Editing Helicobacter pylori (section)

==Pathophysiology==
[[Virulence factor]]s help a pathogen to evade the immune response of the host, and to successfully [[colonisation (biology)|colonize]]. The many virulence factors of ''H. pylori'' include its flagella, the production of urease, adhesins, [[serine protease]] [[Peptidase Do|HtrA]] (high temperature requirement A), and the major [[exotoxin]]s [[CagA]] and [[VacA]].<ref name="Baj" /><ref name="Yamaoka2">{{cite book |vauthors=Yamaoka Y, Saruuljavkhlan B, Alfaray RI, Linz B |chapter=Pathogenomics of Helicobacter pylori |title=Helicobacter pylori and Gastric Cancer |series=Current Topics in Microbiology and Immunology |volume=444 |pages=117–155 |date=2023 |pmid=38231217 |doi=10.1007/978-3-031-47331-9_5 |isbn=978-3-031-47330-2 |chapter-url=}}</ref> The presence of VacA and CagA are associated with more [[Pathogenesis|advanced outcomes]].<ref name="Alfarouk">{{cite journal | vauthors = Alfarouk KO, Bashir AH, Aljarbou AN, Ramadan AM, Muddathir AK, AlHoufie ST, Hifny A, Elhassan GO, Ibrahim ME, Alqahtani SS, AlSharari SD, Supuran CT, Rauch C, Cardone RA, Reshkin SJ, Fais S, Harguindey S | title = Helicobacter pylori in Gastric Cancer and Its Management | journal = Frontiers in Oncology | volume = 9 | pages = 75 | date = 22 February 2019 | pmid = 30854333 | pmc = 6395443 | doi = 10.3389/fonc.2019.00075 | doi-access = free }}</ref> CagA is an oncoprotein associated with the development of gastric cancer.<ref name="cancer.gov2023" />
[[File:H pylori virulence factors en.png|thumb|Diagram of ''H. pylori'' and associated [[virulence factor]]s]]
[[File:Ulcer-causing Bacterium (H.Pylori) Crossing Mucus Layer of Stomach.jpg|thumbnail|Diagram showing how ''H.&nbsp;pylori'' reaches the epithelium of the stomach]]
''H.&nbsp;pylori'' infection is associated with [[epigenetically]] reduced efficiency of the [[DNA repair]] machinery, which favors the accumulation of mutations and genomic instability as well as gastric carcinogenesis.<ref name=Santos>{{cite journal | vauthors = Santos JC, Ribeiro ML | title = Epigenetic regulation of DNA repair machinery in Helicobacter pylori-induced gastric carcinogenesis | journal = World Journal of Gastroenterology | volume = 21 | issue = 30 | pages = 9021–37 | date = August 2015 | pmid = 26290630 | pmc = 4533035 | doi = 10.3748/wjg.v21.i30.9021 | doi-access = free }}</ref> It has been shown that expression of two DNA repair proteins, [[ERCC1]] and [[PMS2]], was severely reduced once ''H.&nbsp;pylori'' infection had progressed to cause [[Indigestion|dyspepsia]].<ref name=Raza2>{{cite journal | vauthors = Raza Y, Ahmed A, Khan A, Chishti AA, Akhter SS, Mubarak M, Bernstein C, Zaitlin B, Kazmi SU | title = Helicobacter pylori severely reduces expression of DNA repair proteins PMS2 and ERCC1 in gastritis and gastric cancer | journal = DNA Repair | volume = 89 | pages = 102836 | date = May 2020 | pmid = 32143126 | doi = 10.1016/j.dnarep.2020.102836 | doi-access = free }}</ref> Dyspepsia occurs in about 20% of infected individuals.<ref name="pmid27239194">{{cite journal | vauthors = Dore MP, Pes GM, Bassotti G, Usai-Satta P | title = Dyspepsia: When and How to Test for Helicobacter pylori Infection | journal = Gastroenterology Research and Practice | volume = 2016 | pages = 8463614 | year = 2016 | pmid = 27239194 | pmc = 4864555 | doi = 10.1155/2016/8463614 | doi-access = free }}</ref> Epigenetically reduced protein expression of DNA repair proteins [[MLH1]], [[O-6-methylguanine-DNA methyltransferase|MGMT]] and [[MRE11A|MRE11]] are also evident. Reduced DNA repair in the presence of increased DNA damage increases carcinogenic mutations and is likely a significant cause of gastric carcinogenesis.<ref name=Raza/><ref name=Muhammad>{{cite journal | vauthors = Muhammad JS, Eladl MA, Khoder G | title = Helicobacter pylori-induced DNA Methylation as an Epigenetic Modulator of Gastric Cancer: Recent Outcomes and Future Direction | journal = Pathogens | volume = 8 | issue = 1 | pages = 23 | date = February 2019 | pmid = 30781778 | pmc = 6471032 | doi = 10.3390/pathogens8010023 | doi-access = free }}</ref><ref name=Noto>{{cite journal | vauthors = Noto JM, Peek RM | title = The role of microRNAs in Helicobacter pylori pathogenesis and gastric carcinogenesis | journal = Frontiers in Cellular and Infection Microbiology | volume = 1 | pages = 21 | date = 2011 | pmid = 22919587 | pmc = 3417373 | doi = 10.3389/fcimb.2011.00021 | doi-access = free }}</ref> These [[Cancer epigenetics|epigenetic alterations]] are due to ''H.&nbsp;pylori''-induced [[CpG site#Promoter CpG hyper/hypo-methylation in cancer|methylation of CpG sites in promoters of genes]]<ref name=Muhammad /> and ''H.&nbsp;pylori''-induced altered expression of multiple [[microRNA]]s.<ref name=Noto/>

