Pathogen-associated molecular pattern

Pathogen-associated molecular patterns (PAMPs) are small molecular motifs conserved within a class of microbes, but not present in the host.{{cite journal | vauthors = Tang D, Kang R, Coyne CB, Zeh HJ, Lotze MT | title = PAMPs and DAMPs: signal 0s that spur autophagy and immunity | journal = Immunological Reviews | volume = 249 | issue = 1 | pages = 158–175 | date = September 2012 | pmid = 22889221 | pmc = 3662247 | doi = 10.1111/j.1600-065X.2012.01146.x }} They are recognized by toll-like receptors (TLRs) and other pattern recognition receptors (PRRs) in both plants and animals.{{cite journal | vauthors = Ingle RA, Carstens M, Denby KJ | title = PAMP recognition and the plant-pathogen arms race | journal = BioEssays | volume = 28 | issue = 9 | pages = 880–889 | date = September 2006 | pmid = 16937346 | doi = 10.1002/bies.20457 | s2cid = 26861625 }} This allows the innate immune system to recognize pathogens and thus, protect the host from infection.{{Cite book |url=https://www.worldcat.org/oclc/951918628 |title=Review of medical microbiology and immunology |vauthors=Levinson W |date=2016 |isbn=978-0-07-184574-8 |edition=14th |location=New York | publisher = McGraw-Hill Education |oclc=951918628}}{{rp|494}}

This initiation of the immune response consists of the secretion of inflammatory cytokines and chemokines.{{cite journal | vauthors = Ciaston I, Dobosz E, Potempa J, Koziel J | title = The subversion of toll-like receptor signaling by bacterial and viral proteases during the development of infectious diseases | journal = Molecular Aspects of Medicine | volume = 88 | pages = 101143 | date = December 2022 | pmid = 36152458 | pmc = 9924004 | doi = 10.1016/j.mam.2022.101143 }} PAMPs can initiate the maturation of immune cells, which can travel to the primary lymph node and trigger the adaptive immune system that involves the production of antibodies against specific antigens.{{cite journal | vauthors = Lester SN, Li K | title = Toll-like receptors in antiviral innate immunity | journal = Journal of Molecular Biology | volume = 426 | issue = 6 | pages = 1246–1264 | date = March 2014 | pmid = 24316048 | doi = 10.1016/j.jmb.2013.11.024 | series = Antiviral Innate Immunity (Part II) | pmc = 3943763 }}

Although the term "PAMP" is relatively new, the concept that molecules derived from microbes must be detected by receptors from multicellular organisms has been held for many decades, and references to an "endotoxin receptor" are found in much of the older literature. The recognition of PAMPs by the PRRs triggers activation of several signaling cascades in the host immune cells like the stimulation of interferons (IFNs){{cite journal | vauthors = Pichlmair A, Reis e Sousa C | title = Innate recognition of viruses | journal = Immunity | volume = 27 | issue = 3 | pages = 370–383 | date = September 2007 | pmid = 17892846 | doi = 10.1016/j.immuni.2007.08.012 | doi-access = free }} or other cytokines.{{cite journal | vauthors = Akira S, Uematsu S, Takeuchi O | title = Pathogen recognition and innate immunity | journal = Cell | volume = 124 | issue = 4 | pages = 783–801 | date = February 2006 | pmid = 16497588 | doi = 10.1016/j.cell.2006.02.015 | doi-access = free }}

Role in the Immune System

Cells that promote innate immunity (dendritic cells, macrophages, neutrophils, and more) express PRRs. Not only do PPRs detect PAMPs, they also detect host-derived damage-associated molecular patterns or DAMPs that are products of tissue damage. Toll-like receptors (TLR), complement receptors (CR), and scavenger receptors are among the many types of PRRs that monitor the cellular environment for invaders and damage.{{Cite journal |last1=Maritska |first1=Ziske |last2=Hidayat |first2=Rachmat |date=2023-05-08 |title=The Role of Pattern Recognition Receptor (PRR) in the Body's Defense System: A Narrative Literature Review |url=https://hmpublisher.com/index.php/OAIJMR/article/view/300 |journal=Open Access Indonesian Journal of Medical Reviews |language=en |volume=3 |issue=2 |pages=365–368 |doi=10.37275/oaijmr.v3i2.300 |issn=2807-6257|doi-access=free }} The innate and adaptive immune systems are connected through TLRs because it leads to the secretion of cytokines and chemokines that go on to help recruit lymphocytes.

