gram-negative, microaerophilic bacterium that selectively colonizes the stomachs of half the world's human population. H pylori is the etiologic agent of several gastric diseases, including chronic gastritis and peptic ulcers. Long-term, chronic inflammation subsequently increases the risk for the development of mucosa-associated lymphoid tissue lymphoma and gastric cancer.1Peek R.M. Fiske C. Wilson K.T. Role of innate immunity in Helicobacter pylori-induced gastric malignancy.Physiol Rev. 2010; 90: 831-858Crossref PubMed Scopus (168) Google Scholar, 2Marshall B.J. Warren J.R. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration.Lancet. 1984; 1: 1311-1315Abstract PubMed Scopus (4167) Google Scholar During a well-choreographed interaction between the bacteria and the host gastric epithelium, H pylori infection initiates an immune response that leads to a massive infiltration of inflammatory cells.1Peek R.M. Fiske C. Wilson K.T. Role of innate immunity in Helicobacter pylori-induced gastric malignancy.Physiol Rev. 2010; 90: 831-858Crossref PubMed Scopus (168) Google Scholar An evolutionarily conserved cellular mechanism, autophagy, functions as an innate defense lysosomal pathway in response to infection to degrade intracellular micro-organisms attempting to establish a replicative niche in the host epithelial cell cytoplasm.3Terebiznik M.R. Raju D. Vázquez C.L. et al.Effect of Helicobacter pylori's vacuolating cytotoxin on the autophagy pathway in gastric epithelial cells.Autophagy. 2009; 5: 370-379Crossref PubMed Scopus (158) Google Scholar Unfortunately, H pylori utilizes a novel escape mechanism to evade lysosomal destruction in host epithelial cells that subsequently supports chronic infection. A study in this month's issue of Gastroenterology identifies, for the first time, an autophagy gene as a candidate for host susceptibility to H pylori infection and disease progression.4Raju D. Hussey S. Ang M. et al.Vacuolating cytotoxin and variants in Atg16l1 that disrupt autophagy promote Helicobacter pylori infection in humans.Gastroenterology. 2012; 142: 1160-1171Abstract Full Text Full Text PDF PubMed Scopus (151) Google ScholarThe H pylori–Vacuolating CytotoxinVacuolating cytotoxin (VacA) is an important virulence factor for H pylori disease pathogenesis. The VacA gene encodes a 96-kDa precursor protein that is secreted and cleaved into an 88-kDa mature protein and a 10.5-kDa passenger domain.1Peek R.M. Fiske C. Wilson K.T. Role of innate immunity in Helicobacter pylori-induced gastric malignancy.Physiol Rev. 2010; 90: 831-858Crossref PubMed Scopus (168) Google Scholar The mature 88-kDa toxin can undergo further proteolytic cleavage to yield the p33 and p50 fragments which represent the VacA functional domains that are required for toxin activity.5Telford J.L. Ghiara P. Dell'Orco M. et al.Gene structure of the Helicobacter pylori cytotoxin and evidence of its key role in gastric disease.J Exp Med. 1994; 179: 1653-1658Crossref PubMed Scopus (520) Google Scholar The most well recognized effect of VacA intoxication of mammalian cells is the induction of vacuolation.6Cover T.L. Krishna U.S. Israel D.A. et al.Induction of gastric epithelial cell apoptosis by Helicobacter pylori vacuolating cytotoxin.Cancer Res. 2003; 63: 951-957PubMed Google Scholar The toxin generates the formation of membrane channels by being secreted as monomers that oligomerize at the host plasma membrane.6Cover T.L. Krishna U.S. Israel D.A. et al.Induction of gastric epithelial cell apoptosis by Helicobacter pylori vacuolating cytotoxin.Cancer Res. 2003; 63: 951-957PubMed Google Scholar Glycosylphosphatidylinositol anchored proteins enriched early endosomal compartments are involved in endocytosis of VacA.7Gauthier N.C. Monzo P. Gonzalez T. et al.Early endosomes associated with dynamic F-actin structures are required for late trafficking of H. pylori VacA toxin.J Cell Biol. 2007; 177: 343-354Crossref PubMed Scopus (76) Google Scholar VacA then traffics to lysosomal compartments where the toxin induces vacuolation via a mechanism dependent on GTPase Rab7,8Papini E. Satin B. Norais N. et al.Selective increase of the permeability of polarized epithelial cell monolayers by Helicobacter pylori vacuolating toxin.J Clin Invest. 1998; 102: 813-820Crossref PubMed Scopus (211) Google Scholar, 9Terebiznik M.R. Vazquez C.L. Torbicki K. et al.Helicobacter pylori VacA toxin promotes bacterial intracellular survival in gastric epithelial cells.Infect Immun. 2006; 74: 6599-65614Crossref PubMed Scopus (87) Google Scholar dynamin,10Suzuki J. Ohnsihi H. Shibata H. et al.Dynamin is involved in human epithelial cell vacuolation caused by the Helicobacter pylori-produced cytotoxin VacA.J Clin Invest. 2001; 107: 363-370Crossref PubMed Scopus (42) Google Scholar and syntaxin 7.11Suzuki J. Ohnishi H. Wada A. et al.Involvement of syntaxin 7 in human gastric epithelial cell vacuolation induced by the Helicobacter pylori-produced cytotoxin VacA.J Biol Chem. 2003; 278: 25585-25590Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar In addition to vacuolation, VacA intoxication has detrimental effects that include inhibition of T-cell proliferation12Wang Y.H. Gorvel J.P. Chu Y.T. et al.Helicobacter pylori impairs murine dendritic cell responses to infection.PLoS One. 2010; 5: e10844Crossref PubMed Scopus (66) Google Scholar and the induction of apoptosis,6Cover T.L. Krishna U.S. Israel D.A. et al.Induction of gastric epithelial cell apoptosis by Helicobacter pylori vacuolating cytotoxin.Cancer Res. 2003; 63: 951-957PubMed Google Scholar increased cellular permeability,8Papini E. Satin B. Norais N. et al.Selective increase of the permeability of polarized epithelial cell monolayers by Helicobacter pylori vacuolating toxin.J Clin Invest. 1998; 102: 813-820Crossref PubMed Scopus (211) Google Scholar and autophagy within gastric epithelial cells.3Terebiznik M.R. Raju D. Vázquez C.L. et al.Effect of Helicobacter pylori's vacuolating cytotoxin on the autophagy pathway in gastric epithelial cells.Autophagy. 2009; 5: 370-379Crossref PubMed Scopus (158) Google Scholar, 9Terebiznik M.R. Vazquez C.L. Torbicki K. et al.Helicobacter pylori VacA toxin promotes bacterial intracellular survival in gastric epithelial cells.Infect Immun. 2006; 74: 6599-65614Crossref PubMed Scopus (87) Google Scholar Initial studies demonstrated that H pylori invades gastric epithelial cells and resides within vacuoles.13Amieva M.R. Salama N.R. Tompkins L.S. et al.Helicobacter pylori enter and survive within multivesicular vacuoles of epithelial cells.Cell Microbiol. 