1,591
Views
16
CrossRef citations to date
0
Altmetric
Editorial

Molecular mimicry

Good artists copy, great artists steal

&
Pages 433-434 | Received 15 Jul 2013, Accepted 16 Jul 2013, Published online: 17 Jul 2013
This article refers to:
Prediction of molecular mimicry candidates in human pathogenic bacteria

Over the course of evolution, microorganisms have developed innovative survival strategies to thrive in their hosts.Citation1 The human body is home to many species of bacteria, viruses, fungi, and other invertebrate parasites. Some of these organisms that live and thrive in humans are commensals and are harmless. They may be also beneficial to the host as they provide certain nutrients or compete with pathogenic organisms for space and recourses.Citation2 However, there is also a myriad of organisms that are pathogenic to the hosts. One of the mechanisms that empower pathogenic organisms to avert or subvert the host’s surveillance and defense mechanisms is molecular mimicry.Citation3-Citation5 The pressure to evolve molecular mimics may have arisen when the primordial free-living organisms “chose” to parasitize other organisms.

Molecular mimicry is the sequence or structural resemblance of molecules of the host and the microbe.Citation1,Citation3 Classically, the phenomenon of molecular mimicry is associated with autoimmune reactions.Citation3,Citation5 Immunological central tolerance mechanisms involve clonally deleting the populations of T cells and B cells that react to self-antigens. However this mechanism is not foolproof, as a considerable number of cells can escape deletion.Citation6 T cells and B cells mount their response to certain portions of a pathogen’s molecule, popularly called antigenic determinants or epitopes. If the antigenic determinants of pathogens are similar to host proteins as a result of mimicry, then the immune system reacts against its own cells and tissues, expressing that epitope resulting in autoimmune reactions. One of the classical examples of bacterial molecular mimics that elicit autoimmune reactions is the M protein of Streptococcus pyogenes that elicits autoantibodies that cross-react with heart myosin leading to heart damage.Citation7 Viral infections may also provoke autoimmune reactions through molecular mimicry. Cross reactive T cell response to islet antigens GAD65 or proinsulin aftermath of herpes, rubella, and coxsackie B viral infections may result in type I diabetes.Citation3

Besides autoimmune reactions, molecular mimicry also influences the subversion of the host surveillance mechanisms and may help promote the survival of parasites or pathogens. Indeed, many parasites and pathogens, including plant pathogens, show evidence of molecular mimicry.Citation1,Citation8-Citation10 In these cases, structural mimicry is usually involved.Citation1 Viruses produce their “own” versions of cytokines or decoy receptors of host’s cytokines, which results in immunomodulation of the host’s response to the advantage of the virus.Citation4 For instance, Human cytomegalovirus produces the immunosuppressive cytokine IL-10 and orthopoxviruses produce decoy receptors for the antiviral cytokines interferon-γ and IL-1.Citation11-Citation13 Another example is the vaccinia virus protein A49 that interferes with NFκB.Citation14 The transcription factor NFκB, which is central to the activation of the host’s immune response, is normally retained in the cytoplasm as an inactive form bound to its inhibitor IκBα. Upon stimulation, IκBα is degraded and NFκB moves in to the nucleus to turn on an array of genes. A49, a mimic of IκBα, binds to the ubiquitin ligase thus preventing IκBα degradation, thus promoting cytoplasmic retention of NFκB.Citation14 Similarly, bacteria produce structural mimics to gain entry in to the host cell. Yersinia pseudotuberculosis produces invasin to bind the host β1 integrin surface receptors to enable attachment and entry.Citation1,Citation15 Invasin out-competes the natural β1 integrin ligand fibronectin, with which it shares structural similarity without any sequence homology. Further, structural mimicry can be also witnessed in pathogens and commensal bacteria mimicking the host’s sialylation patterns to masquerade as “self” to avoid, subvert, or inhibit host innate immunity.Citation16 Many human pathogens coat their surface with sialic acid N-acetylneuraminic acid (Neu5Ac) that enables them to recruit inhibitory siglecs (sialic acid recognizing Ig-superfamily lectins) or to bind to factor H (a serum protein which restricts the alternative complement pathway) thus dampen innate immune response.Citation17,Citation18 Indeed, molecular mimicry in host–pathogen interactions typifies the Picasso quote: “Good artists copy, great artists steal.”