= Innate Immunity =

When an antigen breaches the protective barrier (skin, body hair, gastrointestinal tract, etc) and enters the tissue or the bloodstream, the initial response is known as the innate immune system.{{Cite web |title=Khan Academy |url=https://www.khanacademy.org/test-prep/mcat/organ-systems/the-immune-system/a/innate-immunity#:~:text=The%20following%20cells%20are%20leukocytes%20of%20the,bacteria%20and%20viruses,%20to%20engulf%20and%20destroy |access-date=2025-03-10 |website=www.khanacademy.org |language=en}} PAMPs are critical to the initiation of the innate immune system because they recognize the danger, which will result in a response against the threat. PAMPs interacting with PRRs initiate signaling pathways that produce chemokines and pro-inflammatory cytokines–creating an inflammatory environment.{{Cite journal |last1=Li |first1=Danyang |last2=Wu |first2=Minghua |date=2021-08-04 |title=Pattern recognition receptors in health and diseases |url=https://www.nature.com/articles/s41392-021-00687-0 |journal=Signal Transduction and Targeted Therapy |language=en |volume=6 |issue=1 |pages=1–24 |doi=10.1038/s41392-021-00687-0 |issn=2059-3635|pmc=8333067 }}

The cytokines and chemokines secreted lead to the translocation of dendritic cells that activate T cells, which "help" B-cells secrete antigen-specific antibodies, which is associated with the adaptive immune response. None of these events can occur without the PRR–PAMPs interaction. {{Cite journal |last1=Carty |first1=Michael |last2=Guy |first2=Coralie |last3=Bowie |first3=Andrew G. |date=2021-01-01 |title=Detection of Viral Infections by Innate Immunity |url=https://www.sciencedirect.com/science/article/pii/S0006295220305529 |journal=Biochemical Pharmacology |volume=183 |pages=114316 |doi=10.1016/j.bcp.2020.114316 |issn=0006-2952 |pmid=33152343 |hdl-access=free |hdl=2262/98535}}

Types

A vast array of different types of molecules can serve as PAMPs, including glycans and glycoconjugates.{{cite journal | vauthors = Maverakis E, Kim K, Shimoda M, Gershwin ME, Patel F, Wilken R, Raychaudhuri S, Ruhaak LR, Lebrilla CB | title = Glycans in the immune system and The Altered Glycan Theory of Autoimmunity: a critical review | journal = Journal of Autoimmunity | volume = 57 | issue = 6 | pages = 1–13 | date = February 2015 | pmid = 25578468 | pmc = 4340844 | doi = 10.1016/j.jaut.2014.12.002 }} Flagellin is also another PAMP that is recognized via the constant domain, D1 by TLR5.{{cite journal | vauthors = Akira S, Uematsu S, Takeuchi O | title = Pathogen recognition and innate immunity | journal = Cell | volume = 124 | issue = 4 | pages = 783–801 | date = February 2006 | pmid = 16497588 | doi = 10.1016/j.cell.2006.02.015 | s2cid = 14357403 | doi-access = free }} Despite being a protein, its N- and C-terminal ends are highly conserved, due to its necessity for function of flagella. Nucleic acid variants normally associated with viruses, such as double-stranded RNA (dsRNA), are recognized by TLR3 and unmethylated CpG motifs are recognized by TLR9.{{cite journal | vauthors = Mahla RS, Reddy MC, Prasad DV, Kumar H | title = Sweeten PAMPs: Role of Sugar Complexed PAMPs in Innate Immunity and Vaccine Biology | journal = Frontiers in Immunology | volume = 4 | pages = 248 | date = September 2013 | pmid = 24032031 | pmc = 3759294 | doi = 10.3389/fimmu.2013.00248 | doi-access = free }} The CpG motifs must be internalized in order to be recognized by TLR9. Viral glycoproteins, as seen in the viral-envelope, as well as fungal PAMPS on the cell surface or fungi are recognized by TLR2 and TLR4.

= Gram-negative bacteria =

Bacterial lipopolysaccharides (LPSs), also known as endotoxins, are found on the cell membranes of gram-negative bacteria,{{cite journal | vauthors = Silhavy TJ, Kahne D, Walker S | title = The bacterial cell envelope | journal = Cold Spring Harbor Perspectives in Biology | volume = 2 | issue = 5 | pages = a000414 | date = May 2010 | pmid = 20452953 | pmc = 2857177 | doi = 10.1101/cshperspect.a000414 }} are considered to be the prototypical class of PAMPs. The lipid portion of LPS, lipid A, contains a diglycolamine backbone with multiple acyl chains. This is the conserved structural motif that is recognized by TLR4, particularly the TLR4-MD2 complex.{{cite journal | vauthors = Ahmad-Nejad P, Häcker H, Rutz M, Bauer S, Vabulas RM, Wagner H | title = Bacterial CpG-DNA and lipopolysaccharides activate Toll-like receptors at distinct cellular compartments | journal = European Journal of Immunology | volume = 32 | issue = 7 | pages = 1958–1968 | date = July 2002 | pmid = 12115616 | doi = 10.1002/1521-4141(200207)32:7<1958::AID-IMMU1958>3.0.CO;2-U | s2cid = 31631310 | doi-access = free }} Microbes have two main strategies in which they try to avoid the immune system, either by masking lipid A or directing their LPS towards an immunomodulatory receptor.