Two related mechanisms by which ''H.&nbsp;pylori'' could promote cancer have been proposed. One mechanism involves the enhanced production of [[free radical]]s near ''H.&nbsp;pylori'' and an increased rate of host cell [[mutation]]. The other proposed mechanism has been called a "perigenetic pathway",<ref>{{cite journal | vauthors = Tsuji S, Kawai N, Tsujii M, Kawano S, Hori M | title = Review article: inflammation-related promotion of gastrointestinal carcinogenesis--a perigenetic pathway | journal = Alimentary Pharmacology & Therapeutics | volume = 18 | issue = Suppl 1 | pages = 82–9 | date = July 2003 | pmid = 12925144 | doi = 10.1046/j.1365-2036.18.s1.22.x | s2cid = 22646916 | doi-access = free }}</ref> and involves enhancement of the transformed host cell phenotype by means of alterations in cell proteins, such as [[cell adhesion|adhesion]] proteins. ''H.&nbsp;pylori'' has been proposed to induce inflammation and locally high levels of [[tumor necrosis factor]] (TNF), also known as tumor necrosis factor alpha (TNFα)), and/or [[interleukin 6]] (IL-6).<ref>{{cite journal | vauthors = Yu B, de Vos D, Guo X, Peng S, Xie W, Peppelenbosch MP, Fu Y, Fuhler GM | title = IL-6 facilitates cross-talk between epithelial cells and tumor- associated macrophages in Helicobacter pylori-linked gastric carcinogenesis. | journal = Neoplasia | volume = 50 | pages = 100981 | date = April 2024 | pmid = 38422751 | pmc = 10912637 | doi = 10.1016/j.neo.2024.100981 | doi-access = free}}</ref> According to the proposed perigenetic mechanism, inflammation-associated signaling molecules, such as TNF, can alter gastric epithelial cell adhesion and lead to the dispersion and migration of mutated epithelial cells without the need for additional mutations in [[tumor suppressor gene]]s, such as genes that code for cell adhesion proteins.<ref name="Suganuma">{{cite journal | vauthors = Suganuma M, Yamaguchi K, Ono Y, Matsumoto H, Hayashi T, Ogawa T, Imai K, Kuzuhara T, Nishizono A, Fujiki H | title = TNF-alpha-inducing protein, a carcinogenic factor secreted from H. pylori, enters gastric cancer cells | journal = International Journal of Cancer | volume = 123 | issue = 1 | pages = 117–22 | date = July 2008 | pmid = 18412243 | doi = 10.1002/ijc.23484 | s2cid = 5532769 | doi-access = free }}</ref>

===Flagellum===
The first virulence factor of ''Helicobacter pylori'' that enables colonization is its [[flagellum]].<ref name="Duan">{{cite journal |vauthors=Duan Q, Zhou M, Zhu L, Zhu G |title=Flagella and bacterial pathogenicity |journal=J Basic Microbiol |volume=53 |issue=1 |pages=1–8 |date=January 2013 |pmid=22359233 |doi=10.1002/jobm.201100335 |s2cid=22002199 |url=}}</ref> ''H. pylori'' has from two to seven flagella at [[Lophotrichous|the same polar location]] which gives it a high motility. The flagellar filaments are about 3&nbsp;μm long, and composed of two copolymerized [[flagellin]]s, FlaA and FlaB, coded by the genes ''flaA'', and ''flaB''.<ref name="Kao"/><ref name="Yamaoka2" /> The minor flagellin FlaB is located in the proximal region and the major flagellin FlaA makes up the rest of the flagellum.<ref name="IJMS" /> The flagella are sheathed in a continuation of the bacterial outer membrane which gives protection against the gastric acidity. The sheath is also the location of the origin of the outer membrane vesicles that gives protection to the bacterium from bacteriophages.<ref name="IJMS" />

Flagella motility is provided by the [[proton motive force]] provided by urease-driven hydrolysis allowing [[chemotaxis|chemotactic movements]] towards the less acidic [[pH#pH of various body fluids|pH]] gradient in the mucosa.<ref name="Baj" /> The mucus layer is about 300 [[Micrometre|μm]] thick, and the helical shape of ''H. pylori'' aided by its flagella helps it to burrow through  this layer where it colonises a narrow region of about 25 μm closest to the epithelial cell layer, where the pH is near to neutral. They further colonise the [[gastric pits]] and live in the [[gastric glands]].<ref name="Martínez"/><ref name="IJMS">{{cite journal |vauthors=Nedeljković M, Sastre DE, Sundberg EJ |title=Bacterial Flagellar Filament: A Supramolecular Multifunctional Nanostructure |journal=Int J Mol Sci |volume=22 |issue=14 |date=July 2021 |page=7521 |pmid=34299141 |pmc=8306008 |doi=10.3390/ijms22147521 |doi-access=free |url=}}</ref><ref name="Elbehiry">{{cite journal |vauthors=Elbehiry A, Marzouk E, Aldubaib M, Abalkhail A, Anagreyyah S, Anajirih N, Almuzaini AM, Rawway M, Alfadhel A, Draz A, Abu-Okail A |title=Helicobacter pylori Infection: Current Status and Future Prospects on Diagnostic, Therapeutic and Control Challenges |journal=Antibiotics |volume=12 |issue=2 |date=January 2023 |page=191 |pmid=36830102 |pmc=9952126 |doi=10.3390/antibiotics12020191 |doi-access=free |url=}}</ref> Occasionally the bacteria are found inside the epithelial cells themselves.<ref name="pmid12738380">{{cite journal | vauthors = Petersen AM, Krogfelt KA | title = Helicobacter pylori: an invading microorganism? A review | journal = FEMS Immunology and Medical Microbiology | volume = 36 | issue = 3 | pages = 117–26 | date = May 2003 | pmid = 12738380 | doi = 10.1016/S0928-8244(03)00020-8 | type = Review | doi-access = free }}</ref> The use of [[quorum sensing]] by the bacteria enables the formation of a biofilm which furthers persistent colonisation. In the layers of the biofilm, ''H. pylori'' can escape from the actions of antibiotics, and also be protected from host-immune responses.<ref name=Ali>{{cite journal |vauthors=Ali A, AlHussaini KI |title=Helicobacter pylori: A Contemporary Perspective on Pathogenesis, Diagnosis and Treatment Strategies |journal=Microorganisms |volume=12 |issue=1 |date=January 2024 |page=222 |pmid=38276207 |pmc=10818838 |doi=10.3390/microorganisms12010222 |doi-access=free |url=}}</ref><ref name=Zafer>{{cite journal |vauthors=Zafer MM, Mohamed GA, Ibrahim SR, Ghosh S, Bornman C, Elfaky MA |title=Biofilm-mediated infections by multidrug-resistant microbes: a comprehensive exploration and forward perspectives |journal=Arch Microbiol |volume=206 |issue=3 |pages=101 |date=February 2024 |pmid=38353831 |pmc=10867068 |doi=10.1007/s00203-023-03826-z |bibcode=2024ArMic.206..101Z |url=}}</ref> In the biofilm, ''H. pylori'' can change the flagella to become adhesive structures.<ref name="Sun">{{cite journal |vauthors=Sun Q, Yuan C, Zhou S, Lu J, Zeng M, Cai X, Song H |title=Helicobacter pylori infection: a dynamic process from diagnosis to treatment |journal=Front Cell Infect Microbiol |volume=13 |issue= |pages=1257817 |date=2023 |pmid=37928189 |pmc=10621068 |doi=10.3389/fcimb.2023.1257817 |doi-access=free |url=}}</ref>