Thus, identification of molecular mimics may provide important insights to the understanding of pathogenesis. Although high throughput genome-wide analysis has been used in the past to discover candidate molecular mimics in several different parasites, such studies for bacteria have largely been lacking.Citation9 In this issue, Doxey and McConkey attempt to fill this void.Citation19 Employing in silico tools for high throughput analyses, they have identified almost a hundred of such candidates by screening a total of 128 bacterial proteomes.Citation19 The authors have classified the bacteria analyzed in the study into two broad groups—pathogenic and non-pathogenic species. They matched the whole proteomes of the selected bacteria against the human proteome. Molecular mimicry candidates were observed in both pathogenic species and non-pathogenic species of bacteria. The authors then compared all the candidates to select the unique set of mimics that may aid in pathogen virulence. They do this by applying the criteria of mimics that are specific or enriched in pathogens and either absent or not enriched in non-pathogenic species. Finally, they arrive at a list of 95 such candidates that show unique relationships. Importantly, almost third of the selected candidates could be correlated with published experimental data as possible virulence factors. Molecular mimics that affect host lipid metabolism, phagocytosis, apoptotic pathways of host cells, which enables to destroy the engulfed bacteria, could be readily identified. Finally, the authors also try to uncover the evolutionary origins and relationships of the mimics using collagen mimics and leucine-rich repeat proteins as examples. Both mimics stand out as representatives of independent evolutionary origins yet achieving convergent functions, which is not unusual in pathogenic bacteria.Citation8

An arbitrary classification of pathogenic vs. non-pathogenic bacterial species has been used in the study. However, the work succeeds in identifying putative candidates of virulence and manipulators of host function, which was the primary objective of the study. Nevertheless, one has to remember that this approach may not be sufficient to identify mimics that are not necessarily involved in virulence. For example, selection pressure to evolve mimics that aid in colonizing the host would be similar in both commensal non-pathogenic bacteria as well as pathogens.Citation1,Citation2 Further, mimics may share structural similarity but need not have a similar sequence.Citation1,Citation15 Furthermore, this approach may not also effectively identify mimicry candidates in pathogens that may elicit autoimmunity. Even small regions of similarity, not necessarily the complete sequence of a protein, are sufficient to trigger such autoimmune reactions.Citation3,Citation5 However, this study clearly demonstrates the utility of high-throughput approach to identify virulence factors. It also provides a platform for further research in scrutinizing the identified candidates that may eventually open avenues for better comprehension of pathogenesis and therapeutic interventions.

