Essay: Pneumococcus

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  • Pneumococcus
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The pneumococcus is a main human pathogen responsible for acute invasive diseases such as sepsis , meningitis, and pneumonia in youth children and immunocompromised individuals worldwide (Oetqvist , et al., 2005 ) . Invasive pneumococcal disease seem to depend on both pneumococcal cell wall constituent including lipoteichoic and peptidoglycan ,in addition to a multitude of virulence factor that include pneumolysin [PLY] (Jedrezejas ,2001 ). one of most promising stratagems to control pneumococcal diseases is affecting the colonization factors that elevate pathogen adhesion to human tissues (Kline , et al., 2009 ) .it is also the main causative agent for community-acquired pneumonia [CAP]( Waterer ,et al ., 2011) .
S. pneumoniae is a main cause of morbidity and mortality in the United States (US) , causing over 500.000 cases of pneumonia, above 40.000 cases of invasive pneumococcal disease , and 4,000 associated deaths yearly ( File and Jr , 2004 ).
The most significant of pneumoccal virulence factor and pathogenicity include :- polysaccharide capsule, pneumolysin (PLY), hyaluronidase, neuraminidase A (NanA), pilus, lipoproteins (PsaA, SirA, PpmA), autolysin (LytA), pneumococcal surface proteins (PspA, PspC), genome variation (Mitchell and Mitchell , 2010 ). One of the virulence factor is Pneumolysin (Ply) is a well-established virulence factor (Hirst , et al ., 2008 ) that has been extensively studied for its hemolytic activity and cytotoxic properties. Ply, a 53-kDa surface protein (Price and Camilli ,2009), is a cholesterol-dependent cytolysin that binds cholesterol in eukaryotic cell membranes and forms 400-Å pores that lead to cell lysis (Alouf ,2000). PLY is the only unique that is not secreted into the extracellular medium (reviewed in [(Cassidy and O’Riordan ,2013)]. cholesterol-dependent pore-forming toxin with 4 functional domains (Mitchell and Dalziel, 2014). It is β-barrel pore forming toxins, secreted by Gram-positive bacteria via for S. pneumoniae (Marriott, et al., 2008).
Crystal structure of PLY, The molecule comprises 11% helix and 32% beta-sheet. It is composed of four domains (Lawrence , et al., 2015). Cell lysis by pneumolysin occur in a two-step process: CHO first attaches to the membrane where it induces pneumolysin oligomerization which then forms pore in the membrane, disrupting its integrity (Tilley,et al.,2005) .
β-sitosterol is a candidate aimed at the development of anti-virulence agents against pathogens that depend on on cholesterol dependent toxins for successful infections (Li , et al., 2015 ). β-sitosterol constitutes about 90% of phytosteroles present in plant . It is reported to have, anti-arthrosclerosis, and anti-inflammatory anti-oxidant activities. (Gupta , et al , 2011 ). It is also found to be advantageous in the treatment of benign prostatic hyperplasia (Berges , et al., 1995) .It’s absorbed only in trace quantities and inhibits the absorption of intestinal cholesterol excluding re-circulating endogenous biliary cholesterol, a key move in cholesterol removal.(Ostlund,2002). it has a high affinity for pneumolysin the mechanism of action , we determined the potential interactions between BSS and pneumolysin.,and the β-sitosterol, effectively protects against cell lysis initiated by pneumolysin (Li , et al. 2015 ).
S. pneumoniae are Gram-positive cocci or short rods happening in pairs or in chains. Species are non-motile and non-sporing. Streptococci are facultatively anaerobic (some require CO2) chemo-organotrophs with complex nutritional supplies and a fermentative metabolism resulting in L (+) lactic acid as the main product of glucose fermentation. They are catalase negative.(Hardie and Whiley,1997). One of the first methodologies to division the Streptococci into diverse group was developed by Lancefield in 1933 using differences in precipitin reaction built on group specific carbohydrates (Lancefield , 1933) . In earlier edition of Manual six named species were comprise within the pyogenic hemolysic Streptococci , Streptococcus pyogens (Lancefield group A plus Group A variant ) , Streptococcus agalactiae (Lancefield group B ) , Streptococcus equi (Lancefield group C) , Streptococcus iniae , Streptococcus dysgalactiae ( Lancefield group C ), and Streptococcus pneumoniae together with orther Streptococci of group G,C,L and group E,P,Uand V (William ,et al.,2009).