Peptidoglycan (PG) is also found within the membrane walls of gram-negative bacteria{{cite journal | vauthors = Silhavy TJ, Kahne D, Walker S | title = The bacterial cell envelope | journal = Cold Spring Harbor Perspectives in Biology | volume = 2 | issue = 5 | pages = a000414 | date = May 2010 | pmid = 20452953 | pmc = 2857177 | doi = 10.1101/cshperspect.a000414 }} and is recognized by TLR2, which is usually in a heterodimer of with TLR1 or TLR6.{{cite journal | vauthors = Dammermann W, Wollenberg L, Bentzien F, Lohse A, Lüth S | title = Toll like receptor 2 agonists lipoteichoic acid and peptidoglycan are able to enhance antigen specific IFNγ release in whole blood during recall antigen responses | journal = Journal of Immunological Methods | volume = 396 | issue = 1–2 | pages = 107–115 | date = October 2013 | pmid = 23954282 | doi = 10.1016/j.jim.2013.08.004 }}{{cite journal | vauthors = Janeway CA, Medzhitov R | title = Innate immune recognition | journal = Annual Review of Immunology | volume = 20 | issue = 1 | pages = 197–216 | date = April 2002 | pmid = 11861602 | doi = 10.1146/annurev.immunol.20.083001.084359 | s2cid = 39036433 }}

= Gram-positive bacteria =

Lipoteichoic acid (LTA) from gram-positive bacteria, bacterial lipoproteins (sBLP), a phenol soluble factor from Staphylococcus epidermidis, and a component of yeast walls called zymosan, are all recognized by a heterodimer of TLR2 and TLR1 or TLR6. However, LTAs result in a weaker pro-inflammatory response compared to lipopeptides, as they are only recognized by TLR2 instead of the heterodimer.

= Viruses =

Viral DNA, viral RNA and CpG are the PAMPs associated with viruses. The PRRs that sense viruses are TLRs, RLRs (Rig-I-like receptors), CLRs (C-type lectine receptors), and inflammasomes/DNA sensors.{{Cite journal |last1=Carty |first1=Michael |last2=Guy |first2=Coralie |last3=Bowie |first3=Andrew G. |date=2021-01-01 |title=Detection of Viral Infections by Innate Immunity |url=https://www.sciencedirect.com/science/article/pii/S0006295220305529 |journal=Biochemical Pharmacology |volume=183 |pages=114316 |doi=10.1016/j.bcp.2020.114316 |pmid=33152343 |issn=0006-2952|hdl=2262/98535 |hdl-access=free }} CLRs are mainly located on myeloid cells, and RLRs are cytoplasmic, mainly detecting viral RNA. TLRs can be located on cell surfaces and the endosomal membrane. Bacterial infections can be intracellular and extracellular, while viral infections are largely intracellular, so endosomal TLRs are most associated with virus detection.{{Cite journal |last1=Carty |first1=M |last2=Bowie |first2=A G |date=2010-08-16 |title=Recent insights into the role of Toll-like receptors in viral infection |journal=Clinical and Experimental Immunology |language=en |volume=161 |issue=3 |pages=397–406 |doi=10.1111/j.1365-2249.2010.04196.x |issn=1365-2249 |pmc=2962956 |pmid=20560984}}

TLR3 recognizes dsDNA while TLR7 and TLR8 detect ssRNA. TLR9's detection of hypomethylated CpG DNA could differentiate virus from self molecules because of the higher CpG content in viruses. PAMPs recognition by TLR is followed by signaling pathways. Viruses may evade the immune response by interacting with proteins in these signaling pathways. By attacking the proteins involved in these pathways, viruses can attempt to evade their destruction.