===Urease===
[[File:H. pylori urease enzyme diagram.svg|thumb|''H.&nbsp;pylori'' [[urease]] enzyme diagram]]
In addition to using [[chemotaxis]] to avoid areas of high acidity (low pH), ''H.&nbsp;pylori'' also produces large amounts of [[urease]], an [[enzyme]] which breaks down the [[urea]] present in the stomach to produce [[ammonia]] and [[bicarbonate]], which are released into the bacterial cytosol and the surrounding environment, creating a neutral area.<ref name="Lin2">{{cite journal |vauthors=Lin Q, Lin S, Fan Z, Liu J, Ye D, Guo P |title=A Review of the Mechanisms of Bacterial Colonization of the Mammal Gut |journal=Microorganisms |volume=12 |issue=5 |date=May 2024 |page=1026 |pmid=38792855 |pmc=11124445 |doi=10.3390/microorganisms12051026 |doi-access=free |url=}}</ref> The decreased acidity (higher pH) changes the mucus layer from a gel-like state to a more viscous state that makes it easier for the flagella to move the bacteria through the mucosa and attach to the gastric epithelial cells.<ref name="Lin2"/> ''Helicobacter pylori'' is one of the few known types of bacterium that has a [[urea cycle]] which is uniquely configured in the bacterium.<ref name="FEMS">{{cite journal |vauthors=Hernández VM, Arteaga A, Dunn MF |title=Diversity, properties and functions of bacterial arginases |journal=FEMS Microbiol Rev |volume=45 |issue=6 |pages= |date=November 2021 |pmid=34160574 |doi=10.1093/femsre/fuab034 |url=}}</ref> 10% of the cell is of [[nitrogen]], a balance that needs to be maintained. Any excess is stored in urea excreted in the urea cycle.<ref name="FEMS" />

A final stage enzyme in the urea cycle is [[arginase]], an enzyme that is crucial to the pathogenesis of ''H. pylori''. Arginase produces [[ornithine]] and urea, which the enzyme urease breaks down into carbonic acid and ammonia. Urease is the bacterium's most abundant protein, accounting for 10–15% of the bacterium's total protein content. Its expression is not only required for establishing initial colonization in the breakdown of urea to carbonic acid and ammonia, but is also essential for maintaining chronic infection.<ref name="Li">{{cite journal |vauthors=Li S, Zhao W, Xia L, Kong L, Yang L |title=How Long Will It Take to Launch an Effective Helicobacter pylori Vaccine for Humans? |journal=Infect Drug Resist |volume=16 |issue= |pages=3787–3805 |date=2023 |pmid=37342435 |pmc=10278649 |doi=10.2147/IDR.S412361 |doi-access=free |url=}}</ref><ref name="Debowski">{{cite journal | vauthors = Debowski AW, Walton SM, Chua EG, Tay AC, Liao T, Lamichhane B, Himbeck R, Stubbs KA, Marshall BJ, Fulurija A, Benghezal M | title = Helicobacter pylori gene silencing in vivo demonstrates urease is essential for chronic infection | journal = PLOS Pathogens | volume = 13 | issue = 6 | pages = e1006464 | date = June 2017 | pmid = 28644872 | pmc = 5500380 | doi = 10.1371/journal.ppat.1006464 | doi-access = free }}</ref> Ammonia reduces stomach acidity, allowing the bacteria to become locally established. Arginase promotes the persistence of infection by consuming arginine; arginine is used by macrophages to produce nitric oxide, which has a strong antimicrobial effect.<ref name="FEMS" /><ref name="George">{{cite journal | vauthors = George G, Kombrabail M, Raninga N, Sau AK | title = Arginase of Helicobacter Gastric Pathogens Uses a Unique Set of Non-catalytic Residues for Catalysis | journal = Biophysical Journal | volume = 112 | issue = 6 | pages = 1120–1134 | date = March 2017 | pmid = 28355540 | pmc = 5376119 | doi = 10.1016/j.bpj.2017.02.009 | bibcode = 2017BpJ...112.1120G }}</ref> The ammonia produced to regulate [[pH]] is toxic to epithelial cells.<ref>{{cite journal | vauthors = Smoot DT | title = How does Helicobacter pylori cause mucosal damage? Direct mechanisms | journal = Gastroenterology | volume = 113 | issue = 6 Suppl | pages = S31-4; discussion S50 | date = December 1997 | pmid = 9394757 | doi = 10.1016/S0016-5085(97)80008-X | doi-access = free }}</ref>