Streptococcus was divided into three genera that involved Streptococcus , Lactococcus, and Enterococcus (Schleifer, et al., 1985). Streptococcus including the pyogenic and oral species included both human and animal pathogenic and saprophytic streptococci , Lactococcus was made from the lactic Streptoccci (Schleifer et al., 1985).
The genus Streptococcus containing nearby 40 species is grouped into α , β , and γ – hemolytic species and these groups are sub – divided into six cluster by 16S rDNA comparative sequence analysis (Kawamura et al .,1995). These are the ‘Pyogenic’, ‘Mitis’, ‘Salivarius’, ‘Bovis’, ‘Anginosus’ and ‘Mutans’ groups.(Table1) lists those species resently included in the genus arranged according to their species groups.
Figure 1 :- Hemolytic of streptococcus
Table 1:- Currently recognized species groups in genus Streptococcus
Species include
Group
Strep. pyogenes , Strep. Agalactiae ,Strep. Canis , Strep. Dysgalactiae ,Strep. equi
Strep. Hyointestinalis , Strep. iniae
Strep. Parauberis , Strep. porcinus
Strep. Uberis
Pyogenic
Strep. gordonii , Strep. mitis Strep. oralis
Strep. Parasanguis , Strep. pneumoniae
Strep. Sangui
Mitis
Strep. salivarius , Strep. thermophilus
Strep. vestibularis
Salivarius
Strep. anginosus , Strep. constellatus
Strep. Intermedius Anginosus
Strep. Mutans ,Strep. cricetus , Strep. downei
Strep. Macacae ,Strep. Rattus ,Strep. Sobrinus Mutans
Strep. bovis , Strep. Alactolyticus
Strep. Equinus Bovis
Kawarmura et al. (1995a).
1-2 General characteristics of S. pneumoniae
The bacteria was known in 1881 by Sternberg . USA and Pasteur , France who independently inaccessible diplococcic from rabbits that had been inoculated with human saliva ( Taylor,et al.,2012) .
The pneumococcus is a lancet shaped gram-positive diplococcus characterized by a surrounding polysaccharide capsule , Since it is alpha hemolytic, bile soluble and optochin sensitive, it can be identified by conventional microbiological tests, using morphological characteristics and biochemical tests (Spijkerman ,et al.,2012) .It is an exclusively human pathogen , facultatively anaerobic and although it can grow aerobically ( Bergey, et al., 1974 ) . It is a fermentative metabolism which produce L(+) lactic acid as major product of glucose fermentation . (Hardie and Whiley,1997) .
On blood agar plates , the pneumococcus produce as α- hemolysis when it is incubated in a 5% CO2 atmosphere , as a result of the oxidation of the haemogloin to green methaemoglobin due to the hydrogen peroxide it produces ( Barnrad and Stinson , 1996 ) . However , In anaerobic condition the pneumococcus produces β – hemolysis due to the pneumolysin (Ply) action (Brzin , 1969) .
The colony morphology depends on the capsule and cell well composition ( Watson et al., 1993 ) . Thus , the typical shape of the colonies is ruffled and smooth , with a sunken centre (White , 1938 ) . The pneumococcal surface is covered by a polysaccharide capsule that overlays the cell wall comprised of peptidoglycan and teichoic acid, Although the peptidoglycan has structure of N-acetylglucosamine, N-acetylmuramic acid, and a lysine-containing stem peptide, the teichoic acid is unusual in containing a ribitol phosphate backbone and covalently attached phosphorylcholine (PCho) (Bean and Tomasz, 1977) . S. pneumoniae is differentiated by one of at minimal 90 different polysaccharide capsule (Hathaway , et al., 2012) . The best surface protein are the lipoprotein pneumococcal surface adhesion A(PsaA ), the enzyme immunoglobulin A-protease and neuraminidases and three choline-binding proteins, pneumococcal surface protein A, major pneumococcal autolysin and pneumococcal surface protein C (PspC, also referred to as CbpA or SpsA) (Palmu, et al.,2004) .
Several new proteins and other surface components involved in the adherence and virulence mechanisms have been recognised recently (Koivunen ,et al., 1999). A subpopulation of pneumococci produces pilus-like protein structures, able to extend beyond the polysaccharide capsule (Hyypia, et al., 1998). One of the most intensively studied intracellular structures is pneumolysin, a toxin common to all clinically relevant pneumococcal strains (Heikkinen and Chronmaitree ,2003).
