1932

Abstract

Pore-forming toxins (PFTs) are released by one cell to directly inflict damage on another cell. Hosts use PFTs, including members of the membrane attack complex/perforin protein family, to fight infections and cancer, while bacteria and parasites deploy PFTs to promote infection. Apicomplexan parasites secrete perforin-like proteins as PFTs to egress from infected cells and traverse tissue barriers. Other protozoa, along with helminth parasites, utilize saposin-like PFTs prospectively for nutrient acquisition during infection. This review discusses seminal and more recent advances in understanding how parasite PFTs promote infection and describes how they are regulated and fulfill their roles without causing parasite self-harm. Although exciting progress has been made in defining mechanisms of pore formation by PFTs, many open questions remain to be addressed to gain additional key insights into these remarkable determinants of parasitic infections.

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2024-11-20
2025-02-16
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Literature Cited

  1. 1.
    Amino R, Giovannini D, Thiberge S, Gueirard P, Boisson B, et al. 2008.. Host cell traversal is important for progression of the malaria parasite through the dermis to the liver. . Cell Host Microbe 3:(2):8896
    [Crossref] [Google Scholar]
  2. 2.
    Andrä J, Herbst R, Leippe M. 2003.. Amoebapores, archaic effector peptides of protozoan origin, are discharged into phagosomes and kill bacteria by permeabilizing their membranes. . Dev. Comp. Immunol. 27:(4):291304
    [Crossref] [Google Scholar]
  3. 3.
    Andreadaki M, Hanssen E, Deligianni E, Claudet C, Wengelnik K, et al. 2018.. Sequential membrane rupture and vesiculation during Plasmodium berghei gametocyte egress from the red blood cell. . Sci. Rep. 8::3543
    [Crossref] [Google Scholar]
  4. 4.
    Antia R, Schlegel RA, Williamson P. 1992.. Binding of perforin to membranes is sensitive to lipid spacing and not headgroup. . Immunol. Lett. 32:(2):15357
    [Crossref] [Google Scholar]
  5. 5.
    Barker GC, Bundy DA. 1999.. Isolation of a gene family that encodes the porin-like proteins from the human parasitic nematode Trichuris trichiura. . Gene 229:(1/2):13136
    [Crossref] [Google Scholar]
  6. 6.
    Barnum SR, Bubeck D, Schein TN. 2020.. Soluble membrane attack complex: biochemistry and immunobiology. . Front. Immunol. 11::585108
    [Crossref] [Google Scholar]
  7. 7.
    Beauregard KE, Lee K-D, Collier RJ, Swanson JA. 1997.. pH-dependent perforation of macrophage phagosomes by listeriolysin O from Listeria monocytogenes. . J. Exp. Med. 186:(7):115963
    [Crossref] [Google Scholar]
  8. 8.
    Bracha R, Nuchamowitz Y, Anbar M, Mirelman D. 2006.. Transcriptional silencing of multiple genes in trophozoites of Entamoeba histolytica. . PLOS Pathog. 2:(5):e48
    [Crossref] [Google Scholar]
  9. 9.
    Bundy DA. 1994.. Immunoepidemiology of intestinal helminthic infections. 1. The global burden of intestinal nematode disease. . Trans. R. Soc. Trop. Med. Hyg. 88:(3):25961
    [Crossref] [Google Scholar]
  10. 10.
    Cabán-Hernández K, Espino AM. 2013.. Differential expression and localization of saposin-like protein 2 of Fasciola hepatica. . Acta Trop. 128:(3):59197
    [Crossref] [Google Scholar]
  11. 11.
    Carruthers VB, Tomley FM. 2008.. Microneme proteins in apicomplexans. . Sub-Cell. Biochem. 47::3345
    [Crossref] [Google Scholar]
  12. 12.
    Chang H-F, Schirra C, Pattu V, Krause E, Becherer U. 2023.. Lytic granule exocytosis at immune synapses: lessons from neuronal synapses. . Front. Immunol. 14::1177670
    [Crossref] [Google Scholar]
  13. 13.
    Czajkowsky DM, Hotze EM, Shao Z, Tweten RK. 2004.. Vertical collapse of a cytolysin prepore moves its transmembrane β-hairpins to the membrane. . EMBO J. 23:(16):320615
    [Crossref] [Google Scholar]
  14. 14.