===Adhesins===
''H. pylori'' must make attachment with the epithelial cells to prevent its being swept away with the constant movement and renewal of the mucus. To give them this adhesion, [[Bacterial outer membrane#Outer membrane proteins|bacterial outer membrane proteins]] as virulence factors called [[bacterial adhesin|adhesins]] are produced.<ref name="Doohan">{{cite journal |vauthors=Doohan D, Rezkitha YA, Waskito LA, Yamaoka Y, Miftahussurur M |title=Helicobacter pylori BabA-SabA Key Roles in the Adherence Phase: The Synergic Mechanism for Successful Colonization and Disease Development |journal=Toxins |volume=13 |issue=7 |date=July 2021 |page=485 |pmid=34357957 |pmc=8310295 |doi=10.3390/toxins13070485 |doi-access=free |url=}}</ref> BabA (blood group antigen binding adhesin) is most important during initial colonization, and SabA (sialic acid binding adhesin) is important in persistence. BabA attaches to glycans and mucins in the epithelium.<ref name="Doohan"/> BabA (coded for by the ''babA2'' gene) also binds to the [[Lewis antigen system|Lewis b antigen]] displayed on the surface of the epithelial cells.<ref name="Rad">{{cite journal |last1=Rad |first1=Roland |last2=Gerhard |first2=Markus |last3=Lang |first3=Roland |last4=Schöniger |first4=Martin |last5=Rösch |first5=Thomas |last6=Schepp |first6=Wolfgang |last7=Becker |first7=Ingrid |last8=Wagner |first8=Hermann |last9=Prinz |first9=Christian |title=The Helicobacter pylori Blood Group Antigen-Binding Adhesin Facilitates Bacterial Colonization and Augments a Nonspecific Immune Response |journal=The Journal of Immunology |date=15 March 2002 |volume=168 |issue=6 |pages=3033–3041 |doi=10.4049/jimmunol.168.6.3033|pmid=11884476 |doi-access=free }}</ref> Adherence via BabA is acid sensitive and can be fully reversed by a decreased pH. It has been proposed that BabA's acid responsiveness enables adherence while also allowing an effective escape from an unfavorable environment such as a low pH that is harmful to the organism.<ref>{{cite journal | vauthors = Bugaytsova JA, Björnham O, Chernov YA, Gideonsson P, Henriksson S, Mendez M, Sjöström R, Mahdavi J, Shevtsova A, Ilver D, Moonens K, Quintana-Hayashi MP, Moskalenko R, Aisenbrey C, Bylund G, Schmidt A, Åberg A, Brännström K, Königer V, Vikström S, Rakhimova L, Hofer A, Ögren J, Liu H, Goldman MD, Whitmire JM, Ådén J, Younson J, Kelly CG, Gilman RH, Chowdhury A, Mukhopadhyay AK, Nair GB, Papadakos KS, Martinez-Gonzalez B, Sgouras DN, Engstrand L, Unemo M, Danielsson D, Suerbaum S, Oscarson S, Morozova-Roche LA, Olofsson A, Gröbner G, Holgersson J, Esberg A, Strömberg N, Landström M, Eldridge AM, Chromy BA, Hansen LM, Solnick JV, Lindén SK, Haas R, Dubois A, Merrell DS, Schedin S, Remaut H, Arnqvist A, Berg DE, Borén T | title = Helicobacter pylori Adapts to Chronic Infection and Gastric Disease via pH-Responsive BabA-Mediated Adherence | journal = Cell Host & Microbe | volume = 21 | issue = 3 | pages = 376–389 | date = March 2017 | pmid = 28279347 | pmc = 5392239 | doi = 10.1016/j.chom.2017.02.013 }}</ref> SabA (coded for by the ''sabA'' gene) binds to increased levels of [[sialyl-Lewis x|sialyl-Lewis <sup>X</sup>]] antigen expressed on gastric mucosa.<ref name="pmid12142529">{{cite journal | vauthors = Mahdavi J, Sondén B, Hurtig M, Olfat FO, Forsberg L, Roche N, Angstrom J, Larsson T, Teneberg S, Karlsson KA, Altraja S, Wadström T, Kersulyte D, Berg DE, Dubois A, Petersson C, Magnusson KE, Norberg T, Lindh F, Lundskog BB, Arnqvist A, Hammarström L, Borén T | title = Helicobacter pylori SabA adhesin in persistent infection and chronic inflammation | journal = Science | volume = 297 | issue = 5581 | pages = 573–8 | date = July 2002 | pmid = 12142529 | pmc = 2570540 | doi = 10.1126/science.1069076 | bibcode = 2002Sci...297..573M }}</ref>

===Cholesterol glucoside===
The outer membrane contains ''cholesterol glucoside'', a sterol glucoside that ''H. pylori'' [[Glycosylation|glycosylates]] from the [[cholesterol]] in the gastric gland cells, and inserts it into its outer membrane.<ref name="Testerman">{{cite journal | vauthors = Testerman TL, Morris J | title = Beyond the stomach: an updated view of Helicobacter pylori pathogenesis, diagnosis, and treatment | journal = World Journal of Gastroenterology | volume = 20 | issue = 36 | pages = 12781–808 | date = September 2014 | pmid = 25278678 | pmc = 4177463 | doi = 10.3748/wjg.v20.i36.12781 | type = Review | doi-access = free }}</ref> This cholesterol glucoside is important for membrane stability, morphology and immune evasion, and is rarely found in other bacteria.<ref name="Zhang">{{cite journal |vauthors=Zhang L, Xie J |title=Biosynthesis, structure and biological function of cholesterol glucoside in Helicobacter pylori: A review |journal=Medicine (Baltimore) |volume=102 |issue=36 |pages=e34911 |date=September 2023 |pmid=37682174 |pmc=10489377 |doi=10.1097/MD.0000000000034911 |url=}}</ref><ref name="Ridyard">{{cite journal |vauthors=Ridyard KE, Overhage J |title=The Potential of Human Peptide LL-37 as an Antimicrobial and Anti-Biofilm Agent |journal=Antibiotics |volume=10 |issue=6 |date=May 2021 |page=650 |pmid=34072318 |pmc=8227053 |doi=10.3390/antibiotics10060650 |doi-access=free |url=}}</ref>

The enzyme responsible for this is ''cholesteryl α-glucosyltransferase'' (αCgT or Cgt), encoded by the ''HP0421'' gene.<ref name="Hsu">{{cite journal |vauthors=Hsu CY, Yeh JY, Chen CY, Wu HY, Chiang MH, Wu CL, Lin HJ, Chiu CH, Lai CH |title=Helicobacter pylori cholesterol-α-glucosyltransferase manipulates cholesterol for bacterial adherence to gastric epithelial cells |journal=Virulence |volume=12 |issue=1 |pages=2341–2351 |date=December 2021 |pmid=34506250 |pmc=8437457 |doi=10.1080/21505594.2021.1969171 |url=}}</ref> A major effect of the depletion of host cholesterol by Cgt is to disrupt cholesterol-rich [[lipid raft]]s in the epithelial cells. Lipid rafts are involved in cell signalling and their disruption causes a reduction in the immune inflammatory response, particularly by reducing [[interferon gamma]].<ref name="Morey">{{cite journal |vauthors=Morey P, Pfannkuch L, Pang E, Boccellato F, Sigal M, Imai-Matsushima A, Dyer V, Koch M, Mollenkopf HJ, Schlaermann P, Meyer TF |title=Helicobacter pylori Depletes Cholesterol in Gastric Glands to Prevent Interferon Gamma Signaling and Escape the Inflammatory Response |journal=Gastroenterology |volume=154 |issue=5 |pages=1391–1404.e9 |date=April 2018 |pmid=29273450 |doi=10.1053/j.gastro.2017.12.008 |url=|hdl=21.11116/0000-0001-3B12-9 |hdl-access=free }}</ref> Cgt is also secreted by the type IV secretion system, and is secreted in a selective way so that gastric niches where the pathogen can thrive are created.<ref name="Hsu" /> Its lack has been shown to give vulnerability from environmental stress to bacteria, and also to disrupt CagA-mediated interactions.<ref name="Testerman" />