2002; 4: 677-690Crossref PubMed Scopus (163) Google Scholar Later experiments then showed that these vacuoles were associated with the autophagy pathway and attributed to bacterial intracellular survival of H pylori within gastric epithelial cells.3Terebiznik M.R. Raju D. Vázquez C.L. et al.Effect of Helicobacter pylori's vacuolating cytotoxin on the autophagy pathway in gastric epithelial cells.Autophagy. 2009; 5: 370-379Crossref PubMed Scopus (158) Google Scholar, 9Terebiznik M.R. Vazquez C.L. Torbicki K. et al.Helicobacter pylori VacA toxin promotes bacterial intracellular survival in gastric epithelial cells.Infect Immun. 2006; 74: 6599-65614Crossref PubMed Scopus (87) Google ScholarAutophagy in Response to H pylori VacA and Persistent Bacterial InfectionIn recent years, autophagy has been recognized as being of central importance for the maintenance of cell homeostasis and survival but also for the regulation of inflammation and for bacterial defense at body surfaces.14Sokollik C. Ang M. Jones N. Autophagy: a primer for the gastroenterologist/hepatologist.Can J Gastroenterol. 2011; 25: 667-674Crossref PubMed Scopus (11) Google Scholar Although H pylori is generally considered to be a noninvasive pathogen, emerging evidence demonstrates that the bacteria also invade and replicate within autophagasomes of macrophages, dendritic, and epithelial cells.3Terebiznik M.R. Raju D. Vázquez C.L. et al.Effect of Helicobacter pylori's vacuolating cytotoxin on the autophagy pathway in gastric epithelial cells.Autophagy. 2009; 5: 370-379Crossref PubMed Scopus (158) Google Scholar, 9Terebiznik M.R. Vazquez C.L. Torbicki K. et al.Helicobacter pylori VacA toxin promotes bacterial intracellular survival in gastric epithelial cells.Infect Immun. 2006; 74: 6599-65614Crossref PubMed Scopus (87) Google Scholar, 12Wang Y.H. Gorvel J.P. Chu Y.T. et al.Helicobacter pylori impairs murine dendritic cell responses to infection.PLoS One. 2010; 5: e10844Crossref PubMed Scopus (66) Google Scholar, 15Wang Y.H. Wu J.J. Lei H.Y. The autophagic induction in Helicobacter pylori-infected macrophage.Exp Biol Med (Maywood). 2009; 234: 171-180Crossref PubMed Scopus (77) Google Scholar In view of the observation that H pylori infection induces autophagy within epithelial cells,3Terebiznik M.R. Raju D. Vázquez C.L. et al.Effect of Helicobacter pylori's vacuolating cytotoxin on the autophagy pathway in gastric epithelial cells.Autophagy. 2009; 5: 370-379Crossref PubMed Scopus (158) Google Scholar, 9Terebiznik M.R. Vazquez C.L. Torbicki K. et al.Helicobacter pylori VacA toxin promotes bacterial intracellular survival in gastric epithelial cells.Infect Immun. 2006; 74: 6599-65614Crossref PubMed Scopus (87) Google Scholar the question then remains as to how H pylori are allowed to replicate within the autophagasome and evade lysosomal-induced degradation.Raju et al4Raju D. Hussey S. Ang M. et al.Vacuolating cytotoxin and variants in Atg16l1 that disrupt autophagy promote Helicobacter pylori infection in humans.Gastroenterology. 2012; 142: 1160-1171Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar recently reinforced that VacA, independent of the bacteria, alters the degradative capacity of the endocytic pathway. Using gastric cancer epithelial AGS cells treated with culture supernatants from VacA-positive H pylori the investigators show that although VacA intoxication induces autophagasome–lysosomal fusion cathepsin D levels were negligible.4Raju D. Hussey S. Ang M. et al.Vacuolating cytotoxin and variants in Atg16l1 that disrupt autophagy promote Helicobacter pylori infection in humans.Gastroenterology. 2012; 142: 1160-1171Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar Cathepsin D is a key hydrolase necessary for lysosomal-induced degradation. Therefore, lack of cathepsin D alternately disrupts autophagic degradative process and thus offers a plausible mechanism by which H pylori replicate within autophagasomes.The investigators then extended the in vitro findings by studying the status of autophagy within human gastric biopsies collected from patients infected with H pylori. The signaling adaptor p62 is a multidomain protein implicated in the activation of the transcription factor nuclear factor-κB, apoptosis, and autophagy. Dysfunctional autophagy leads to an accumulation of p62 that contributes directly to tumorigenesis.16Mathew R. Karp C.M. Beaudoin B. et al.Autophagy suppresses tumorigenesis through elimination of p62.Cell. 2009; 137: 1062-1075Abstract Full Text Full Text PDF PubMed Scopus (1339) Google Scholar Indeed, gastric tissue sections collected from patients infected with the toxigenic s1m1 VacA-producing H pylori strain showed increased accumulation of p62 expression in the foveolar cells of the gastric epithelium.4Raju D. Hussey S. Ang M. et al.Vacuolating cytotoxin and variants in Atg16l1 that disrupt autophagy promote Helicobacter pylori infection in humans.Gastroenterology. 2012; 142: 1160-1171Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar However, the most interesting discovery that was made by Raju et al4Raju D. Hussey S. Ang M. et al.Vacuolating cytotoxin and variants in Atg16l1 that disrupt autophagy promote Helicobacter pylori infection in humans.Gastroenterology. 2012; 142: 1160-1171Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar was that H pylori infection was increased in individuals harboring a polymorphism in the ATG16L1 autophagy gene.The Crohn's Variant of ATG16L1 as It Relates to H pylori SusceptibilityIn autophagasomes, structures that need to be eliminated are sequestered into double membrane-enclosed vesicles and delivered to lysosomes for final degradation. Autophagasome assembly involves activation of beclin-1 and conjugation of ATG12-ATG5 that is catalyzed by ATG7 and ATG10.17Deretic V. Autophagy in immunity and cell-autonomous defense against intracellular microbes.Immunol Rev. 2011; 240: 92-104Crossref PubMed Scopus (295) Google Scholar The resulting ATG5–ATG12 conjugate is stabilized by a noncovalent complex with ATG16L1 that mediates, in addition to ATG7 and ATG3, the conversion of LC3B-I to LC3B-II by lipidation with phosphatidylethanolamine.17Deretic V. Autophagy in immunity and cell-autonomous defense against intracellular microbes.Immunol Rev. 2011; 240: 92-104Crossref PubMed Scopus (295) Google Scholar Interestingly, a variant of the ATG16L1 gene (rs2241880, causing amino acid substitution T300A) has been associated with the risk of developing Crohn's disease.18Baldassano R. Bradfield J.P. Monos D.S. et al.Association of the T300A non-synonymous variant of the ATG16L1 gene with susceptibility to paediatric Crohn's disease.Gut. 2007; 56: 1171-1173Crossref PubMed Scopus (55) Google Scholar, 19Prescott N.J. Fisher S.A. Franke A. et al.A nonsynonymous SNP in ATG16L1 predisposes to ileal Crohn's disease and is independent of CARD15 and IBD5.Gastroenterology. 