    Das S, Lemgruber L, Tay CL, Baum J, Meissner M. 2017.. Multiple essential functions of Plasmodium falciparum actin-1 during malaria blood-stage development. . BMC Biol. 15::70
    [Crossref] [Google Scholar]
  15. 15.
    Deligianni E, Morgan RN, Bertuccini L, Wirth CC, Silmon de Monerri NC, et al. 2013.. A perforin-like protein mediates disruption of the erythrocyte membrane during egress of Plasmodium berghei male gametocytes. . Cell. Microbiol. 15:(8):143855
    [Crossref] [Google Scholar]
  16. 16.
    Deligianni E, Silmon de Monerri NC, McMillan PJ, Bertuccini L, Superti F, et al. 2018.. Essential role of Plasmodium perforin-like protein 4 in ookinete midgut passage. . PLOS ONE 13:(8):e0201651
    [Crossref] [Google Scholar]
  17. 17.
    DeMarco R, Mathieson W, Manuel SJ, Dillon GP, Curwen RS, et al. 2010.. Protein variation in blood-dwelling schistosome worms generated by differential splicing of micro-exon gene transcripts. . Genome Res. 20:(8):111221
    [Crossref] [Google Scholar]
  18. 18.
    Diaz N, Lico C, Capodicasa C, Baschieri S, Dessì D, et al. 2020.. Production and functional characterization of a recombinant predicted pore-forming protein (TvSAPLIP12) of Trichomonas vaginalis in Nicotiana benthamiana plants. . Front. Cell Infect. Microbiol. 10::581066
    [Crossref] [Google Scholar]
  19. 19.
    Drake LJ, Barker GC, Korchev Y, Lab M, Brooks H, Bundy DA. 1998.. Molecular and functional characterization of a recombinant protein of Trichuris trichiura. . Proc. Biol. Sci. 265:(1405):155965
    [Crossref] [Google Scholar]
  20. 20.
    Drake LJ, Korchev Y, Bashford L, Djamgoz M, Wakelin D, et al. 1994.. The major secreted product of the whipworm, Trichuris, is a pore-forming protein. . Proc. Biol. Sci. 257:(1350):25561
    [Crossref] [Google Scholar]
  21. 21.
    Ecker A, Bushell ES, Tewari R, Sinden RE. 2008.. Reverse genetics screen identifies six proteins important for malaria development in the mosquito. . Mol. Microbiol. 70:(1):20920
    [Crossref] [Google Scholar]
  22. 22.
    Ecker A, Pinto SB, Baker KW, Kafatos FC, Sinden RE. 2007.. Plasmodium berghei: Plasmodium perforin-like protein 5 is required for mosquito midgut invasion in Anopheles stephensi. . Exp. Parasitol. 116:(4):5048
    [Crossref] [Google Scholar]
  23. 23.
    Felizatti AP, Zeraik AE, Basso LGM, Kumagai PS, Lopes JLS, et al. 2020.. Interactions of amphipathic α-helical MEG proteins from Schistosoma mansoni with membranes. . Biochim. Biophys. Acta Biomembr. 1862:(3):183173
    [Crossref] [Google Scholar]
  24. 24.
    Garg S, Agarwal S, Kumar S, Yazdani SS, Chitnis CE, Singh S. 2013.. Calcium-dependent permeabilization of erythrocytes by a perforin-like protein during egress of malaria parasites. . Nat. Commun. 4::1736
    [Crossref] [Google Scholar]
  25. 25.
    Garg S, Sharma V, Ramu D, Singh S. 2015.. In silico analysis of calcium binding pocket of perforin like protein 1: insights into the regulation of pore formation. . Syst. Synth. Biol. 9:(Suppl. 1):1721
    [Crossref] [Google Scholar]
  26. 26.
    Garg S, Shivappagowdar A, Hada RS, Ayana R, Bathula C, et al. 2020.. Plasmodium perforin-like protein pores on the host cell membrane contribute in its multistage growth and erythrocyte senescence. . Front. Cell. Infect. Microbiol. 10::121
    [Crossref] [Google Scholar]
  27. 27.