===Catalase===
Colonization induces an intense anti-inflammatory response as a first-line immune system defence. Phagocytic leukocytes and monocytes infiltrate the site of infection, and antibodies are produced.<ref name="Ramarao">{{cite journal |vauthors=Ramarao N, Gray-Owen SD, Meyer TF |title=Helicobacter pylori induces but survives the extracellular release of oxygen radicals from professional phagocytes using its catalase activity |journal=Mol Microbiol |volume=38 |issue=1 |pages=103–13 |date=October 2000 |pmid=11029693 |doi=10.1046/j.1365-2958.2000.02114.x |url=|hdl=11858/00-001M-0000-000E-C7AD-8 |hdl-access=free }}</ref> ''H. pylori'' is able to adhere to the surface of the phagocytes and impede their action. This is responded to by the phagocyte in the generation and release of oxygen metabolites into the surrounding space. ''H. pylori'' can survive this response by the activity of [[catalase]] at its attachment to the phagocytic cell surface. Catalase decomposes hydrogen peroxide into water and oxygen, protecting the bacteria from toxicity. Catalase has been shown to almost completely inhibit the phagocytic oxidative response.<ref name="Ramarao" /> It is coded for by the gene ''katA''.<ref name="UniProt1">{{cite web |title=UniProt |url=https://www.uniprot.org/uniprotkb/P77872/entry |website=www.uniprot.org |access-date=20 March 2024}}</ref>

===Tipα===
TNF-inducing protein alpha (Tipα) is a carcinogenic protein encoded by ''HP0596'' unique to ''H. pylori'' that induces the expression of [[tumor necrosis factor]].<ref name="Suganuma"/><ref name="UniProt">{{cite web |title=TNF-alpha inducing protein |url=https://www.uniprot.org/uniprotkb/O25318/entry |website=www.uniprot.org |access-date=8 April 2024}}</ref> Tipα enters gastric cancer cells where it binds to cell surface [[nucleolin]], and induces the expression of [[vimentin]]. Vimentin is important in the [[epithelial–mesenchymal transition]] associated with the progression of tumors.<ref name="IJoC">{{cite journal |last1=Watanabe |first1=Tatsuro |last2=Takahashi |first2=Atsushi |last3=Suzuki |first3=Kaori |last4=Kurusu-Kanno |first4=Miki |last5=Yamaguchi |first5=Kensei |last6=Fujiki |first6=Hirota |last7=Suganuma |first7=Masami |title=Epithelial-mesenchymal transition in human gastric cancer cell lines induced by TNF-α-inducing protein of Helicobacter pylori: Cell migration induced by Tipα of H. pylori |journal=International Journal of Cancer |date=15 May 2014 |volume=134 |issue=10 |pages=2373–2382 |doi=10.1002/ijc.28582|pmid=24249671 }}</ref>

===CagA===
'''CagA''' (cytotoxin-associated antigen A) is a major [[virulence factor]] for ''H.&nbsp;pylori'', an [[oncoprotein]] that is encoded by the ''cagA'' gene. Bacterial strains with the ''cagA'' gene are associated with the ability to cause ulcers, MALT lymphomas, and gastric cancer.<ref name="Wallden">{{cite journal |vauthors=Wallden K, Rivera-Calzada A, Waksman G |title=Type IV secretion systems: versatility and diversity in function |journal=Cell Microbiol |volume=12 |issue=9 |pages=1203–12 |date=September 2010 |pmid=20642798 |pmc=3070162 |doi=10.1111/j.1462-5822.2010.01499.x |url=}}</ref><ref name="pmid11283049">{{cite journal | vauthors = Broutet N, Marais A, Lamouliatte H, de Mascarel A, Samoyeau R, Salamon R, Mégraud F | title = cagA Status and eradication treatment outcome of anti-Helicobacter pylori triple therapies in patients with nonulcer dyspepsia | journal = Journal of Clinical Microbiology | volume = 39 | issue = 4 | pages = 1319–22 | date = April 2001 | pmid = 11283049 | pmc = 87932 | doi = 10.1128/JCM.39.4.1319-1322.2001 }}</ref> The ''cagA'' gene codes for a relatively long (1186-[[amino acid]]) protein. The ''cag'' [[pathogenicity island]] (PAI) has about 30 genes, part of which code for a complex [[type IV secretion system]] (T4SS or TFSS). The low [[GC-content]] of the ''cag'' PAI relative to the rest of the ''Helicobacter'' genome suggests the island was acquired by [[horizontal gene transfer|horizontal transfer]] from another bacterial species.<ref name="Tomb 1997"/> The [[serine protease]] [[Peptidase Do|HtrA]] also plays a major role in the pathogenesis of ''H.&nbsp;pylori''. The HtrA protein enables the bacterium to transmigrate across the host cells' epithelium, and is also needed for the translocation of CagA.<ref name="Zawilak-Pawlik2019">{{cite journal | vauthors = Zawilak-Pawlik A, Zarzecka U, Żyła-Uklejewicz D, Lach J, Strapagiel D, Tegtmeyer N, Böhm M, Backert S, Skorko-Glonek J | title = Establishment of serine protease htrA mutants in Helicobacter pylori is associated with secA mutations | journal = Scientific Reports | volume = 9 | issue = 1 | pages = 11794 | date = August 2019 | pmid = 31409845 | pmc = 6692382 | doi = 10.1038/s41598-019-48030-6 | bibcode = 2019NatSR...911794Z }}</ref>

The virulence of ''H.&nbsp;pylori'' may be increased by genes of the ''cag'' pathogenicity island; about 50–70% of ''H.&nbsp;pylori'' strains in Western countries carry it.<ref name="Peek 2006">{{cite journal | vauthors = Peek RM, Crabtree JE | title = Helicobacter infection and gastric neoplasia | journal = The Journal of Pathology | volume = 208 | issue = 2 | pages = 233–48 | date = January 2006 | pmid = 16362989 | doi = 10.1002/path.1868 | s2cid = 31718278 | doi-access = free }}</ref> Western people infected with strains carrying the ''cag'' PAI have a stronger inflammatory response in the stomach and are at a greater risk of developing peptic ulcers or stomach cancer than those infected with strains lacking the island.<ref name="Kusters2006"/> Following attachment of ''H.&nbsp;pylori'' to stomach epithelial cells, the type IV secretion system expressed by the ''cag'' PAI "injects" the [[inflammation]]-inducing agent, peptidoglycan, from their own [[cell wall]]s into the epithelial cells. The injected peptidoglycan is recognized by the cytoplasmic [[pattern recognition receptor]] (immune sensor) Nod1, which then stimulates expression of [[cytokines]] that promote inflammation.<ref>{{cite journal | vauthors = Viala J, Chaput C, Boneca IG, Cardona A, Girardin SE, Moran AP, Athman R, Mémet S, Huerre MR, Coyle AJ, DiStefano PS, Sansonetti PJ, Labigne A, Bertin J, Philpott DJ, Ferrero RL | title = Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island | journal = Nature Immunology | volume = 5 | issue = 11 | pages = 1166–74 | date = November 2004 | pmid = 15489856 | doi = 10.1038/ni1131 | s2cid = 2898805 }}</ref>