Figure 2 :-Electron Micrograph of S. pneumoniae (Pneumococcus; Streptococci ).
1-3 Epidemiology of S. pneumonia
S. pneumoniae is a main cause of morbidity and mortality in the United States (US) , causing over 500.000 cases of pneumonia, above 40.000 cases of invasive pneumococcal disease , and 4,000 associated deaths yearly ( File and Jr , 2004 ). Total of patient demographics and comorbidities , including diabetes mellitus , age , chronic liver disease , chronic cardiovascular disease , chronic lung disease ,chronic renal failure , and immune deficiencies , increase one ‘s risk of developing pneumococcal disease (Van Hoek , et al., 2012 ). It is also the main ausative agent for community-acquired pneumonia [CAP]( Waterer ,et al ., 2011) .It patient with fundamental medical condition the incidence of pneumococcal infection may be as high as 176 to 483 per 100.000 persons ,while the incidence for patient with immunocompromising condition has been notify to be even higher from 342 to 2,031 per 100,000 persons (Siemieniuk , et al., 2011 ).
Pneumonia was the main cause of child loss in progressive polity, and in the US in 1900 , it is likely that pneumonia killed 47 of every 1,000 children previously the age of 5 years (scott ,et al. ,2000) . Improvement in nutrition and living values in the US in the first 40 years of the 20 th century directed to a substantial decrease in pneumonia mortality fully before antibiotics developed available as an active treatment However , in the low – income countries of Africa and Asia, pneumonia is yet the leading cause of child doom . in the developing countries , above one – quartier of children have an occurrence of clinical pneumonia each year during the first 5 year of the lives (Rudan , et al.,2004). On average , 2%- 3% of children each year need pneumonia severe enough to require hospitalization , and several of these disease incident are potentially fetal (Rudan , et al.,2004) . Children attending Child – care centers [CCC] are at a 6x higher danger of becoming pneumococcal carriers than children not attending CCCs and these institutions are important for the variability of pneumococcal serotypes in carriage in the population (Dagan and O’ Brien ,2005 ). Socioeconomic factors also play a role in infections as revealed by the fact that Moraxella catarrhalis, Staphylococcus aureus and antibiotic resistant S. pneumoniae were more often carried by children from lower socio-economic schools in Belgium as vaccination is less common than in higher socio-economic schools (Jourdain , et al., 2011) . Thus, often young children are responsible for the introduction of new serotypes into a household (Millar , et al., 2008) . Vaccinating children provides herd immunity to non vaccinated adult ,and has drive to a nearly one – third decrease in the rate of invasive pneumococcal disease amongst adults aged 50 and older (Lexau, et al., 2005 ).
Nterestingly,there are differences in pneumococcal infections saw between different ethnicities, For example, the indigenous populations in Alaska, Canada, Greenland as well as the American Indians, African Americans in the USA, Australian Aborigines, Maoris of New Zealand and the Bedouins of Israel are more often affected by invasive pneumococcal diseases and there is confirmation that genetic factors play a role ( Hammitt , et al., 2006 ).
Universal the pneumococcus is responsible for more than 14.5 million episodes of IPD annually and up to 11% of all deaths in children (O’ Brien , et al., 2009).Remarkably , in individuals Larger than 65 years of age the case – fatality rate for IPD can be as high as 30 % (Maruyama , et al., 2010 ).The arrhythmia , cardiac failure and acute coronary syndrome , which are associated with an increased overall danger of mortality from (13.9 to 36)%(Corrales – Medina , et al., 2012 ). Cardiac depression occurs in 40-50 % of patient with severe sepsis and increases the death rate to 80 –90% ( Zanotti – Cavazzoni and Hollenberg ,2009 ) . Cardiomyocyte destruction indicator by elevated troponin level happens in 61 % (Bessiere , et al., 2013).
1-4 Pathogenicity of S. pneumoniae
S. pneumoniae (the pneumococcus) is a main human pathogen responsible for acute invasive diseases such as sepsis , meningitis, and pneumonia in youth children and immunocompromised individuals worldwide (Oetqvist , et al., 2005 ) . Invasive pneumococcal disease seem to depend on both pneumococcal cell wall constituent including lipoteichoic and peptidoglycan ,in addition to a multitude of virulence factor that include pneumolysin [PLY] (Jedrezejas ,2001 ). one of most promising stratagems to control pneumococcal diseases is affecting the colonization factors that elevate pathogen adhesion to human tissues (Kline , et al., 2009 ) . Although knowledge of the mechanism important to pneumococcal colonization is still limited , it seems that a critical tread in this process is the binding of human host protein via a complex array of bacterial adhesions (Hammerschmidt , 2006 ).