In mycobacteria

Mycobacteria are intracellular bacteria which survive in host macrophages. The mycobacterial wall is composed of lipids and polysaccharides and also contains high amounts of mycolic acid. Purified cell wall components of mycobacteria activate mainly TLR2 and also TLR4. Lipomannan and lipoarabinomannan are strong immunomodulatory lipoglycans.{{cite journal | vauthors = Quesniaux V, Fremond C, Jacobs M, Parida S, Nicolle D, Yeremeev V, Bihl F, Erard F, Botha T, Drennan M, Soler MN, Le Bert M, Schnyder B, Ryffel B | title = Toll-like receptor pathways in the immune responses to mycobacteria | journal = Microbes and Infection | volume = 6 | issue = 10 | pages = 946–959 | date = August 2004 | pmid = 15310472 | doi = 10.1016/j.micinf.2004.04.016 | doi-access = free }} TLR2 with association of TLR1 can recognize cell wall lipoprotein antigens from Mycobacterium tuberculosis, which also induce production of cytokines by macrophages.{{cite journal | vauthors = Thoma-Uszynski S, Stenger S, Takeuchi O, Ochoa MT, Engele M, Sieling PA, Barnes PF, Rollinghoff M, Bolcskei PL, Wagner M, Akira S, Norgard MV, Belisle JT, Godowski PJ, Bloom BR, Modlin RL | title = Induction of direct antimicrobial activity through mammalian toll-like receptors | journal = Science | volume = 291 | issue = 5508 | pages = 1544–1547 | date = February 2001 | pmid = 11222859 | doi = 10.1126/science.291.5508.1544 | bibcode = 2001Sci...291.1544T }} TLR9 can be activated by mycobacterial DNA.

History

First introduced by Charles Janeway in 1989, PAMP was used to describe microbial components that would be considered foreign in a multicellular host.{{cite encyclopedia | vauthors = Silva-Gomes S |title=Pathogen-Associated Molecular Patterns (PAMPs) |date=2014 |url=https://link.springer.com/10.1007/978-3-0348-0620-6_35-1 |encyclopedia=Encyclopedia of Inflammatory Diseases |pages=1–16 | veditors = Parnham M, Decout A, Nigou J |access-date=2023-03-10 | location = Basel |publisher=Springer |language=en |doi=10.1007/978-3-0348-0620-6_35-1 |isbn=978-3-0348-0620-6 |url-access=subscription }} The term "PAMP" has been criticized on the grounds that most microbes, not only pathogens, express the molecules detected; the term microbe-associated molecular pattern (MAMP),{{cite journal | vauthors = Koropatnick TA, Engle JT, Apicella MA, Stabb EV, Goldman WE, McFall-Ngai MJ | title = Microbial factor-mediated development in a host-bacterial mutualism | journal = Science | volume = 306 | issue = 5699 | pages = 1186–1188 | date = November 2004 | pmid = 15539604 | doi = 10.1126/science.1102218 | s2cid = 41603462 | bibcode = 2004Sci...306.1186K }}{{cite journal | vauthors = Ausubel FM | title = Are innate immune signaling pathways in plants and animals conserved? | journal = Nature Immunology | volume = 6 | issue = 10 | pages = 973–979 | date = October 2005 | pmid = 16177805 | doi = 10.1038/ni1253 | s2cid = 7451505 }}{{cite journal | vauthors = Didierlaurent A, Simonet M, Sirard JC | title = Innate and acquired plasticity of the intestinal immune system | journal = Cellular and Molecular Life Sciences | volume = 62 | issue = 12 | pages = 1285–1287 | date = June 2005 | pmid = 15971103 | pmc = 1865479 | doi = 10.1007/s00018-005-5032-4 }} has therefore been proposed. A virulence signal capable of binding to a pathogen receptor, in combination with a MAMP, has been proposed as one way to constitute a (pathogen-specific) PAMP.{{cite journal | vauthors = Rumbo M, Nempont C, Kraehenbuhl JP, Sirard JC | title = Mucosal interplay among commensal and pathogenic bacteria: lessons from flagellin and Toll-like receptor 5 | journal = FEBS Letters | volume = 580 | issue = 12 | pages = 2976–2984 | date = May 2006 | pmid = 16650409 | doi = 10.1016/j.febslet.2006.04.036 | bibcode = 2006FEBSL.580.2976R | s2cid = 14300007 | citeseerx = 10.1.1.320.8479 }} (Free full text available) Plant immunology frequently treats the terms "PAMP" and "MAMP" interchangeably, considering their recognition to be the first step in plant immunity, PTI (PAMP-triggered immunity), a relatively weak immune response that occurs when the host plant does not also recognize pathogenic effectors that damage it or modulate its immune response.{{cite journal | vauthors = Jones JD, Dangl JL | title = The plant immune system | journal = Nature | volume = 444 | issue = 7117 | pages = 323–329 | date = November 2006 | pmid = 17108957 | doi = 10.1038/nature05286 | doi-access = free | bibcode = 2006Natur.444..323J }}