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PNEUMOCOCCAL SURFACE PROTEIN A

Gene Name - PspA

Cell Location - Cell wall - PspA is bound to the cell wall via phosphoryl-choline moiety [1]. PspA is attached to the surface of the pneumococcus by the C-terminal end of the molecule [2]. The N-terminal half of the molecule is thought to be surface exposed as all protective monoclonal antibodies reactive to PspA on the pneumococcal cell surface bind it [3].

FUNCTION                                                                                                                                                                             

Present in all pneumococcal isolates regardless of serotype, PspA has been proven to play a key role in the virulence of Streptococcus pneumoniae. It is a human lactoferrin-binding protein which inhibits complement deposition on the surface of pneumococci [4] [3]. It plays a role in cellular metabolic processes and immune evasion in the body [5]. The presence of PspA in pneumococci is also known to delay/slow down the clearance of the bacteria from the blood stream. PspA also aids in colonisation by adhering to epithelial cell membranes [6].

STRUCTURE                                                                                                                                                                           

litemol_screenshot pspa.png

Click on the image for more information on the secondary and tertiary structure of pneumococcal surface protein A.

PROTEIN SEQUENCE                                                                                                                                                       

10                         20                         30                         40                         50         
MNKKKMILTS     LASVAILGAG      FVTSSPTFVR       AEEAPVASQS     KAEKDYDAAK
60                         70                         80                         90                         100
KDAKNAKKAV    EDAQKALDDA  KAAQKKYDED    QKKTEKKAAA    VKKIDEEHQA
110                       120                       130                       140                       150
ANLKSQQALV    EFLAAQREGN    PKKKKAAQAK    LEEAEKAEKE     KKKEFDKAQA
160                       170                       180                       190                       200     

VVVPEATELA      ETKKKADEAK     VKEPELTKKL       EEAKAKSEEA     EKKATEAKQK
210                       220                       230                       240                       250    

VDAEHAKEVV    PQAKIAELEN      EVQKLEKDLK     EIDESDSEDY      VKEGLRAPLQ
260                       270                       280                       290                       300      
SELDAKQAKL     SKLEELSDKI       DELDAEIAKL       EKNVEDFKNS    NGEQAEQYRA
310                       320                       330                       340                       350
AAEEDLAAKQ    AELEKTEADL     KKAVNEPEKP     APAPETPAPE      APAEQPKPAP
360                       370                       380                       390                       400     

APQPAPAPKP     EKPAEQPKAE     KTDDQQAEED  YARRSEEEYN      RLTQQQPPKA
410                       420                       430                       440                       450
EKPAPAPKPE      QPAPAPKIGW     KQENGMWYFY NTDGSMATGW LQNNGSWYYL
460                       470                       480                       490                       500
NANGSMVTGW LQNNGSWYYL  NANGSMATGW LQNNGSWYYL   NANGAMATGW
510                       520                       530                       540                       550
LQNNDSWYYL   NASGAMATGW AKVNGSWYYL   NANGAMATGW LQYNGSWYYL
560                       570                       580                       590                       600
NANGAMATGW VKVNGSWYYL   NANGSMATGW VKDGDTWYYL   EASGAMKASQ
610                       620                       630                
WFKVSDKWYY   VNGLGALAVN   TTVDGYKVNA     NGEWV 

SEQUENCE LENGTH - 635

CURRENT FIELD STATUS

cdc-IFpQtennlj8-unsplash.jpg

CURRENT TRIAL STATUS

Phase I [1] [7]​

​

  • Clinical trials in adults.

  • Immunisation of mice with human sera [8].

  • Humans immunised orally with Salmonella expressing PspA [9].

  • Humans immunised with recombinant PspA [10].

michael-longmire-L9EV3OogLh0-unsplash.jp

IMMUNE RESPONSE GENERATED

  • It is hypothesised that PspA will be able to protect against many diverse strains of Streptococcus pneumoniae due to its location in all known strains [11].

  • Recombinant PspA proteins elicit capabilities of inducing a protective mechanism against S. pneumonia in different animal models and against different serotypes [10].

  • Immunoglobulin G (IgG) antibodies were observed to be the leading serum antibody to PspA, with peak antibody response by the host occurring in childhood.

  • Immunoglobulin M (IgM) antibodies showed comparable levels of IgM antibodies to those of IgG in children, however, IgG antibodies levels are significantly higher to IgM levels in adults.

  • The number of Immunoglobulin A (IgA) antibody-secreting cells are proven to be less than both IgG and IgM, with levels of IgA staying low after immunisation for the first 2 years of life [12].

  • PspA immunisation has been shown to protect against otherwise fatal sepsis caused by pneumococci when the hosts (mice) are challenged with a dose of >105 times the 50% lethal dose and pneumococci was cleared from the hosts bloodstream [8] [11].