The pneumococcus is capable to cause anumber of primary infection through escaping it’s nasopharyngeal niche to other anatomical position ( Bogaert , et al ., 2004 a ) . S. pneumoniae infection of the sinuses [sinusitis ] , conjunctive [conjunctivitis ] and inner ear [otitis media ] are not usually life threatening , but they have a great socioeconomic cost and there evidence that the antibiotic use to treat these disease rises the proportion of drug resistant S. pneumoniae separates being carried in the circulating population ( Ktein , 2000).
Pneumonia results when pneumococci descend into the lungs and inflame the alveoli, leading to fluid inflowing the air space and inhibiting oxygenation of the blood. Empyema, a complication including the infection of the pleura or pericardium, arises in amid 0.6 and 30% of pneumonias with a strong association with serotype 1 pneumococcal infections (Byington, et al., 2002).
Penetration of the alveolar wall, allowing S. pneumoniae to enter the tream, results in bacteraemia (Marrie, 1992). This too allows the bacterium to metastasise and cause ‘secondary infections’. These include bones (osteomylitis) and joints (arthritis) ,the abdominal cavity (peritonitis) and the kidneys, where the pathology can both be defined as nephritis or haemolytic-uraemic syndrome (Brandt et al., 2002). The valves of the heart can also be colonised (endocarditis) in some cases. The furthermost severe threat to health is when the bacteria penetrate the blood-brain barrier and cause meningitis (Koedel et al., 2002). Other infections are seen more seldom, but comprise pancreatic abscesses and necrotising fasciitis (Taylor and Sanders, 1999).
1-5 Laboratory diagnosis of S.pneumoniae
The laboratory identification of S. pneumoniae isolates depend on the recognition of classic morphological characteristics and on the results of a few phenotypic examinations.
microscopic evaluation, S. pneumonia seem as lancet-shaped, gram-positive diplococci or chains of cocci . If saw by experienced microscopists, these features have high specificity for the existence of S. pneumoniae and should be reported as such. However, typical looks can be altered by antimicrobial therapy, and over-decolorization of the stain can provide the false impression that they are gram-negative diplococci (Spijkerman ,et al., 2012) .
Figure 3:- Gram stain of a sputum sample showing S. pneumoniae as gram-positive diplococci.
The quellung reaction is a more definite method for pneumococcal detection from pure cultures otherwise sputum samples (Merrill , et al.,1973 ). Once reaction of the pneumococcus with streptococcal anticapsular antisera, the pneumococcal capsule develops visually enhanced, and the bacterial cell looks to be surrounded by a halo (Figure 4). Although the quelling reaction is generally regarded as being very specific for pneumococcus, cross reactions have been stated with other streptococcal polysaccharides, and unencapsulated strains will create false-negative results. (Lee,et al.,1984).
Figure 4 :- Quellung reaction, showing both positive (for Streptococcus pneumoniae) and negative results.
After instant incubation at 35°C with 5% CO2 on 5% sheep blood agar or chocolate agar, S. pneumoniae colonies seem to be small, grayish, and mucoid and are bounded by a greenish zone of α-hemolysis. After 24–48 h of incubation, the colonies developed centrally depressed (“draughtsman” colonies) (figure 5). Additional identification is important to confirm the identity. Laboratory difference between S. pneumonia and other viridans streptococci is generally accomplished by 2 key reactions: optochin susceptibility as well as bile solubility. Optochin [ethylhydrocupreine] is an antibacterial agent that is not used remedially but is used for the laboratory identification of streptococci. The bile solubility test is grounded on the autolysis of S. pneumoniae in the existence of the surfactant sodium deoxycholate. S. pneumoniae isolates are typically susceptible to optochin and are bile soluble, while other viridans streptococci are usually resistant to optochin and are bile insoluble. Although bile solubility is generally considered as being very sensitive and specific for identification ofS. pneumoniae, the finding that up to 10% of S. pneumoniae isolates can be resistant to optochin has reduced dependence on the latter test (Kellogg, et al.,2001) .
Figure 5 :-Streptococcus pneumoniae growing on sheep blood agar as “draughtsman” colonies. The disk contains optochin and is surrounded by a zone of inhibition.