2007; 132: 1665-1671Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar Functional studies have shown that ATG16L1 and autophagy is critically involved in host defense against intracellular pathogens, such as Listeria monocytogenes or Salmonella typhimurium.20Travassos L.H. Carneiro L.A. Ramjeet M. et al.Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry.Nat Immunol. 2010; 11: 55-62Crossref PubMed Scopus (1011) Google Scholar, 21Birmingham C.L. Canadien V. Gouin E. et al.Listeria monocytogenes evades killing by autophagy during colonization of host cells.Autophagy. 2007; 3: 442-451Crossref PubMed Scopus (191) Google Scholar Dysfunction of ATG16L1 has been implicated not only in defective autophagy and, consequently, bacterial handling, but also in altered gene/protein expression patterns in intestinal cells.20Travassos L.H. Carneiro L.A. Ramjeet M. et al.Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry.Nat Immunol. 2010; 11: 55-62Crossref PubMed Scopus (1011) Google Scholar, 22Cadwell K. Liu J.Y. Brown S.L. et al.A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells.Nature. 2008; 456: 259-263Crossref PubMed Scopus (1142) Google Scholar The presence of the Crohn's disease associated T300A polymorphism within the ATG16L1 gene leads to the development of dysmorphic and dysfunctional Paneth cells in the intestine of Crohn's disease patients.22Cadwell K. Liu J.Y. Brown S.L. et al.A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells.Nature. 2008; 456: 259-263Crossref PubMed Scopus (1142) Google ScholarIn this month's issue of Gastroenterology, Raju et al4Raju D. Hussey S. Ang M. et al.Vacuolating cytotoxin and variants in Atg16l1 that disrupt autophagy promote Helicobacter pylori infection in humans.Gastroenterology. 2012; 142: 1160-1171Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar demonstrate that the T300A variant of ATG16L1 increases the susceptibility to H pylori infection and partially prevents the VacA-induced induction of autophagy. This indeed indicates that the process of autophagy has a protective role for bacterial invasion, not only in the ileum or colon, but also in the gastric mucosa. Autophagy under this view seems to be a very basic and broad innate defense mechanism, not only to eliminate whole bacteria, but also their toxins during infection. However, the prolonged exposure to VacA leads to an impairment of autophagy and subsequently a failure to clear H pylori infection. Thus, chronic infection and subsequent accumulation of toxic material may aggravate the process.In conclusion, the study by Raju et al4Raju D. Hussey S. Ang M. et al.Vacuolating cytotoxin and variants in Atg16l1 that disrupt autophagy promote Helicobacter pylori infection in humans.Gastroenterology. 2012; 142: 1160-1171Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar advances our current knowledge of VacA as an important pathogenic factor for H pylori. Figure 1 illustrates the process of increased H pylori susceptibility and disease progression in response to the ATG16L1 variant associated with the risk to develop Crohn's disease. During the initial stages of H pylori infection VacA initiates autophagy. The data presented by Raju et al4Raju D. Hussey S. Ang M. et al.Vacuolating cytotoxin and variants in Atg16l1 that disrupt autophagy promote Helicobacter pylori infection in humans.Gastroenterology. 2012; 142: 1160-1171Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar collectively suggests that the bacterial load and level of VacA intoxication may be driving factors that determine the overall susceptibility to chronic infection and development of disease. Based on this notion, during initial H pylori exposure, if the bacterial load and VacA intoxication is low, one would expect that host cell autophagy reduces the effects of the toxin and clears infection (Figure 1A). However, the current study also elegantly demonstrates that in individuals carrying the ATG16L1 risk allele there is a reduced autophagic response. Therefore, levels of low bacterial load and VacA toxin become enhanced, subsequently increasing the susceptibility of infection and disease progression (Figure 1B). Prolonged exposure of VacA intoxication, which would commonly be associated with chronic infection, then results in the disruption of the autophagic degradative process that further exacerbated bacterial infection and disease by promoting H pylori intracellular survival (Figure 1B). Therapeutic options for the treatment of not only Crohn's disease patients, but also H pylori infection, may arise from insights into how impaired autophagy can be restored under these conditions. See “Vacuolating cytotoxin and variants in Atg16L1 that disrupt autophagy promote Helicobacter pylori infection in humans” by Raju D, Hussey S, Ang M, et al, on page 1160. See “Vacuolating cytotoxin and variants in Atg16L1 that disrupt autophagy promote Helicobacter pylori infection in humans” by Raju D, Hussey S, Ang M, et al, on page 1160. See “Vacuolating cytotoxin and variants in Atg16L1 that disrupt autophagy promote Helicobacter pylori infection in humans” by Raju D, Hussey S, Ang M, et al, on page 1160. Helicobacter pylori (H pylori) is a Gram-negative, microaerophilic bacterium that selectively colonizes the stomachs of half the world's human population. H pylori is the etiologic agent of several gastric diseases, including chronic gastritis and peptic ulcers. Long-term, chronic inflammation subsequently increases the risk for the development of mucosa-associated lymphoid tissue lymphoma and gastric cancer.1Peek R.M. Fiske C. Wilson K.T. Role of innate immunity in Helicobacter pylori-induced gastric malignancy.Physiol Rev. 2010; 90: 831-858Crossref PubMed Scopus (168) Google Scholar, 2Marshall B.J. Warren J.R. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration.Lancet. 1984; 1: 1311-1315Abstract PubMed Scopus (4167) Google Scholar During a well-choreographed interaction between the bacteria and the host gastric epithelium, H pylori infection initiates an immune response that leads to a massive infiltration of inflammatory cells.1Peek R.M. Fiske C. Wilson K.T. Role of innate immunity in Helicobacter pylori-induced gastric malignancy.Physiol Rev. 2010; 90: 831-858Crossref PubMed Scopus (168) Google Scholar An evolutionarily conserved cellular mechanism, autophagy, functions as an innate defense lysosomal pathway in response to infection to degrade intracellular micro-organisms attempting to establish a replicative niche in the host epithelial cell cytoplasm.3Terebiznik M.R. Raju D. Vázquez C.L. et al.Effect of Helicobacter pylori's vacuolating cytotoxin on the autophagy pathway in gastric epithelial cells.Autophagy. 