    Grams R, Adisakwattana P, Ritthisunthorn N, Eursitthichai V, Vichasri-Grams S, Viyanant V. 2006.. The saposin-like proteins 1, 2, and 3 of Fasciola gigantica. . Mol. Biochem. Parasitol. 148:(2):13343
    [Crossref] [Google Scholar]
  28. 28.
    Guerra AJ, Carruthers VB. 2017.. Structural features of apicomplexan pore-forming proteins and their roles in parasite cell traversal and egress. . Toxins 9:(9):265
    [Crossref] [Google Scholar]
  29. 29.
    Guerra AJ, Zhang O, Bahr CME, Huynh M-H, DelProposto J, et al. 2018.. Structural basis of Toxoplasma gondii perforin-like protein 1 membrane interaction and activity during egress. . PLOS Pathog. 14:(12):e1007476
    [Crossref] [Google Scholar]
  30. 30.
    Hecht O, Van Nuland NA, Schleinkofer K, Dingley AJ, Bruhn H, et al. 2004.. Solution structure of the pore-forming protein of Entamoeba histolytica. . J. Biol. Chem. 279:(17):1783441
    [Crossref] [Google Scholar]
  31. 31.
    Herbst R, Marciano-Cabral F, Leippe M. 2004.. Antimicrobial and pore-forming peptides of free-living and potentially highly pathogenic Naegleria fowleri are released from the same precursor molecule. . J. Biol. Chem. 279:(25):2595558
    [Crossref] [Google Scholar]
  32. 32.
    Huynh M-H, Carruthers VB. 2022.. Toxoplasma gondii excretion of glycolytic products is associated with acidification of the parasitophorous vacuole during parasite egress. . PLOS Pathog. 18:(5):e1010139
    [Crossref] [Google Scholar]
  33. 33.
    Ishino T, Chinzei Y, Yuda M. 2005.. A Plasmodium sporozoite protein with a membrane attack complex domain is required for breaching the liver sinusoidal cell layer prior to hepatocyte infection. . Cell. Microbiol. 7:(2):199208
    [Crossref] [Google Scholar]
  34. 34.
    Kadota K, Ishino T, Matsuyama T, Chinzei Y, Yuda M. 2004.. Essential role of membrane-attack protein in malarial transmission to mosquito host. . PNAS 101:(46):1631015
    [Crossref] [Google Scholar]
  35. 35.
    Kafsack BFC, Pena JDO, Coppens I, Ravindran S, Boothroyd JC, Carruthers VB. 2009.. Rapid membrane disruption by a perforin-like protein facilitates parasite exit from host cells. . Science 323:(5913):53033
    [Crossref] [Google Scholar]
  36. 36.
    Kafsack BFC, Carruthers VB. 2010.. Apicomplexan perforin-like proteins. . Commun. Integr. Biol. 3::1823
    [Crossref] [Google Scholar]
  37. 37.
    Kolter T, Sandhoff K. 2010.. Lysosomal degradation of membrane lipids. . FEBS Lett. 584:(9):170012
    [Crossref] [Google Scholar]
  38. 38.
    Krawczyk PA, Laub M, Kozik P. 2020.. To kill but not be killed: controlling the activity of mammalian pore-forming proteins. . Front. Immunol. 11::601405
    [Crossref] [Google Scholar]
  39. 39.
    Law RH, Lukoyanova N, Voskoboinik I, Caradoc-Davies TT, Baran K, et al. 2010.. The structural basis for membrane binding and pore formation by lymphocyte perforin. . Nature 468:(7322):44751
    [Crossref] [Google Scholar]
  40. 40.
    Lee J-Y, Cho P-Y, Kim TY, Kang S-Y, Song K-Y, Hong S-J. 2002.. Hemolytic activity and developmental expression of pore-forming peptide, clonorin. . Biochem. Biophys. Res. Commun. 296:(5):123844
    [Crossref] [Google Scholar]
  41. 41.
    Leippe M, Ebel S, Schoenberger OL, Horstmann RD, Müller-Eberhard HJ. 1991.. Pore-forming peptide of pathogenic Entamoeba histolytica. . PNAS 88:(17):765963
    [Crossref] [Google Scholar]
  42. 42.
    Lopes JLS, Orcia D, Araujo APU, DeMarco R, Wallace BA. 2013.. Folding factors and partners for the intrinsically disordered protein micro-exon gene 14 (MEG-14). . Biophys. J. 104:(11):251220
    [Crossref] [Google Scholar]
  43. 43.