Marketable slide agglutination, coagulation, and DNA probe hybridization tests are alternative approaches for rapid identification of S.pneumonia isolates(Kellogg, et al.,2001) . All of these approaches are highly sensitive but infrequently produce positive results with other viridans streptococci [specificity range, 85%–95])(Kellogg, et al.,2001) .
1-6 pneumococcal virulence factors
S. pneumoniae produce a variety of virulence factor that promote bacterial pathogenesis (Kadioglu , et al., 2008). It is fine documented that the polysaccharide capsule of the pneumococcus is an essential virulence factor of the microorganism, and on the basis of differences in the immunochemistry of the capsule, it has been recognized that there are further than 90 pneumococcal serotypes (Rodrigo and Lim , 2014 ). The importance of information of these diverse serotypes is that it has been documented more newly that certain serotypes are further virulent than others, are more probable to be related with invasive disease or certain clinical disease presentations , and are more probable to be related with a poorer outcome when initiating infection(Rodrigo and Lim , 2014 ). Furthermore, continuing surveillance for the circulating serotypes is vital in both the development and use of pneumococcal vaccines, for example the pneumococcal conjugate vaccine (Rodrigo and Lim , 2014 ) .
The most significant of pneumoccal virulence factor and pathogenicity which describe in table 2.
Table 2: Virulence factor of S. pneumoniae
Virulence factor
Effect
polysaccharide capsule
protection from phagocytosis by avoidance of binding of iC3b (complement system) and Fc (immunoglobulin)
enhancement of colonization
prevention of mechanical removal by mucus
restriction of autolysis
pneumolysin (PLY)
high, lytic concentrations:
pore formation and cell lysis/death
low, sub-lytic concentrations:
activation of the classical complement pathway promotion of inflammation
production of reactive oxygen intermediates (both mediated by interaction with TRL-4)
astrocytic process retraction, cortical astroglial reorganization, interstitial tissue retention
enhanced penetration of bacteria and toxic macromolecules [Hupp et al., 2012], and brain damage in general
hyaluronidase
enhancement of spreading and colonization
neuraminidase A (NanA)
enhancement of colonization
biofilm formation
pilus
enhancement of binding to epithelial cells
stimulation of proinflammatory cytokines
lipoproteins (PsaA, SirA, PpmA)
adhesion to cells
colonization
autolysin (LytA)
release of PLY from the bacteria
release of inflammatory cell wall degradation products
pneumococcal surface proteins (PspA, PspC)
interaction with the complement
adhesion
genome variation
evolutionary advantages
resistance against antibiotics
(Mitchell and Mitchell , 2010 ) .
1-6-1 Pneumolysin
1-6-1-1 Pore-forming toxins
Toxins are often defined as bacterial effectors that can act in the absence of the bacteria. Other bacterial effectors, in contrast, depend on delivery into the host, and thus on the presence of the pathogen (reviewed in [Aktories, et al., 2011]). Pore-forming protein toxins are an aggressive approach of pathogens, meant to enter, to damage/destroy, or to manipulate host cells for their own advantage. Those proteins encounter biological membranes and are known to lead to either membrane collapse, or to induction of signaling events downstream of membrane binding events, e. g. activation of small GTPases (reviewed in [Aktories and Barbieri, 2005]). Pore-forming proteins were identified in a wide range of organisms, including bacteria, plants, fungi, and even animals (Iacovache ,et al., 2008).
1-6-1-2 General characteristics of Pneumolysin
Pneumolysin (Ply) is a well-established virulence factor (Hirst , et al ., 2008 ) that has been extensively studied for its hemolytic activity and cytotoxic properties. Ply, a 53-kDa surface protein (Price and Camilli ,2009), is a cholesterol-dependent cytolysin that binds cholesterol in eukaryotic cell membranes and forms 400-Å pores that lead to cell lysis (Alouf ,2000). Through its activity at the bacterial cell surface, or upon release through pneumococcal autolysis, Ply is responsible for almost all pneumococcal hemolytic activity (Berry and Alexander , 1995) . PLY is the only one that is not secreted into the extracellular medium (reviewed in [Cassidy and O’Riordan ,(2013)]). cholesterol-dependent pore-forming toxin with 4 functional domains (Mitchell and Dalziel, 2014). It is β-barrel pore forming toxins, secreted via Gram-positive bacteria via for S. pneumoniae (Marriott et al., 2008).