The type-IV [[secretion]] apparatus also injects the ''cag'' PAI-encoded protein CagA into the stomach's epithelial cells, where it disrupts the [[cytoskeleton]], adherence to adjacent cells, intracellular signaling, [[Epithelial polarity|cell polarity]], and other cellular activities.<ref name="Backert 2008">{{cite journal | vauthors = Backert S, Selbach M | title = Role of type IV secretion in Helicobacter pylori pathogenesis | journal = Cellular Microbiology | volume = 10 | issue = 8 | pages = 1573–81 | date = August 2008 | pmid = 18410539 | doi = 10.1111/j.1462-5822.2008.01156.x | s2cid = 37626 | doi-access = free }}</ref> Once inside the cell, the CagA protein is [[Phosphorylation|phosphorylated]] on [[Protein kinase#Tyrosine-specific protein kinases|tyrosine residues]] by a host cell membrane-associated [[tyrosine kinase]] (TK). CagA then allosterically activates [[protein tyrosine phosphatase]]/[[protooncogene]] [[Shp2]].<ref name="Hatakeyama">{{cite journal | vauthors = Hatakeyama M | title = Oncogenic mechanisms of the Helicobacter pylori CagA protein | journal = Nature Reviews. Cancer | volume = 4 | issue = 9 | pages = 688–94 | date = September 2004 | pmid = 15343275 | doi = 10.1038/nrc1433 | s2cid = 1218835 }}</ref>
These proteins are directly toxic to cells lining the stomach and signal strongly to the immune system that an invasion is under way. As a result of the bacterial presence, neutrophils and macrophages set up residence in the tissue to fight the bacteria assault.<ref>{{cite journal | doi=10.1007/s12156-008-0068-y | title=The role of Helicobacter pylori in the pathogenesis of gastric malignancies | date=2008 | journal=Oncology Reviews | volume=2 | issue=3 | pages=131–140 | vauthors = Kim W, Moss SF }}</ref> Pathogenic strains of ''H.&nbsp;pylori'' have been shown to activate the [[epidermal growth factor receptor]] (EGFR), a [[membrane protein]] with a TK [[protein domain|domain]]. Activation of the EGFR by ''H.&nbsp;pylori'' is associated with altered [[signal transduction]] and [[gene expression]] in host epithelial cells that may contribute to pathogenesis. A [[C-terminus|C-terminal]] region of the CagA protein (amino acids 873–1002) has also been suggested to be able to regulate host cell [[Transcription (genetics)|gene transcription]], independent of protein tyrosine phosphorylation.<ref name="pmid11283049"/> A great deal of diversity exists between strains of ''H.&nbsp;pylori'', and the strain that infects a person can predict the outcome.

===VacA===
'''VacA''' (vacuolating cytotoxin autotransporter) is another major virulence factor encoded by the ''vacA'' gene.<ref name="UniProt2">{{cite web |title=UniProt |url=https://www.uniprot.org/uniprotkb/Q48245/entry |website=www.uniprot.org |access-date=21 March 2024}}</ref> All strains of ''H. pylori'' carry this gene but there is much diversity, and only 50% produce the encoded cytotoxin.<ref name="Li"/><ref name="Alzahrani"/> The four main subtypes of ''vacA'' are ''s1/m1, s1/m2, s2/m1,'' and ''s2/m2''. ''s1/m1'' and ''s1/m2'' are known to cause an increased risk of gastric cancer.<ref>{{cite journal | vauthors = Miehlke S, Yu J, Schuppler M, Frings C, Kirsch C, Negraszus N, Morgner A, Stolte M, Ehninger G, Bayerdörffer E | title = Helicobacter pylori vacA, iceA, and cagA status and pattern of gastritis in patients with malignant and benign gastroduodenal disease | journal = The American Journal of Gastroenterology | volume = 96 | issue = 4 | pages = 1008–13 | date = April 2001 | doi = 10.1111/j.1572-0241.2001.03685.x | pmid = 11316139 | s2cid = 24024542 | url = http://journals.lww.com/10.1111/j.1572-0241.2001.03685.x | access-date = 24 June 2020 | archive-date = 23 February 2022 | archive-url = https://web.archive.org/web/20220223203948/https://journals.lww.com/ajg/Abstract/2001/04000/Helicobacter_Pylori_Vaca,_Icea,andCagaStatus_and.17.aspx | url-status = live }}</ref> VacA is an oligomeric protein complex that causes a progressive vacuolation in the epithelial cells leading to their death.<ref name="Hisatsune"/> The vacuolation has also been associated with promoting intracellular reservoirs of ''H. pylori'' by disrupting the calcium channel cell membrane [[MCOLN1|TRPML1]].<ref>{{cite journal | vauthors = Capurro MI, Greenfield LK, Prashar A, Xia S, Abdullah M, Wong H, Zhong XZ, Bertaux-Skeirik N, Chakrabarti J, Siddiqui I, O'Brien C, Dong X, Robinson L, Peek RM, Philpott DJ, Zavros Y, Helmrath M, Jones NL | title = VacA generates a protective intracellular reservoir for Helicobacter pylori that is eliminated by activation of the lysosomal calcium channel TRPML1 | journal = Nature Microbiology | volume = 4 | issue = 8 | pages = 1411–1423 | date = August 2019 | pmid = 31110360 | pmc = 6938649 | doi = 10.1038/s41564-019-0441-6 }}</ref> VacA has been shown to increase the levels of [[Cyclooxygenase-2|COX2]], an up-regulation that increases the production of a [[prostaglandin]] indicating a strong host cell inflammatory response.<ref name="Hisatsune">{{cite journal |vauthors=Hisatsune J, Yamasaki E, Nakayama M, Shirasaka D, Kurazono H, Katagata Y, Inoue H, Han J, Sap J, Yahiro K, Moss J, Hirayama T |title=Helicobacter pylori VacA enhances prostaglandin E2 production through induction of cyclooxygenase 2 expression via a p38 mitogen-activated protein kinase/activating transcription factor 2 cascade in AZ-521 cells |journal=Infect Immun |volume=75 |issue=9 |pages=4472–81 |date=September 2007 |pmid=17591797 |pmc=1951161 |doi=10.1128/IAI.00500-07 |url=}}</ref><ref>{{cite journal | vauthors = Sajib S, Zahra FT, Lionakis MS, German NA, Mikelis CM | title = Mechanisms of angiogenesis in microbe-regulated inflammatory and neoplastic conditions | journal = Angiogenesis | volume = 21 | issue = 1 | pages = 1–14 | date = February 2018 | pmid = 29110215 | doi = 10.1007/s10456-017-9583-4 | s2cid = 3346742 }}</ref>