Submitted

07/15/13

Accepted

07/16/13

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

References

  • Stebbins CE, Galán JE. Structural mimicry in bacterial virulence. Nature 2001; 412:701 - 5; http://dx.doi.org/10.1038/35089000; PMID: 11507631
  • Kamada N, Seo SU, Chen GY, Núñez G. Role of the gut microbiota in immunity and inflammatory disease. Nat Rev Immunol 2013; 13:321 - 35; http://dx.doi.org/10.1038/nri3430; PMID: 23618829
  • Cusick MF, Libbey JE, Fujinami RS. Molecular mimicry as a mechanism of autoimmune disease. Clin Rev Allergy Immunol 2012; 42:102 - 11; http://dx.doi.org/10.1007/s12016-011-8294-7; PMID: 22095454
  • Epperson ML, Lee CA, Fremont DH. Subversion of cytokine networks by virally encoded decoy receptors. Immunol Rev 2012; 250:199 - 215; http://dx.doi.org/10.1111/imr.12009; PMID: 23046131
  • Babu Chodisetti S, Rai PK, Gowthaman U, Pahari S, Agrewala JN. Potential T cell epitopes of Mycobacterium tuberculosis that can instigate molecular mimicry against host: implications in autoimmune pathogenesis. BMC Immunol 2012; 13:13; http://dx.doi.org/10.1186/1471-2172-13-13; PMID: 22435930
  • Mueller DL. Mechanisms maintaining peripheral tolerance. Nat Immunol 2010; 11:21 - 7; http://dx.doi.org/10.1038/ni.1817; PMID: 20016506
  • Whitton JL, Feuer R. Myocarditis, microbes and autoimmunity. Autoimmunity 2004; 37:375 - 86; http://dx.doi.org/10.1080/08916930410001713089; PMID: 15621561
  • Sikora S, Strongin A, Godzik A. Convergent evolution as a mechanism for pathogenic adaptation. Trends Microbiol 2005; 13:522 - 7; http://dx.doi.org/10.1016/j.tim.2005.08.010; PMID: 16153847
  • Ludin P, Nilsson D, Mäser P. Genome-wide identification of molecular mimicry candidates in parasites. PLoS One 2011; 6:e17546; http://dx.doi.org/10.1371/journal.pone.0017546; PMID: 21408160
  • Hogenhout SA, Van der Hoorn RA, Terauchi R, Kamoun S. Emerging concepts in effector biology of plant-associated organisms. Mol Plant Microbe Interact 2009; 22:115 - 22; http://dx.doi.org/10.1094/MPMI-22-2-0115; PMID: 19132864
  • Kotenko SV, Saccani S, Izotova LS, Mirochnitchenko OV, Pestka S. Human cytomegalovirus harbors its own unique IL-10 homolog (cmvIL-10). Proc Natl Acad Sci U S A 2000; 97:1695 - 700; http://dx.doi.org/10.1073/pnas.97.4.1695; PMID: 10677520
  • Alcamí A, Smith GL. A soluble receptor for interleukin-1 beta encoded by vaccinia virus: a novel mechanism of virus modulation of the host response to infection. Cell 1992; 71:153 - 67; http://dx.doi.org/10.1016/0092-8674(92)90274-G; PMID: 1394428
  • Alcamí A, Smith GL. Vaccinia, cowpox, and camelpox viruses encode soluble gamma interferon receptors with novel broad species specificity. J Virol 1995; 69:4633 - 9; PMID: 7609027
  • Mansur DS, Maluquer de Motes C, Unterholzner L, Sumner RP, Ferguson BJ, Ren H, et al. Poxvirus targeting of E3 ligase β-TrCP by molecular mimicry: a mechanism to inhibit NF-κB activation and promote immune evasion and virulence. PLoS Pathog 2013; 9:e1003183; http://dx.doi.org/10.1371/journal.ppat.1003183; PMID: 23468625
  • Van Nhieu GT, Isberg RR. The Yersinia pseudotuberculosis invasin protein and human fibronectin bind to mutually exclusive sites on the alpha 5 beta 1 integrin receptor. J Biol Chem 1991; 266:24367 - 75; PMID: 1837020
  • Varki A, Gagneux P. Multifarious roles of sialic acids in immunity. Ann N Y Acad Sci 2012; 1253:16 - 36; http://dx.doi.org/10.1111/j.1749-6632.2012.06517.x; PMID: 22524423
  • Carlin AF, Uchiyama S, Chang YC, Lewis AL, Nizet V, Varki A. Molecular mimicry of host sialylated glycans allows a bacterial pathogen to engage neutrophil Siglec-9 and dampen the innate immune response. Blood 2009; 113:3333 - 6; http://dx.doi.org/10.1182/blood-2008-11-187302; PMID: 19196661
  • Khatua B, Ghoshal A, Bhattacharya K, Mandal C, Saha B, Crocker PR, et al. Sialic acids acquired by Pseudomonas aeruginosa are involved in reduced complement deposition and siglec mediated host-cell recognition. FEBS Lett 2010; 584:555 - 61; http://dx.doi.org/10.1016/j.febslet.2009.11.087; PMID: 19945458
  • Doxey AC, McConkey BJ. Prediction of molecular mimicry candidates in human pathogenic bacteria. Virulence 2013; 4:453 - 66; http://dx.doi.org/10.4161/viru.25180; PMID: 23715053