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PNEUMOLYSIN

Gene Name - Ply

Cell Location - Located in the cell membrane, pneumolysin is a multi-pass membrane protein. Ply is a secretory enzyme that is not surface exposed [1].

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FUNCTION                                                                                                                                                                             

Pneumolysin is attributed to many biological functions in S. pneumoniae. It plays a role in Fc binding, complement fixation and activation, and damaging epithelial cells. It plays a role in causing infections of the eye and pneumococcal infection caused by intranasal, intratracheal, and parenteral routes. It is involved in many aspects of infection by pneumococci such as transmission and colonisation [2].
It is a cholesterol-dependent cytolysin (CDC) toxin which mediates cell death in the host by attaching to membrane cholesterol and oligomerizing. This then form lytic pores in the cell membrane of the host. The formation of these pores then can lead to the loss of cytoplasmic content and an invasion by extracellular ions. It also facilitates pathogenesis of pneumococcal diseases by triggering the activation of inflammatory immune cells and controlling inflammatory response [3].    
 

STRUCTURE                                                                                                                                                                           

Click on the image for more information on the secondary and tertiary structure of Pneumolysin.

PROTEIN SEQUENCE                                                                                                                                                       

10                         20                         30                         40                         50     
MANKAVNDFI    LAMNYDKKKL    LTHQGESIEN     RFIKEGNQLP      DEFVVIERKK
60                         70                         80                         90                         100
RSLSTNTSDI       SVTATNDSRL      YPGALLVVDE      TLLENNPTLL      AVDRAPMTYS
110                       120                       130                       140                       150
IDLPGLASSD      SFLQVEDPSN     SSVRGAVNDL     LAKWHQDYGQ VNNVPARMQY
160                       170                       180                       190                       200
EKITAHSMEQ     LKVKFGSDFE     KTGNSLDIDF      NSVHSGEKQI     QIVNFKQIYY
210                       220                       230                       240                       250     

TVSVDAVKNP     GDVFQDTVTV    EDLKQRGISA     ERPLVYISSV         AYGRQVYLKL
260                       270                       280                       290                       300       

ETTSKSDEVE      AAFEALIKGV      KVAPQTEWKQ   ILDNTEVKAV       ILGGDPSSGA
310                       320                       330                       340                       350
RVVTGKVDMV    EDLIQEGSRF      TADHPGLPIS      YTTSFLRDNV      VATFQNSTDY
360                       370                       380                       390                       400
VETKVTAYRN      GDLLLDHSGA    YVAQYYITWD     ELSYDHQGKE    VLTPKAWDRN
410                       420                       430                       440                       450
GQDLTAHFTT    SIPLKGNVRN      LSVKIRECTG       LAWEWWRTVY   EKTDLPLVRK
460                       470
RTISIWGTTL       YPQVEDKVEN    D

SEQUENCE LENGTH - 471

litemol_screenshot ply.png

CURRENT FIELD STATUS

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CURRENT TRIAL STATUS

Phase I [4]

  • Combination of Ply with PspA as a vaccine candidate [4]

  • Immunisation of mice with Ply

  • In vivo sepsis model

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IMMUNE RESPONSE GENERATED

  • Mice immunised with a fusion of Ply and PspA produce significant levels of protective antibodies, the fusion proteins increase immune response, and show high levels of protection against fatal challenge.

  • Mice infected with S. pneumoniae, Ply antibodies protected mice from adverse fatal effects caused by the purified toxins. Mice also showed significantly greater survival times than control mice [5] [6].

  • In vivo sepsis models show an increase of survival times when mice are immunised with reduced-toxicity variants of pneumolysin [7].

  • Immunisation with Ply shows noteworthy reduction in lung burden caused by Streptococcus pneumoniae in infected mice [7].

  • Elicits protection against more than one serotype.

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MECHANISM OF VIRULENCE

  • Helps with surface adhesion and forms pores in the membrane of the cell.

  • Inhibits the response of neutrophils which provide the primary host defence against the pathogen.

  • Interferes with the rapid multiplication of antibody cells and the generation of antibodies.

  • Hinders/prevents ciliary epithelial cell beat frequency.

  • Toxic for epithelial cells found in the alveoli of the lung [4].

  • Pneumolysin binds to cholesterol within the plasma membrane of host cells and assembles to form trans‐membrane pores, which can lead to Ca2+ influx and cell death [8] [9].

RELATED ARTICLES

Bibliography

[1]         M. J. Jedrzejas, “Pneumococcal Virulence Factors: Structure and Function,” Microbiology and Molecular Biology Reviews, vol. 65, no. 2, pp. 187–207, Jun. 2001, doi: 10.1128/mmbr.65.2.187-207.2001.

 

[2]         D. E. Briles et al., “Pneumococcal diversity: Considerations for new vaccine strategies with emphasis on pneumococcal surface protein A (PspA),” Clinical Microbiology Reviews, vol. 11, no. 4. American Society for Microbiology, pp. 645–657, 1998. doi: 10.1128/cmr.11.4.645.

 

[3]         P. Rai, F. He, J. Kwang, B. P. Engelward, and V. T. K. Chow, “Pneumococcal Pneumolysin Induces DNA Damage and Cell Cycle Arrest,” Scientific Reports, vol. 6, no. 1, pp. 1–12, Mar. 2016, doi: 10.1038/srep22972.

 

[4]         C. C. Daniels, P. D. Rogers, and C. M. Shelton, “A review of pneumococcal vaccines: Current polysaccharide vaccine recommendations and future protein antigens,” Journal of Pediatric Pharmacology and Therapeutics, vol. 21, no. 1. Pediatric Pharmacy Advocacy Group, Inc., pp. 27–35, Jan. 01, 2016. doi: 10.5863/1551-6776-21.1.27.

 

[5]         M. del Mar García-Suárez et al., “Protection against pneumococcal pneumonia in mice by monoclonal antibodies to pneumolysin,” Infection and Immunity, vol. 72, no. 8, pp. 4534–4540, Aug. 2004, doi: 10.1128/IAI.72.8.4534-4540.2004.

 

[6]         S. S. Tai, “Streptococcus pneumoniae protein vaccine candidates: Properties, activities and animal studies,” Critical Reviews in Microbiology, vol. 32, no. 3. Crit Rev Microbiol, pp. 139–153, Sep. 01, 2006. doi: 10.1080/10408410600822942.

 

[7]         D. Salha et al., “Neutralizing antibodies elicited by a novel detoxified pneumolysin derivative, PlyD1, provide protection against both pneumococcal infection and lung injury,” Infection and Immunity, vol. 80, no. 6, pp. 2212–2220, 2012, doi: 10.1128/IAI.06348-11.

 

[8]         Y. Larpin et al., “Bacterial pore-forming toxin pneumolysin: Cell membrane structure and microvesicle shedding capacity determines differential survival of immune cell types,” FASEB Journal, vol. 34, no. 1, pp. 1665–1678, Jan. 2020, doi: 10.1096/fj.201901737RR.

 

[9]         T. J. Mitchell, P. W. Andrew, F. K. Saunders, A. N. Smith, and G. J. Boulnois, “Complement activation and antibody binding by pneumolysin via a region of the toxin homologous to a human acute‐phase protein,” Molecular Microbiology, vol. 5, no. 8, pp. 1883–1888, 1991, doi: 10.1111/j.1365-2958.1991.tb00812.x.

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