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HISTIDINE TRIAD PROTEIN D

Gene Name - PhtD

Cell Location - PhtD is a well conserved protein found on the surface of the cell wall of all strains of Streptococcus pneumonia. [1] [2]. 

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FUNCTION                                                                                                                                                                             

The roles of PhtD in S. pneumoniae are linked to surface binding and helping the pathogen evade the host immune response. It works to adhere pneumococci to the respiratory epithelial tissue and mucosal surfaces, thereby increasing the ability of pneumococcus to invade a host. It has also been shown to inhibit complement deposition thus decreasing the ability of antibodies to clear pathogens.  [2] [3]. 

STRUCTURE                                                                                                                                                                           

litemol_screenshot phtd.png

Click on the image for more information on the secondary and tertiary structure of Histidine triad protein D.

PROTEIN SEQUENCE                                                                                                                                                       

10                         20                         30                         40                         50      
MKINKKYLAG     SVAVLALSVC      SYELGRHQAG    QVKKESNRVS    YIDGDQAGQK
60                         70                         80                         90                         100
AENLTPDEVS      KREGINAEQI     VIKITDQGYV       TSHGDHYHYY    NGKVPYDAII
110                       120                       130                       140                       150
SEELLMKDPN     YQLKDSDIVN     EIKGGYVIKV       DGKYYVYLKD     AAHADNIRTK
160                       170                       180                       190                       200    
EEIKRQKQER     SHNHNSRADN   AVAAARAQGR   YTTDDGYIFN     ASDIIEDTGD
210                       220                       230                       240                       250
AYIVPHGDHY     HYIPKSDLSA       SELAAAQAYW   NGKQGSRPSS    SSSHNANPAQ
260                       270                       280                       290                       300 
PRLSENHNLT      VTPTYHQNQG  ENISSLLREL        YAKPLSERHV       ESDGLIFDPA
310                       320                       330                       340                       350     

QITSRTANGV     AVPHGDHYHF    IPYSQLSPLE        EKLARIIPLR         YRSNHWVPDS
360                       370                       380                       390                       400      

RPEQPSPQST     PEPSPSPQPA      PNPQPAPSNP    IDEKLVKEAV       RKVGDGYVFE
410                       420                       430                       440                       450
ENGVPRYIPA      KDLSAETAAG     IDSKLAKQES      LSHKLGAKKT     DLPSSDREFY
460                       470                       480                       490                       500      

NKAYDLLARI      HQDLLDNKGR   QVDFEALDNL    LERLKDVSSD      KVKLVDDILA
510                       520                       530                       540                       550      

FLAPIRHPER       LGKPNAQITY     TDDEIQVAKL      AGKYTTEDGY    IFDPRDITSD
560                       570                       580                       590                       600   

EGDAYVTPHM   THSHWIKKDS     LSEAERAAAQ    AYAKEKGLTP      PSTDHQDSGN
610                       620                       630                       640                       650
TEAKGAEAIY     NRVKAAKKVP     LDRMPYNLQY    TVEVKNGSLI      IPHYDHYHNI
660                       670                       680                       690                       700
KFEWFDEGLY    EAPKGYSLED      LLATVKYYVE       HPNERPHSDN   GFGNASDHVQ
710                       720                       730                       740                       750
RNKNGQADTN QTEKPNEEKP     QTEKPEEDKE     HDEVSEPTHP    ESDEKENHVG
760                       770                       780                       790                       800     

LNPSADNLYK     PSTDTEETEE      EAEDTTDEAE     IPQVEHSVIN      AKIAEAEALL
810                       820                       830                       840                       850
EKVTDSSIRQ      NAVETLTGLK      SSLLLGTKDN      NTISAEVDSL      LALLKESQPT

PIQ                                                               

SEQUENCE LENGTH - 853

CURRENT FIELD STATUS

cdc-IFpQtennlj8-unsplash.jpg

CURRENT TRIAL STATUS

Phase II [4]

  • Immunisation of rhesus macaques [2]

  • Immunisation of mice in a sepsis model [4]

  • Immunisation of mice in a colonisation model [4]

  • Immunisation of toddlers with PhtD, PlyD1 and PcpA [2]

michael-longmire-L9EV3OogLh0-unsplash.jp

IMMUNE RESPONSE GENERATED

  • PhtD was proven to be highly immunogenic and have a capability to encourage protecting humoral immunity [2].