2009; 5: 370-379Crossref PubMed Scopus (158) Google Scholar Unfortunately, H pylori utilizes a novel escape mechanism to evade lysosomal destruction in host epithelial cells that subsequently supports chronic infection. A study in this month's issue of Gastroenterology identifies, for the first time, an autophagy gene as a candidate for host susceptibility to H pylori infection and disease progression.4Raju D. Hussey S. Ang M. et al.Vacuolating cytotoxin and variants in Atg16l1 that disrupt autophagy promote Helicobacter pylori infection in humans.Gastroenterology. 2012; 142: 1160-1171Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar The H pylori–Vacuolating CytotoxinVacuolating cytotoxin (VacA) is an important virulence factor for H pylori disease pathogenesis. The VacA gene encodes a 96-kDa precursor protein that is secreted and cleaved into an 88-kDa mature protein and a 10.5-kDa passenger domain.1Peek R.M. Fiske C. Wilson K.T. Role of innate immunity in Helicobacter pylori-induced gastric malignancy.Physiol Rev. 2010; 90: 831-858Crossref PubMed Scopus (168) Google Scholar The mature 88-kDa toxin can undergo further proteolytic cleavage to yield the p33 and p50 fragments which represent the VacA functional domains that are required for toxin activity.5Telford J.L. Ghiara P. Dell'Orco M. et al.Gene structure of the Helicobacter pylori cytotoxin and evidence of its key role in gastric disease.J Exp Med. 1994; 179: 1653-1658Crossref PubMed Scopus (520) Google Scholar The most well recognized effect of VacA intoxication of mammalian cells is the induction of vacuolation.6Cover T.L. Krishna U.S. Israel D.A. et al.Induction of gastric epithelial cell apoptosis by Helicobacter pylori vacuolating cytotoxin.Cancer Res. 2003; 63: 951-957PubMed Google Scholar The toxin generates the formation of membrane channels by being secreted as monomers that oligomerize at the host plasma membrane.6Cover T.L. Krishna U.S. Israel D.A. et al.Induction of gastric epithelial cell apoptosis by Helicobacter pylori vacuolating cytotoxin.Cancer Res. 2003; 63: 951-957PubMed Google Scholar Glycosylphosphatidylinositol anchored proteins enriched early endosomal compartments are involved in endocytosis of VacA.7Gauthier N.C. Monzo P. Gonzalez T. et al.Early endosomes associated with dynamic F-actin structures are required for late trafficking of H. pylori VacA toxin.J Cell Biol. 2007; 177: 343-354Crossref PubMed Scopus (76) Google Scholar VacA then traffics to lysosomal compartments where the toxin induces vacuolation via a mechanism dependent on GTPase Rab7,8Papini E. Satin B. Norais N. et al.Selective increase of the permeability of polarized epithelial cell monolayers by Helicobacter pylori vacuolating toxin.J Clin Invest. 1998; 102: 813-820Crossref PubMed Scopus (211) Google Scholar, 9Terebiznik M.R. Vazquez C.L. Torbicki K. et al.Helicobacter pylori VacA toxin promotes bacterial intracellular survival in gastric epithelial cells.Infect Immun. 2006; 74: 6599-65614Crossref PubMed Scopus (87) Google Scholar dynamin,10Suzuki J. Ohnsihi H. Shibata H. et al.Dynamin is involved in human epithelial cell vacuolation caused by the Helicobacter pylori-produced cytotoxin VacA.J Clin Invest. 2001; 107: 363-370Crossref PubMed Scopus (42) Google Scholar and syntaxin 7.11Suzuki J. Ohnishi H. Wada A. et al.Involvement of syntaxin 7 in human gastric epithelial cell vacuolation induced by the Helicobacter pylori-produced cytotoxin VacA.J Biol Chem. 2003; 278: 25585-25590Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar In addition to vacuolation, VacA intoxication has detrimental effects that include inhibition of T-cell proliferation12Wang Y.H. Gorvel J.P. Chu Y.T. et al.Helicobacter pylori impairs murine dendritic cell responses to infection.PLoS One. 2010; 5: e10844Crossref PubMed Scopus (66) Google Scholar and the induction of apoptosis,6Cover T.L. Krishna U.S. Israel D.A. et al.Induction of gastric epithelial cell apoptosis by Helicobacter pylori vacuolating cytotoxin.Cancer Res. 2003; 63: 951-957PubMed Google Scholar increased cellular permeability,8Papini E. Satin B. Norais N. et al.Selective increase of the permeability of polarized epithelial cell monolayers by Helicobacter pylori vacuolating toxin.J Clin Invest. 1998; 102: 813-820Crossref PubMed Scopus (211) Google Scholar and autophagy within gastric epithelial cells.3Terebiznik M.R. Raju D. Vázquez C.L. et al.Effect of Helicobacter pylori's vacuolating cytotoxin on the autophagy pathway in gastric epithelial cells.Autophagy. 2009; 5: 370-379Crossref PubMed Scopus (158) Google Scholar, 9Terebiznik M.R. Vazquez C.L. Torbicki K. et al.Helicobacter pylori VacA toxin promotes bacterial intracellular survival in gastric epithelial cells.Infect Immun. 2006; 74: 6599-65614Crossref PubMed Scopus (87) Google Scholar Initial studies demonstrated that H pylori invades gastric epithelial cells and resides within vacuoles.13Amieva M.R. Salama N.R. Tompkins L.S. et al.Helicobacter pylori enter and survive within multivesicular vacuoles of epithelial cells.Cell Microbiol. 2002; 4: 677-690Crossref PubMed Scopus (163) Google Scholar Later experiments then showed that these vacuoles were associated with the autophagy pathway and attributed to bacterial intracellular survival of H pylori within gastric epithelial cells.3Terebiznik M.R. Raju D. Vázquez C.L. et al.Effect of Helicobacter pylori's vacuolating cytotoxin on the autophagy pathway in gastric epithelial cells.Autophagy. 2009; 5: 370-379Crossref PubMed Scopus (158) Google Scholar, 9Terebiznik M.R. Vazquez C.L. Torbicki K. et al.Helicobacter pylori VacA toxin promotes bacterial intracellular survival in gastric epithelial cells.Infect Immun. 