===Outer membrane proteins and vesicles===
About 4% of the genome encodes for [[outer membrane proteins]] that can be grouped into five families.<ref name="da Costa">{{cite journal |vauthors=da Costa DM, Pereira Edos S, Rabenhorst SH |title=What exists beyond cagA and vacA? Helicobacter pylori genes in gastric diseases |journal=World J Gastroenterol |volume=21 |issue=37 |pages=10563–72 |date=October 2015 |pmid=26457016 |pmc=4588078 |doi=10.3748/wjg.v21.i37.10563 |doi-access=free |url=}}</ref> The largest family includes [[bacterial adhesin]]s. The other four families are [[Porin (protein)|porin]]s, iron transporters, [[flagella|flagellum]]-associated proteins, and proteins of unknown function. Like other typical gram-negative bacteria, the outer membrane of ''H.&nbsp;pylori'' consists of [[phospholipids]] and [[lipopolysaccharide]] (LPS). The [[Lipopolysaccharide#O-antigen|O-antigen]] of LPS may be [[fucose|fucosylated]] and mimic [[Lewis antigen system|Lewis blood group antigens]] found on the gastric epithelium.<ref name="Kusters2006"/>

''H. pylori'' forms blebs from the outer membrane that pinch off as [[outer membrane vesicle]]s to provide an alternative delivery system for virulence factors including CagA.<ref name="Testerman"/>

A ''Helicobacter'' [[cysteine-rich protein]] HcpA is known to trigger an immune response, causing inflammation.<ref name="pmid19393649">{{cite journal | vauthors = Dumrese C, Slomianka L, Ziegler U, Choi SS, Kalia A, Fulurija A, Lu W, Berg DE, Benghezal M, Marshall B, Mittl PR | title = The secreted Helicobacter cysteine-rich protein A causes adherence of human monocytes and differentiation into a macrophage-like phenotype | journal = FEBS Letters | volume = 583 | issue = 10 | pages = 1637–43 | date = May 2009 | pmid = 19393649 | pmc = 2764743 | doi = 10.1016/j.febslet.2009.04.027 | bibcode = 2009FEBSL.583.1637D }}</ref> 
A ''Helicobacter pylori'' virulence factor ''DupA'' is associated with the development of duodenal ulcers.<ref name="Alam">{{cite journal |vauthors=Alam J, Sarkar A, Karmakar BC, Ganguly M, Paul S, Mukhopadhyay AK |title=Novel virulence factor dupA of Helicobacter pylori as an important risk determinant for disease manifestation: An overview |journal=World J Gastroenterol |volume=26 |issue=32 |pages=4739–4752 |date=August 2020 |pmid=32921954 |pmc=7459207 |doi=10.3748/wjg.v26.i32.4739 |doi-access=free |url=}}</ref>

===Mechanisms of tolerance===
The need for survival has led to the development of different mechanisms of tolerance that enable the persistence of ''H. pylori''.<ref name="Trastoy">{{cite journal |vauthors=Trastoy R, Manso T, Fernández-García L, Blasco L, Ambroa A, Pérez Del Molino ML, Bou G, García-Contreras R, Wood TK, Tomás M |title=Mechanisms of Bacterial Tolerance and Persistence in the Gastrointestinal and Respiratory Environments |journal=Clin Microbiol Rev |volume=31 |issue=4 |pages= |date=October 2018 |pmid=30068737 |pmc=6148185 |doi=10.1128/CMR.00023-18 |url=}}</ref> These mechanisms can also help to overcome the effects of antibiotics.<ref name="Trastoy" /> ''H. pylori'' has to not only survive the harsh gastric acidity but also the sweeping of mucus by continuous [[peristalsis]], and [[phagocytic]] attack accompanied by the release of [[reactive oxygen species]].<ref>{{cite journal | vauthors = Olczak AA, Olson JW, Maier RJ | title = Oxidative-stress resistance mutants of Helicobacter pylori | journal = Journal of Bacteriology | volume = 184 | issue = 12 | pages = 3186–93 | date = June 2002 | pmid = 12029034 | pmc = 135082 | doi = 10.1128/JB.184.12.3186-3193.2002 }}</ref>  All organisms encode genetic programs for response to stressful conditions including those that cause DNA damage.<ref name=Dorer /> Stress conditions activate bacterial response mechanisms that are regulated by proteins expressed by [[regulator gene]]s.<ref name="Trastoy" /> The [[oxidative stress]] can induce potentially lethal mutagenic [[DNA adduct]]s in its genome. Surviving this [[DNA damage]] is supported by [[Genetic transformation|transformation]]-mediated [[homologous recombination|recombinational repair]], that contributes to successful colonization.<ref>{{cite journal | vauthors = O'Rourke EJ, Chevalier C, Pinto AV, Thiberge JM, Ielpi L, Labigne A, Radicella JP | title = Pathogen DNA as target for host-generated oxidative stress: role for repair of bacterial DNA damage in Helicobacter pylori colonization | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 5 | pages = 2789–94 | date = March 2003 | pmid = 12601164 | pmc = 151419 | doi = 10.1073/pnas.0337641100 | bibcode = 2003PNAS..100.2789O | doi-access = free }}</ref><ref>{{cite journal | vauthors = Michod RE, Bernstein H, Nedelcu AM | title = Adaptive value of sex in microbial pathogens | journal = Infection, Genetics and Evolution | volume = 8 | issue = 3 | pages = 267–85 | date = May 2008 | pmid = 18295550 | doi = 10.1016/j.meegid.2008.01.002 | bibcode = 2008InfGE...8..267M }}</ref> ''H.&nbsp;pylori'' is naturally competent for transformation. While many organisms are competent only under certain environmental conditions, such as starvation, ''H.&nbsp;pylori'' is competent throughout logarithmic growth.<ref name=Dorer>{{cite journal | vauthors = Dorer MS, Fero J, Salama NR | title = DNA damage triggers genetic exchange in Helicobacter pylori | journal = PLOS Pathogens | volume = 6 | issue = 7 | pages = e1001026 | date = July 2010 | pmid = 20686662 | pmc = 2912397 | doi = 10.1371/journal.ppat.1001026 | editor1-last = Blanke | editor1-first = Steven R. | doi-access = free }}</ref>