    Lukoyanova N, Kondos SC, Farabella I, Law RHP, Reboul CF, et al. 2015.. Conformational changes during pore formation by the perforin-related protein pleurotolysin. . PLOS Biol. 13:(2):e1002049
    [Crossref] [Google Scholar]
  44. 44.
    Madden JC, Ruiz N, Caparon M. 2001.. Cytolysin-mediated translocation (CMT): a functional equivalent of type III secretion in gram-positive bacteria. . Cell 104:(1):14352
    [Crossref] [Google Scholar]
  45. 45.
    Merselis LC, Rivas ZP, Munson GP. 2021.. Breaching the bacterial envelope: the pivotal role of perforin-2 (MPEG1) within phagocytes. . Front. Immunol. 12::597951
    [Crossref] [Google Scholar]
  46. 46.
    Mota MM, Pradel G, Vanderberg JP, Hafalla JC, Frevert U, et al. 2001.. Migration of Plasmodium sporozoites through cells before infection. . Science 291:(5501):14144
    [Crossref] [Google Scholar]
  47. 47.
    Nedvědová Š, De Stefano D, Walker O, Hologne M, Miele AE. 2023.. Revisiting Schistosoma mansoni micro-exon gene (MEG) protein family: a tour into conserved motifs and annotation. . Biomolecules 13:(9):1275
    [Crossref] [Google Scholar]
  48. 48.
    Ni T, Williams SI, Rezelj S, Anderluh G, Harlos K, et al. 2018.. Structures of monomeric and oligomeric forms of the Toxoplasma gondii perforin-like protein 1. . Sci. Adv. 4:(3):aaq0762
    [Crossref] [Google Scholar]
  49. 49.
    Noronha FS, Cruz JS, Beirão PS, Horta MF. 2000.. Macrophage damage by Leishmania amazonensis cytolysin: evidence of pore formation on cell membrane. . Infect. Immun. 68:(8):457884
    [Crossref] [Google Scholar]
  50. 50.
    Paoletta MS, Laughery JM, Arias LSL, Ortiz JMJ, Montenegro VN, et al. 2021.. The key to egress? Babesia bovis perforin-like protein 1 (PLP1) with hemolytic capacity is required for blood stage replication and is involved in the exit of the parasite from the host cell. . Int. J. Parasitol. 51:(8):64358
    [Crossref] [Google Scholar]
  51. 51.
    Paton JC, Rowan-Kelly B, Ferrante A. 1984.. Activation of human complement by the pneumococcal toxin pneumolysin. . Infect. Immun. 43:(3):108587
    [Crossref] [Google Scholar]
  52. 52.
    Pradel G, Frevert U. 2001.. Malaria sporozoites actively enter and pass through rat Kupffer cells prior to hepatocyte invasion. . Hepatology 33:(5):115465
    [Crossref] [Google Scholar]
  53. 53.
    Pszenny V, Ehrenman K, Romano JD, Kennard A, Schultz A, et al. 2016.. A lipolytic lecithin:cholesterol acyltransferase secreted by Toxoplasma facilitates parasite replication and egress. . J. Biol. Chem. 291:(8):372546
    [Crossref] [Google Scholar]
  54. 54.
    Ramaprasad A, Burda P-C, Koussis K, Thomas JA, Pietsch E, et al. 2023.. A malaria parasite phospholipase facilitates efficient asexual blood stage egress. . PLOS Pathog. 19:(6):e1011449
    [Crossref] [Google Scholar]
  55. 55.
    Risco-Castillo V, Topçu S, Marinach C, Manzoni G, Bigorgne AE, et al. 2015.. Malaria sporozoites traverse host cells within transient vacuoles. . Cell Host Microbe 18:(5):593603
    [Crossref] [Google Scholar]
  56. 56.
    Roiko MS, Carruthers VB. 2009.. New roles for perforins and proteases in apicomplexan egress. . Cell. Microbiol. 11:(10):144452
    [Crossref] [Google Scholar]
  57. 57.
    Roiko MS, Carruthers VB. 2013.. Functional dissection of Toxoplasma gondii perforin-like protein 1 reveals a dual domain mode of membrane binding for cytolysis and parasite egress. . J. Biol. Chem. 288:(12):871225
    [Crossref] [Google Scholar]
  58. 58.