2006; 74: 6599-65614Crossref PubMed Scopus (87) Google Scholar Vacuolating cytotoxin (VacA) is an important virulence factor for H pylori disease pathogenesis. The VacA gene encodes a 96-kDa precursor protein that is secreted and cleaved into an 88-kDa mature protein and a 10.5-kDa passenger domain.1Peek R.M. Fiske C. Wilson K.T. Role of innate immunity in Helicobacter pylori-induced gastric malignancy.Physiol Rev. 2010; 90: 831-858Crossref PubMed Scopus (168) Google Scholar The mature 88-kDa toxin can undergo further proteolytic cleavage to yield the p33 and p50 fragments which represent the VacA functional domains that are required for toxin activity.5Telford J.L. Ghiara P. Dell'Orco M. et al.Gene structure of the Helicobacter pylori cytotoxin and evidence of its key role in gastric disease.J Exp Med. 1994; 179: 1653-1658Crossref PubMed Scopus (520) Google Scholar The most well recognized effect of VacA intoxication of mammalian cells is the induction of vacuolation.6Cover T.L. Krishna U.S. Israel D.A. et al.Induction of gastric epithelial cell apoptosis by Helicobacter pylori vacuolating cytotoxin.Cancer Res. 2003; 63: 951-957PubMed Google Scholar The toxin generates the formation of membrane channels by being secreted as monomers that oligomerize at the host plasma membrane.6Cover T.L. Krishna U.S. Israel D.A. et al.Induction of gastric epithelial cell apoptosis by Helicobacter pylori vacuolating cytotoxin.Cancer Res. 2003; 63: 951-957PubMed Google Scholar Glycosylphosphatidylinositol anchored proteins enriched early endosomal compartments are involved in endocytosis of VacA.7Gauthier N.C. Monzo P. Gonzalez T. et al.Early endosomes associated with dynamic F-actin structures are required for late trafficking of H. pylori VacA toxin.J Cell Biol. 2007; 177: 343-354Crossref PubMed Scopus (76) Google Scholar VacA then traffics to lysosomal compartments where the toxin induces vacuolation via a mechanism dependent on GTPase Rab7,8Papini E. Satin B. Norais N. et al.Selective increase of the permeability of polarized epithelial cell monolayers by Helicobacter pylori vacuolating toxin.J Clin Invest. 1998; 102: 813-820Crossref PubMed Scopus (211) Google Scholar, 9Terebiznik M.R. Vazquez C.L. Torbicki K. et al.Helicobacter pylori VacA toxin promotes bacterial intracellular survival in gastric epithelial cells.Infect Immun. 2006; 74: 6599-65614Crossref PubMed Scopus (87) Google Scholar dynamin,10Suzuki J. Ohnsihi H. Shibata H. et al.Dynamin is involved in human epithelial cell vacuolation caused by the Helicobacter pylori-produced cytotoxin VacA.J Clin Invest. 2001; 107: 363-370Crossref PubMed Scopus (42) Google Scholar and syntaxin 7.11Suzuki J. Ohnishi H. Wada A. et al.Involvement of syntaxin 7 in human gastric epithelial cell vacuolation induced by the Helicobacter pylori-produced cytotoxin VacA.J Biol Chem. 2003; 278: 25585-25590Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar In addition to vacuolation, VacA intoxication has detrimental effects that include inhibition of T-cell proliferation12Wang Y.H. Gorvel J.P. Chu Y.T. et al.Helicobacter pylori impairs murine dendritic cell responses to infection.PLoS One. 2010; 5: e10844Crossref PubMed Scopus (66) Google Scholar and the induction of apoptosis,6Cover T.L. Krishna U.S. Israel D.A. et al.Induction of gastric epithelial cell apoptosis by Helicobacter pylori vacuolating cytotoxin.Cancer Res. 2003; 63: 951-957PubMed Google Scholar increased cellular permeability,8Papini E. Satin B. Norais N. et al.Selective increase of the permeability of polarized epithelial cell monolayers by Helicobacter pylori vacuolating toxin.J Clin Invest. 1998; 102: 813-820Crossref PubMed Scopus (211) Google Scholar and autophagy within gastric epithelial cells.3Terebiznik M.R. Raju D. Vázquez C.L. et al.Effect of Helicobacter pylori's vacuolating cytotoxin on the autophagy pathway in gastric epithelial cells.Autophagy. 2009; 5: 370-379Crossref PubMed Scopus (158) Google Scholar, 9Terebiznik M.R. Vazquez C.L. Torbicki K. et al.Helicobacter pylori VacA toxin promotes bacterial intracellular survival in gastric epithelial cells.Infect Immun. 2006; 74: 6599-65614Crossref PubMed Scopus (87) Google Scholar Initial studies demonstrated that H pylori invades gastric epithelial cells and resides within vacuoles.13Amieva M.R. Salama N.R. Tompkins L.S. et al.Helicobacter pylori enter and survive within multivesicular vacuoles of epithelial cells.Cell Microbiol. 2002; 4: 677-690Crossref PubMed Scopus (163) Google Scholar Later experiments then showed that these vacuoles were associated with the autophagy pathway and attributed to bacterial intracellular survival of H pylori within gastric epithelial cells.3Terebiznik M.R. Raju D. Vázquez C.L. et al.Effect of Helicobacter pylori's vacuolating cytotoxin on the autophagy pathway in gastric epithelial cells.Autophagy. 2009; 5: 370-379Crossref PubMed Scopus (158) Google Scholar, 9Terebiznik M.R. Vazquez C.L. Torbicki K. et al.Helicobacter pylori VacA toxin promotes bacterial intracellular survival in gastric epithelial cells.Infect Immun. 2006; 74: 6599-65614Crossref PubMed Scopus (87) Google Scholar Autophagy in Response to H pylori VacA and Persistent Bacterial InfectionIn recent years, autophagy has been recognized as being of central importance for the maintenance of cell homeostasis and survival but also for the regulation of inflammation and for bacterial defense at body surfaces.14Sokollik C. Ang M. Jones N. Autophagy: a primer for the gastroenterologist/hepatologist.Can J Gastroenterol. 2011; 25: 667-674Crossref PubMed Scopus (11) Google Scholar Although H pylori is generally considered to be a noninvasive pathogen, emerging evidence demonstrates that the bacteria also invade and replicate within autophagasomes of macrophages, dendritic, and epithelial cells.3Terebiznik M.R. Raju D. Vázquez C.L. et al.Effect of Helicobacter pylori's vacuolating cytotoxin on the autophagy pathway in gastric epithelial cells.Autophagy. 2009; 5: 370-379Crossref PubMed Scopus (158) Google Scholar, 9Terebiznik M.R. Vazquez C.L. Torbicki K. et al.Helicobacter pylori VacA toxin promotes bacterial intracellular survival in gastric epithelial cells.Infect Immun. 2006; 74: 6599-65614Crossref PubMed Scopus (87) Google Scholar, 12Wang Y.H. Gorvel J.P. Chu Y.T. et al.Helicobacter pylori impairs murine dendritic cell responses to infection.PLoS One. 2010; 5: e10844Crossref PubMed Scopus (66) Google Scholar, 15Wang Y.H. Wu J.J. Lei H.Y. The autophagic induction in Helicobacter pylori-infected macrophage.Exp Biol Med (Maywood). 2009; 234: 171-180Crossref PubMed Scopus (77) Google Scholar In view of the observation that H pylori infection induces autophagy within epithelial cells,3Terebiznik M.R. Raju D. Vázquez C.L. et al.Effect of Helicobacter pylori's vacuolating cytotoxin on the autophagy pathway in gastric epithelial cells.Autophagy. 2009; 5: 370-379Crossref PubMed Scopus (158) Google Scholar, 9Terebiznik M.R. Vazquez C.L. Torbicki K. et al.Helicobacter pylori VacA toxin promotes bacterial intracellular survival in gastric epithelial cells.Infect Immun. 2006; 74: 6599-65614Crossref PubMed Scopus (87) Google Scholar the question then remains as to how H pylori are allowed to replicate within the autophagasome and evade lysosomal-induced degradation.Raju et al4Raju D. Hussey S. Ang M. et al.Vacuolating cytotoxin and variants in Atg16l1 that disrupt autophagy promote Helicobacter pylori infection in humans.Gastroenterology. 