[[Transformation (genetics)|Transformation]] (the transfer of DNA from one bacterial cell to another through the intervening medium) appears to be part of an adaptation for [[DNA repair]].<ref name=Dorer/> [[Homologous recombination]] is required for repairing [[double-strand break]]s (DSBs). The AddAB helicase-nuclease complex resects DSBs and loads [[RecA]] onto single-strand DNA (ssDNA), which then mediates strand exchange, leading to homologous recombination and repair. The requirement of RecA plus AddAB for efficient gastric colonization suggests that ''H.&nbsp;pylori'' is either exposed to double-strand DNA damage that must be repaired or requires some other recombination-mediated event. In particular, natural transformation is increased by DNA damage in ''H.&nbsp;pylori'', and a connection exists between the DNA damage response and DNA uptake in ''H.&nbsp;pylori''.<ref name=Dorer />  This natural competence contributes to the persistence of ''H.&nbsp;pylori''. ''H. pylori'' has much greater rates of recombination and mutation than other bacteria.<ref name="Yamaoka"/>  Genetically different strains can be found in the same host, and also in different regions of the stomach.<ref name="Ailloud">{{cite journal |vauthors=Ailloud F, Didelot X, Woltemate S, Pfaffinger G, Overmann J, Bader RC, Schulz C, Malfertheiner P, Suerbaum S |title=Within-host evolution of Helicobacter pylori shaped by niche-specific adaptation, intragastric migrations and selective sweeps |journal=Nat Commun |volume=10 |issue=1 |pages=2273 |date=May 2019 |pmid=31118420 |pmc=6531487 |doi=10.1038/s41467-019-10050-1 |bibcode=2019NatCo..10.2273A |url=}}</ref> An overall response to multiple stressors can result from an interaction of the mechanisms.<ref name="Trastoy" />

[[RuvABC]] proteins are essential to the process of recombinational repair, since they resolve intermediates in this process termed [[Holliday junction]]s. ''H.&nbsp;pylori'' mutants that are defective in RuvC have increased sensitivity to DNA-damaging agents and to oxidative stress, exhibit reduced survival within macrophages, and are unable to establish successful infection in a mouse model.<ref>{{cite journal | vauthors = Loughlin MF, Barnard FM, Jenkins D, Sharples GJ, Jenks PJ | title = Helicobacter pylori mutants defective in RuvC Holliday junction resolvase display reduced macrophage survival and spontaneous clearance from the murine gastric mucosa | journal = Infection and Immunity | volume = 71 | issue = 4 | pages = 2022–31 | date = April 2003 | pmid = 12654822 | pmc = 152077 | doi = 10.1128/IAI.71.4.2022-2031.2003 }}</ref> Similarly, RecN protein plays an important role in DSB repair.<ref name=Wang>{{cite journal | vauthors = Wang G, Maier RJ | title = Critical role of RecN in recombinational DNA repair and survival of Helicobacter pylori | journal = Infection and Immunity | volume = 76 | issue = 1 | pages = 153–60 | date = January 2008 | pmid = 17954726 | pmc = 2223656 | doi = 10.1128/IAI.00791-07 }}</ref> An ''H.&nbsp;pylori'' recN mutant displays an attenuated ability to colonize mouse stomachs, highlighting the importance of recombinational DNA repair in survival of ''H.&nbsp;pylori'' within its host.<ref name=Wang/>

====Biofilm====
An effective sustained colonization response is the formation of a [[biofilm]].
Having first adhered to cellular surfaces, the bacteria produce and secrete [[extracellular polymeric substance]] (EPS). EPS consists largely of [[biopolymer]]s and provides the framework for the biofilm structure.<ref name="Lin2"/> ''H. pylori'' helps the biofilm formation by altering its flagella into adhesive structures that provide adhesion between the cells.<ref name="Sun"/> Layers of aggregated bacteria as microcolonies accumulate to thicken the biofilm.

The matrix of EPS prevents the entry of antibiotics and immune cells, and provides protection from heat and competition from other microorganisms.<ref name="Lin2"/> Channels form between the cells in the biofilm matrix allowing the transport of nutrients, enzymes, metabolites, and waste.<ref name="Lin2"/> Cells in the deep layers may be nutritionally deprived and enter into the coccoid dormant-like state.<ref name="Bahmaninejad">{{cite journal |vauthors=Bahmaninejad P, Ghafourian S, Mahmoudi M, Maleki A, Sadeghifard N, Badakhsh B |title=Persister cells as a possible cause of antibiotic therapy failure in Helicobacter pylori |journal=JGH Open |volume=5 |issue=4 |pages=493–497 |date=April 2021 |pmid=33860100 |pmc=8035453 |doi=10.1002/jgh3.12527 |url=}}</ref><ref name="Cammarota">{{cite journal |last1=Cammarota |first1=G. |last2=Sanguinetti |first2=M. |last3=Gallo |first3=A. |last4=Posteraro |first4=B. |title=Review article: biofilm formation by H elicobacter pylori as a target for eradication of resistant infection |url=https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2036.2012.05165.x |journal=Alimentary Pharmacology & Therapeutics |access-date=3 March 2024 |pages=222–230 |language=en |doi=10.1111/j.1365-2036.2012.05165.x |date=August 2012|volume=36 |issue=3 |pmid=22650647 |s2cid=24026187 }}</ref> By changing the shape of the bacterium to a coccoid form, the exposure of [[Lipopolysaccharide|LPS]] (targeted by antibiotics) becomes limited, and so evades detection by the immune system.<ref name="Shadvar"/> It has also been shown that the ''cag'' pathogenicity island remains intact in the coccoid form.<ref name="Shadvar"/> Some of these antibiotic resistant cells may remain in the host as [[persister cell]]s. Following eradication, the persister cells can cause a recurrence of the infection.<ref name="Bahmaninejad"/><ref name="Cammarota"/> Bacteria can detach from the biofilm to relocate and colonize elsewhere in the stomach to form other biofilms.<ref name="Lin2"/>