    Roiko MS, Svezhova N, Carruthers VB. 2014.. Acidification activates Toxoplasma gondii motility and egress by enhancing protein secretion and cytolytic activity. . PLOS Pathog. 10:(11):e1004488
    [Crossref] [Google Scholar]
  59. 59.
    Rosado CJ, Buckle AM, Law RH, Butcher RE, Kan WT, et al. 2007.. A common fold mediates vertebrate defense and bacterial attack. . Science 317:(5844):154851
    [Crossref] [Google Scholar]
  60. 60.
    Rudd-Schmidt JA, Hodel AW, Noori T, Lopez JA, Cho H-J, et al. 2019.. Lipid order and charge protect killer T cells from accidental death. . Nat. Commun. 10::5396
    [Crossref] [Google Scholar]
  61. 61.
    Sassmannshausen J, Pradel G, Bennink S. 2020.. Perforin-like proteins of apicomplexan parasites. . Front. Cell Infect. Microbiol. 10::578883
    [Crossref] [Google Scholar]
  62. 62.
    Schultz AJ, Carruthers VB. 2018.. Toxoplasma gondii LCAT primarily contributes to tachyzoite egress. . mSphere 3:(1):00073-18
    [Crossref] [Google Scholar]
  63. 63.
    Suss-Toby E, Zimmerberg J, Ward GE. 1996.. Toxoplasma invasion: The parasitophorous vacuole is formed from host cell plasma membrane and pinches off via a fusion pore. . PNAS 93::841318
    [Crossref] [Google Scholar]
  64. 64.
    Tavares J, Formaglio P, Thiberge S, Mordelet E, Rooijen NV, et al. 2013.. Role of host cell traversal by the malaria sporozoite during liver infection. . J. Exp. Med. 210:(5):90515
    [Crossref] [Google Scholar]
  65. 65.
    Tilley SJ, Orlova EV, Gilbert RJ, Andrew PW, Saibil HR. 2005.. Structural basis of pore formation by the bacterial toxin pneumolysin. . Cell 121:(2):24756
    [Crossref] [Google Scholar]
  66. 66.
    Voskoboinik I, Thia MC, Fletcher J, Ciccone A, Browne K, et al. 2005.. Calcium-dependent plasma membrane binding and cell lysis by perforin are mediated through its C2 domain: a critical role for aspartate residues 429, 435, 483, and 485 but not 491. . J. Biol. Chem. 280:(9):842634
    [Crossref] [Google Scholar]
  67. 67.
    Wade KR, Tweten RK. 2015.. The apicomplexan CDC/MACPF-like pore-forming proteins. . Curr. Opin. Microbiol. 26::4852
    [Crossref] [Google Scholar]
  68. 68.
    WHO (World Health Organ.). 2021.. Schistosomiasis and soil-transmitted helminthiases: progress report, 2021. Rep. , WHO, Geneva:
    [Google Scholar]
  69. 69.
    Williams SI, Yu X, Ni T, Gilbert RJC, Stansfeld PJ. 2022.. Structural, functional and computational studies of membrane recognition by Plasmodium perforin-like proteins 1 and 2. . J. Mol. Biol. 434:(13):167642
    [Crossref] [Google Scholar]
  70. 70.
    Wirth CC, Bennink S, Scheuermayer M, Fischer R, Pradel G. 2015.. Perforin-like protein PPLP4 is crucial for mosquito midgut infection by Plasmodium falciparum. . Mol. Biochem. Parasitol. 201:(2):9099
    [Crossref] [Google Scholar]
  71. 71.
    Yang AS, O'Neill MT, Jennison C, Lopaticki S, Allison CC, et al. 2017.. Cell traversal activity is important for Plasmodium falciparum liver infection in humanized mice. . Cell Rep. 18:(13):310516
    [Crossref] [Google Scholar]
  72. 72.
    Zhou XW, Kafsack BF, Cole RN, Beckett P, Shen RF, Carruthers VB. 2005.. The opportunistic pathogen Toxoplasma gondii deploys a diverse legion of invasion and survival proteins. . J. Biol. Chem. 280:(40):3423344
    [Crossref] [Google Scholar]
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