2012; 142: 1160-1171Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar recently reinforced that VacA, independent of the bacteria, alters the degradative capacity of the endocytic pathway. Using gastric cancer epithelial AGS cells treated with culture supernatants from VacA-positive H pylori the investigators show that although VacA intoxication induces autophagasome–lysosomal fusion cathepsin D levels were negligible.4Raju D. Hussey S. Ang M. et al.Vacuolating cytotoxin and variants in Atg16l1 that disrupt autophagy promote Helicobacter pylori infection in humans.Gastroenterology. 2012; 142: 1160-1171Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar Cathepsin D is a key hydrolase necessary for lysosomal-induced degradation. Therefore, lack of cathepsin D alternately disrupts autophagic degradative process and thus offers a plausible mechanism by which H pylori replicate within autophagasomes.The investigators then extended the in vitro findings by studying the status of autophagy within human gastric biopsies collected from patients infected with H pylori. The signaling adaptor p62 is a multidomain protein implicated in the activation of the transcription factor nuclear factor-κB, apoptosis, and autophagy. Dysfunctional autophagy leads to an accumulation of p62 that contributes directly to tumorigenesis.16Mathew R. Karp C.M. Beaudoin B. et al.Autophagy suppresses tumorigenesis through elimination of p62.Cell. 2009; 137: 1062-1075Abstract Full Text Full Text PDF PubMed Scopus (1339) Google Scholar Indeed, gastric tissue sections collected from patients infected with the toxigenic s1m1 VacA-producing H pylori strain showed increased accumulation of p62 expression in the foveolar cells of the gastric epithelium.4Raju D. Hussey S. Ang M. et al.Vacuolating cytotoxin and variants in Atg16l1 that disrupt autophagy promote Helicobacter pylori infection in humans.Gastroenterology. 2012; 142: 1160-1171Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar However, the most interesting discovery that was made by Raju et al4Raju D. Hussey S. Ang M. et al.Vacuolating cytotoxin and variants in Atg16l1 that disrupt autophagy promote Helicobacter pylori infection in humans.Gastroenterology. 2012; 142: 1160-1171Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar was that H pylori infection was increased in individuals harboring a polymorphism in the ATG16L1 autophagy gene. In recent years, autophagy has been recognized as being of central importance for the maintenance of cell homeostasis and survival but also for the regulation of inflammation and for bacterial defense at body surfaces.14Sokollik C. Ang M. Jones N. Autophagy: a primer for the gastroenterologist/hepatologist.Can J Gastroenterol. 2011; 25: 667-674Crossref PubMed Scopus (11) Google Scholar Although H pylori is generally considered to be a noninvasive pathogen, emerging evidence demonstrates that the bacteria also invade and replicate within autophagasomes of macrophages, dendritic, and epithelial cells.3Terebiznik M.R. Raju D. Vázquez C.L. et al.Effect of Helicobacter pylori's vacuolating cytotoxin on the autophagy pathway in gastric epithelial cells.Autophagy. 2009; 5: 370-379Crossref PubMed Scopus (158) Google Scholar, 9Terebiznik M.R. Vazquez C.L. Torbicki K. et al.Helicobacter pylori VacA toxin promotes bacterial intracellular survival in gastric epithelial cells.Infect Immun. 2006; 74: 6599-65614Crossref PubMed Scopus (87) Google Scholar, 12Wang Y.H. Gorvel J.P. Chu Y.T. et al.Helicobacter pylori impairs murine dendritic cell responses to infection.PLoS One. 2010; 5: e10844Crossref PubMed Scopus (66) Google Scholar, 15Wang Y.H. Wu J.J. Lei H.Y. The autophagic induction in Helicobacter pylori-infected macrophage.Exp Biol Med (Maywood). 2009; 234: 171-180Crossref PubMed Scopus (77) Google Scholar In view of the observation that H pylori infection induces autophagy within epithelial cells,3Terebiznik M.R. Raju D. Vázquez C.L. et al.Effect of Helicobacter pylori's vacuolating cytotoxin on the autophagy pathway in gastric epithelial cells.Autophagy. 2009; 5: 370-379Crossref PubMed Scopus (158) Google Scholar, 9Terebiznik M.R. Vazquez C.L. Torbicki K. et al.Helicobacter pylori VacA toxin promotes bacterial intracellular survival in gastric epithelial cells.Infect Immun. 2006; 74: 6599-65614Crossref PubMed Scopus (87) Google Scholar the question then remains as to how H pylori are allowed to replicate within the autophagasome and evade lysosomal-induced degradation. Raju et al4Raju D. Hussey S. Ang M. et al.Vacuolating cytotoxin and variants in Atg16l1 that disrupt autophagy promote Helicobacter pylori infection in humans.Gastroenterology. 2012; 142: 1160-1171Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar recently reinforced that VacA, independent of the bacteria, alters the degradative capacity of the endocytic pathway. Using gastric cancer epithelial AGS cells treated with culture supernatants from VacA-positive H pylori the investigators show that although VacA intoxication induces autophagasome–lysosomal fusion cathepsin D levels were negligible.4Raju D. Hussey S. Ang M. et al.Vacuolating cytotoxin and variants in Atg16l1 that disrupt autophagy promote Helicobacter pylori infection in humans.Gastroenterology. 2012; 142: 1160-1171Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar Cathepsin D is a key hydrolase necessary for lysosomal-induced degradation. Therefore, lack of cathepsin D alternately disrupts autophagic degradative process and thus offers a plausible mechanism by which H pylori replicate within autophagasomes. The investigators then extended the in vitro findings by studying the status of autophagy within human gastric biopsies collected from patients infected with H pylori. The signaling adaptor p62 is a multidomain protein implicated in the activation of the transcription factor nuclear factor-κB, apoptosis, and autophagy. Dysfunctional autophagy leads to an accumulation of p62 that contributes directly to tumorigenesis.16Mathew R. Karp C.M. Beaudoin B. et al.Autophagy suppresses tumorigenesis through elimination of p62.Cell. 2009; 137: 1062-1075Abstract Full Text Full Text PDF PubMed Scopus (1339) Google Scholar Indeed, gastric tissue sections collected from patients infected with the toxigenic s1m1 VacA-producing H pylori strain showed increased accumulation of p62 expression in the foveolar cells of the gastric epithelium.4Raju D. Hussey S. Ang M. et al.Vacuolating cytotoxin and variants in Atg16l1 that disrupt autophagy promote Helicobacter pylori infection in humans.Gastroenterology. 