  • PhtD has been found to protect very effectively against pneumonia, nasopharyngeal colonisation, and sepsis [4] [5].

  • Mutants of PhtD show less virulence in mice challenged with pneumococcal infection. PhtD was also shown to protect mice from pneumococcal infection caused by a number of different serotypes. 

  • Fusion proteins containing PhtD elicit an improved antibody response with higher antibody levels, when compared to control groups, with higher survival rates and a reduced bacterial load [4] [6].

  • PhtD combination vaccine  immunising toddlers and infants proved to be safe and immunogenic [7]. 

cdc-ljiPMfg-0m0-unsplash.jpg

MECHANISM OF VIRULENCE

  • PhtD is a lipoprotein. Lipoproteins have been shown to modulate inflammatory processes and aid in the movement of other virulence factors into the cell [1].  

  • Mediates the adhesion of pneumococci to the respiratory tissue and mucosa [8].    

  • Plays a role in zinc acquisition in pneumococcal virulence [9].  

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.

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[2]        A. Kallio, K. Sepponen, P. Hermand, P. Denoël, F. Godfroid, and M. Melin, “Role of Pht proteins in attachment of Streptococcus pneumoniae to respiratory epithelial cells,” Infection and Immunity, vol. 82, no. 4, pp. 1683–1691, 2014, doi: 10.1128/IAI.00699-13.

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[3]        E. Holmlund et al., “Antibodies to pneumococcal proteins PhtD, CbpA, and LytC in filipino pregnant women and their infants in relation to pneumococcal carriage,” Clinical and Vaccine Immunology, vol. 16, no. 6, pp. 916–923, Jun. 2009, doi: 10.1128/CVI.00050-09.

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[4]        C. D. Plumptre, A. D. Ogunniyi, and J. C. Paton, “Vaccination against Streptococcus pneumoniae Using Truncated Derivatives of Polyhistidine Triad Protein D,” PLoS ONE, vol. 8, no. 10, p. e78916, Oct. 2013, doi: 10.1371/journal.pone.0078916.

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[5]        M. N. Khan and M. E. Pichichero, “Vaccine candidates PhtD and PhtE of Streptococcus pneumoniae are adhesins that elicit functional antibodies in humans,” Vaccine, vol. 30, no. 18, pp. 2900–2907, Apr. 2012, doi: 10.1016/j.vaccine.2012.02.023.

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[6]        P. Denoël, M. T. Philipp, L. Doyle, D. Martin, G. Carletti, and J. T. Poolman, “A protein-based pneumococcal vaccine protects rhesus macaques from pneumonia after experimental infection with Streptococcus pneumoniae,” Vaccine, vol. 29, no. 33, pp. 5495–5501, Jul. 2011, doi: 10.1016/j.vaccine.2011.05.051.

 

[7]        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.

 

[8]        A. Kovacs-Simon, R. W. Titball, and S. L. Michell, “Lipoproteins of bacterial pathogens,” Infection and Immunity, vol. 79, no. 2. American Society for Microbiology (ASM), pp. 548–561, Feb. 2011, doi: 10.1128/IAI.00682-10.

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[9]         B. A. Eijkelkamp et al., “The first histidine triad motif of PhtD is critical for zinc homeostasis in Streptococcus pneumoniae,” Infection and Immunity, vol. 84, no. 2, pp. 407–415, Feb. 2016, doi: 10.1128/IAI.01082-15.

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