  • A phase I trial with recombinant PspA showed the protein to be immunogenic in humans [10]. 

cdc-ljiPMfg-0m0-unsplash.jpg

MECHANISM OF VIRULENCE

  • Choline-binding protein, plays relevant physiological role in virulence.

  • Delays/slows down the ability for the host to clear the blood of pneumococci.

  • Interferes with the antiphagocytic properties of Streptococcus pneumoniae [11].

  • Inhibits complement deposition on the bacterial surface.

  • The presence of PspA makes the killing of pneumococci by apolactoferrin much less effective, when PspA is absent it can be observed that apolactoferrin acts as a great tool to killing pneumococci and when present these capabilities are diminished [13].

  • A possible mechanism of virulence of PspA is also the ionic interactions between the positively charged amino acid Lysine which is found in PspA and the negatively charged polysaccharide layer. These interactions can act as a mechanism to stabilise the capsule and increase virulence [11]. 

RELATED GENE BANKS                                                                                                                                                    

RELATED ARTICLES                                                                                                                                                            

[1]         T. Lagousi, P. Basdeki, J. Routsias, and V. Spoulou, “Novel protein-based pneumococcal vaccines: Assessing the use of distinct protein fragments instead of full-length proteins as vaccine antigens,” Vaccines, vol. 7, no. 1. MDPI AG, 2019. doi: 10.3390/vaccines7010009.

 

[2]         G. O. Andre et al., “Role of Streptococcus Pneumoniae proteins in evasion of complement-mediated immunity,” Frontiers in Microbiology, vol. 8, no. FEB. Frontiers Media S.A., p. 224, Feb. 20, 2017. doi: 10.3389/fmicb.2017.00224.

 

[3]         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.

 

[4]         A. Håkansson, H. Roche, S. Mirza, L. S. McDaniel, A. Brooks-Walter, and D. E. Briles, “Characterization of binding of human lactoferrin to pneumococcal surface protein A,” Infection and Immunity, vol. 69, no. 5, pp. 3372–3381, 2001, doi: 10.1128/IAI.69.5.3372-3381.2001.

 

[5]         L. R. Quin, Q. C. Moore, and L. S. McDaniel, “Pneumolysin, PspA, and PspC contribute to pneumococcal evasion of early innate immune responses during bacteremia in mice,” Infection and Immunity, vol. 75, no. 4, pp. 2067–2070, Apr. 2007, doi: 10.1128/IAI.01727-06.

 

[6]         L. R. K. Brooks and G. I. Mias, “Streptococcus pneumoniae’s virulence and host immunity: Aging, diagnostics, and prevention,” Frontiers in Immunology, vol. 9, no. JUN. Frontiers Media S.A., p. 1, Jun. 22, 2018. doi: 10.3389/fimmu.2018.01366.

 

[7]         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.

 

[8]         E. Swiatlo, J. King, G. S. Nabors, B. Mathews, and D. E. Briles, “Pneumococcal Surface Protein A Is Expressed in Vivo, and Antibodies to PspA Are Effective for Therapy in a Murine Model of Pneumococcal Sepsis,” Infection and Immunity, vol. 71, no. 12, pp. 7149–7153, Dec. 2003, doi: 10.1128/IAI.71.12.7149-7153.2003.

 

[9]         K. Moffitt and R. Malley, “Rationale and prospects for novel pneumococcal vaccines,” Human Vaccines and Immunotherapeutics, vol. 12, no. 2, pp. 383–392, Feb. 2016, doi: 10.1080/21645515.2015.1087625.

 

[10]      P. L. Vernazza, C. Kahlert, and W. Fierz, “Immunization of humans with recombinant pneumococcal surface

protein A (rPspA) elicits antibodies that passively protect mice from fatal infection with Streptococcus pneumoniae bearing heterologous PspA,” Journal of Infectious Diseases, vol. 182, no. 6, pp. 1694–1701, Dec. 2000, doi: 10.1086/317602.

 

[11]      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.

 

[12]      Q. Zhang, S. Choo, and A. Finn, “Immune responses to novel pneumococcal proteins pneumolysin, PspA,

PsaA, and CbpA in adenoidal B cells from children,” Infection and Immunity, vol. 70, no. 10, pp. 5363–5369, Oct. 2002, doi: 10.1128/IAI.70.10.5363-5369.2002.

 

[13]      M. Shaper, S. K. Hollingshead, W. H. Benjamin, and D. E. Briles, “PspA protects Streptococcus pneumoniae from killing by apolactoferrin, and antibody to PspA enhances killing of pneumococci by apolactoferrin,” Infection and Immunity, vol. 72, no. 9, pp. 5031–5040, Sep. 2004, doi: 10.1128/IAI.72.9.5031-5040.2004.

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