2012; 142: 1160-1171Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar However, the most interesting discovery that was made by Raju et al4Raju D. Hussey S. Ang M. et al.Vacuolating cytotoxin and variants in Atg16l1 that disrupt autophagy promote Helicobacter pylori infection in humans.Gastroenterology. 2012; 142: 1160-1171Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar was that H pylori infection was increased in individuals harboring a polymorphism in the ATG16L1 autophagy gene. The Crohn's Variant of ATG16L1 as It Relates to H pylori SusceptibilityIn autophagasomes, structures that need to be eliminated are sequestered into double membrane-enclosed vesicles and delivered to lysosomes for final degradation. Autophagasome assembly involves activation of beclin-1 and conjugation of ATG12-ATG5 that is catalyzed by ATG7 and ATG10.17Deretic V. Autophagy in immunity and cell-autonomous defense against intracellular microbes.Immunol Rev. 2011; 240: 92-104Crossref PubMed Scopus (295) Google Scholar The resulting ATG5–ATG12 conjugate is stabilized by a noncovalent complex with ATG16L1 that mediates, in addition to ATG7 and ATG3, the conversion of LC3B-I to LC3B-II by lipidation with phosphatidylethanolamine.17Deretic V. Autophagy in immunity and cell-autonomous defense against intracellular microbes.Immunol Rev. 2011; 240: 92-104Crossref PubMed Scopus (295) Google Scholar Interestingly, a variant of the ATG16L1 gene (rs2241880, causing amino acid substitution T300A) has been associated with the risk of developing Crohn's disease.18Baldassano R. Bradfield J.P. Monos D.S. et al.Association of the T300A non-synonymous variant of the ATG16L1 gene with susceptibility to paediatric Crohn's disease.Gut. 2007; 56: 1171-1173Crossref PubMed Scopus (55) Google Scholar, 19Prescott N.J. Fisher S.A. Franke A. et al.A nonsynonymous SNP in ATG16L1 predisposes to ileal Crohn's disease and is independent of CARD15 and IBD5.Gastroenterology. 2007; 132: 1665-1671Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar Functional studies have shown that ATG16L1 and autophagy is critically involved in host defense against intracellular pathogens, such as Listeria monocytogenes or Salmonella typhimurium.20Travassos L.H. Carneiro L.A. Ramjeet M. et al.Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry.Nat Immunol. 2010; 11: 55-62Crossref PubMed Scopus (1011) Google Scholar, 21Birmingham C.L. Canadien V. Gouin E. et al.Listeria monocytogenes evades killing by autophagy during colonization of host cells.Autophagy. 2007; 3: 442-451Crossref PubMed Scopus (191) Google Scholar Dysfunction of ATG16L1 has been implicated not only in defective autophagy and, consequently, bacterial handling, but also in altered gene/protein expression patterns in intestinal cells.20Travassos L.H. Carneiro L.A. Ramjeet M. et al.Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry.Nat Immunol. 2010; 11: 55-62Crossref PubMed Scopus (1011) Google Scholar, 22Cadwell K. Liu J.Y. Brown S.L. et al.A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells.Nature. 2008; 456: 259-263Crossref PubMed Scopus (1142) Google Scholar The presence of the Crohn's disease associated T300A polymorphism within the ATG16L1 gene leads to the development of dysmorphic and dysfunctional Paneth cells in the intestine of Crohn's disease patients.22Cadwell K. Liu J.Y. Brown S.L. et al.A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells.Nature. 2008; 456: 259-263Crossref PubMed Scopus (1142) Google ScholarIn this month's issue of Gastroenterology, Raju et al4Raju D. Hussey S. Ang M. et al.Vacuolating cytotoxin and variants in Atg16l1 that disrupt autophagy promote Helicobacter pylori infection in humans.Gastroenterology. 2012; 142: 1160-1171Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar demonstrate that the T300A variant of ATG16L1 increases the susceptibility to H pylori infection and partially prevents the VacA-induced induction of autophagy. This indeed indicates that the process of autophagy has a protective role for bacterial invasion, not only in the ileum or colon, but also in the gastric mucosa. Autophagy under this view seems to be a very basic and broad innate defense mechanism, not only to eliminate whole bacteria, but also their toxins during infection. However, the prolonged exposure to VacA leads to an impairment of autophagy and subsequently a failure to clear H pylori infection. Thus, chronic infection and subsequent accumulation of toxic material may aggravate the process.In conclusion, the study by Raju et al4Raju D. Hussey S. Ang M. et al.Vacuolating cytotoxin and variants in Atg16l1 that disrupt autophagy promote Helicobacter pylori infection in humans.Gastroenterology. 2012; 142: 1160-1171Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar advances our current knowledge of VacA as an important pathogenic factor for H pylori. Figure 1 illustrates the process of increased H pylori susceptibility and disease progression in response to the ATG16L1 variant associated with the risk to develop Crohn's disease. During the initial stages of H pylori infection VacA initiates autophagy. The data presented by Raju et al4Raju D. Hussey S. Ang M. et al.Vacuolating cytotoxin and variants in Atg16l1 that disrupt autophagy promote Helicobacter pylori infection in humans.Gastroenterology. 2012; 142: 1160-1171Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar collectively suggests that the bacterial load and level of VacA intoxication may be driving factors that determine the overall susceptibility to chronic infection and development of disease. Based on this notion, during initial H pylori exposure, if the bacterial load and VacA intoxication is low, one would expect that host cell autophagy reduces the effects of the toxin and clears infection (Figure 1A). However, the current study also elegantly demonstrates that in individuals carrying the ATG16L1 risk allele there is a reduced autophagic response. Therefore, levels of low bacterial load and VacA toxin become enhanced, subsequently increasing the susceptibility of infection and disease progression (Figure 1B). Prolonged exposure of VacA intoxication, which would commonly be associated with chronic infection, then results in the disruption of the autophagic degradative process that further exacerbated bacterial infection and disease by promoting H pylori intracellular survival (Figure 1B). Therapeutic options for the treatment of not only Crohn's disease patients, but also H pylori infection, may arise from insights into how impaired autophagy can be restored under these conditions. In autophagasomes, structures that need to be eliminated are sequestered into double membrane-enclosed vesicles and delivered to lysosomes for final degradation. Autophagasome assembly involves activation of beclin-1 and conjugation of ATG12-ATG5 that is catalyzed by ATG7 and ATG10.17Deretic V. Autophagy in immunity and cell-autonomous defense against intracellular microbes.Immunol Rev. 2011; 240: 92-104Crossref PubMed Scopus (295) Google Scholar The resulting ATG5–ATG12 conjugate is stabilized by a noncovalent complex with ATG16L1 that mediates, in addition to ATG7 and ATG3, the conversion of LC3B-I to LC3B-II by lipidation with phosphatidylethanolamine.17Deretic V. Autophagy in immunity and cell-autonomous defense against intracellular microbes.Immunol Rev. 2011; 240: 92-104Crossref PubMed Scopus (295) Google Scholar Interestingly, a variant of the ATG16L1 gene (rs2241880, causing amino acid substitution T300A) has been associated with the risk of developing Crohn's disease.18Baldassano R. Bradfield J.P. Monos D.S. et al.Association of the T300A non-synonymous variant of the ATG16L1 gene with susceptibility to paediatric Crohn's disease.Gut. 2007; 56: 1171-1173Crossref PubMed Scopus (55) Google Scholar, 19Prescott N.J. Fisher S.A. Franke A. et al.A nonsynonymous SNP in ATG16L1 predisposes to ileal Crohn's disease and is independent of CARD15 and IBD5.Gastroenterology. 2007; 132: 1665-1671Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar Functional studies have shown that ATG16L1 and autophagy is critically involved in host defense against intracellular pathogens, such as Listeria monocytogenes or Salmonella typhimurium.20Travassos L.H. Carneiro L.A. Ramjeet M. et al.Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry.Nat Immunol. 2010; 11: 55-62Crossref PubMed Scopus (1011) Google Scholar, 21Birmingham C.L. Canadien V. Gouin E. et al.Listeria monocytogenes evades killing by autophagy during colonization of host cells.Autophagy. 2007; 3: 442-451Crossref PubMed Scopus (191) Google Scholar Dysfunction of ATG16L1 has been implicated not only in defective autophagy and, consequently, bacterial handling, but also in altered gene/protein expression patterns in intestinal cells.20Travassos L.H. Carneiro L.A. Ramjeet M. et al.Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry.Nat Immunol. 2010; 11: 55-62Crossref PubMed Scopus (1011) Google Scholar, 22Cadwell K. Liu J.Y. Brown S.L. et al.A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells.Nature. 2008; 456: 259-263Crossref PubMed Scopus (1142) Google Scholar The presence of the Crohn's disease associated T300A polymorphism within the ATG16L1 gene leads to the development of dysmorphic and dysfunctional Paneth cells in the intestine of Crohn's disease patients.22Cadwell K. Liu J.Y. Brown S.L. et al.A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells.Nature. 2008; 456: 259-263Crossref PubMed Scopus (1142) Google Scholar In this month's issue of Gastroenterology, Raju et al4Raju D. Hussey S. Ang M. et al.Vacuolating cytotoxin and variants in Atg16l1 that disrupt autophagy promote Helicobacter pylori infection in humans.Gastroenterology. 2012; 142: 1160-1171Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar demonstrate that the T300A variant of ATG16L1 increases the susceptibility to H pylori infection and partially prevents the VacA-induced induction of autophagy. This indeed indicates that the process of autophagy has a protective role for bacterial invasion, not only in the ileum or colon, but also in the gastric mucosa. Autophagy under this view seems to be a very basic and broad innate defense mechanism, not only to eliminate whole bacteria, but also their toxins during infection. However, the prolonged exposure to VacA leads to an impairment of autophagy and subsequently a failure to clear H pylori infection. Thus, chronic infection and subsequent accumulation of toxic material may aggravate the process. In conclusion, the study by Raju et al4Raju D. Hussey S. Ang M. et al.Vacuolating cytotoxin and variants in Atg16l1 that disrupt autophagy promote Helicobacter pylori infection in humans.Gastroenterology. 2012; 142: 1160-1171Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar advances our current knowledge of VacA as an important pathogenic factor for H pylori. Figure 1 illustrates the process of increased H pylori susceptibility and disease progression in response to the ATG16L1 variant associated with the risk to develop Crohn's disease. During the initial stages of H pylori infection VacA initiates autophagy. The data presented by Raju et al4Raju D. Hussey S. Ang M. et al.Vacuolating cytotoxin and variants in Atg16l1 that disrupt autophagy promote Helicobacter pylori infection in humans.Gastroenterology. 2012; 142: 1160-1171Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar collectively suggests that the bacterial load and level of VacA intoxication may be driving factors that determine the overall susceptibility to chronic infection and development of disease. Based on this notion, during initial H pylori exposure, if the bacterial load and VacA intoxication is low, one would expect that host cell autophagy reduces the effects of the toxin and clears infection (Figure 1A). However, the current study also elegantly demonstrates that in individuals carrying the ATG16L1 risk allele there is a reduced autophagic response. Therefore, levels of low bacterial load and VacA toxin become enhanced, subsequently increasing the susceptibility of infection and disease progression (Figure 1B). Prolonged exposure of VacA intoxication, which would commonly be associated with chronic infection, then results in the disruption of the autophagic degradative process that further exacerbated bacterial infection and disease by promoting H pylori intracellular survival (Figure 1B). Therapeutic options for the treatment of not only Crohn's disease patients, but also H pylori infection, may arise from insights into how impaired autophagy can be restored under these conditions. Vacuolating Cytotoxin and Variants in Atg16L1 That Disrupt Autophagy Promote Helicobacter pylori Infection in HumansGastroenterologyVol. 142Issue 5PreviewThe Helicobacter pylori toxin vacuolating cytotoxin (VacA) promotes gastric colonization, and its presence (VacA+) is associated with more-severe disease. The exact mechanisms by which VacA contributes to infection are unclear. We previously found that limited exposure to VacA induces autophagy of gastric cells, which eliminates the toxin; we investigated whether autophagy serves as a defense mechanism against H pylori infection. Full-Text PDF