Crystal structure of PLY
The molecule contains 11% helix and 32% beta-sheet. It is composed of four domains (Fig. 3): -domain 1 (D1) consists of three α -helices and one β -sheet, domain 2 (D2) contains one β -sheet, domain 3 (D3) is composed of a 5-stranded anti-parallel β –sheet that is surrounded by the two α -helical bundles that become transmembrane hairpins TMH1 and TMH2 ,and domain 4 (D4) is folded into a compact β -sandwich. Domain 2 is joined to domain 4 by a single glycine linker. Parts of domain 2 are greatly mobile with ambiguous or weak electron density for certain residues in these regions (Lawrence , et al., 2015).
Figure 6:-. Crystal structure of the PLY monomer
Pneumolysin mode of action :-
PLY is created as a water-soluble monomer and distinguishes mammalian cells by its C-terminal domain (domain 4) before collecting into circular prepores of ~30–50 monomers on the surface of cholesterol-rich membrane (Tweten, 2004 ). The monomers in the prepore endure critical structural changes, counting the unfurling of two alpha helical bundles (α-HB1 and α-HB2) in domain 3 in both monomer that are then refolded into β-hairpins (transmembrane hairpins TMH1 and TMH2) for insert into the membrane, which is assisted by a structural collapse to the membrane surface ( Shatursky, et al.,1999). The resultant PLY β-barrel pore has a diameter of ~300Å that causes lysis of the target cell (Tilley,et al.,2005) (figure 2 ) . Domain 4 [D4] is the membrane-sensing domain of CDCs and, for many CDCs, membrane-bound cholesterol seems to be the receptor (Giddings,et al.,2003) . Two remains at the tip of D4 [Leu and Thr] have been identified as a recognition site for cholesterol ( Farrand,et al.,2010). CDCs comprise a highly conserved undecapeptide region (ECTGLAWEWWR), so-called the Trp-rich loop that is also found at the tip of D4 and forms an interaction site with membranes (Alou, et al.,2005). Tryptophan fluorescence studies propose cholesterol binds in a 1:1 complex with PLY and the cholesterol-binding site is close to the Trp-rich loop (Nollmann , et al.,2004). This loop is too a key element in the allosteric pathway that couples membrane binding in domain 4 to the conformational changes that have to happen in domain 3 for the conversion of the prepore to pore (Dowd , et al., 2012).
Figure 7 :-Steps in pore formation by pneumolysin.
1-6-1-3 Pneumolysin role in pathogenicity
Pneumolysin plays an extraordinary role in the pathogenicity of S. pneumoniae. In a new study, binding of PLY domain [4] to the sialyl LewisX glycolipid cellular receptor on the surface of human erythrocytes was shown to be an essential step before membrane insertion and pore formation (Shewell ,et al.,2014). PLY is a cytoplasmic thiol-activated toxin with cytolytic and complement-activating properties (Lucas, et al., 2013). PLY is local mostly to the cell wall compartment in the absence of detectable cell lysis (Price, et al., 2012). However, different other cholesterol-binding cytolysins, PLY lacks secretion signal sequences and is not actively secreted into the extracellular milieu (Cassidy and O’Riordan, 2013). The cytolytic action of PLY and its discharge into the extracellular environment are repressed by branched stem peptides in the peptidoglycan cell wall (Greene, et al., 2015). PLY is free into the alveolar compartment upon bacterial lysis tempted by autolysis otherwise by antibiotic treatment of pneumococcal pneumonia patients (Anderson ,et al.,2007). However, in the lack of cell lysis, PLY is spread from the cytoplasm and attached to the cell wall by a yet-to-be-characterized mechanism (Price, et al., 2012). PLY is directly toxic for a wide variety of host cells and tissues and also provokes strong inflammatory responses at the site of infection, triggering signalling by TLR4 (Malley ,et al., 2003), in addition to activation of the NLRP3 inflammasome (McNeela ,et al., 2010).
Circulating PLY also encourages myocardial injury in a mouse model of invasive pneumococcal disease also dose-dependent damage to cardiomyocytes in vitro (Alhamdi, et al., 2015). In pneumococcal meningitis, the common of the damage to the blood–brain barrier has been attributed to PLY (Mitchell and Dalziel, 2014). Structural homology to the Fc region of immunoglobulin G (IgG) also lets PLY to activate the classical complement pathway away from intact bacteria to deplete host serum complement levels and encourage survival and spread ( Alcantara ,et al., 2001). Newly, PLY was also revealed to contribute to the assembly of pneumococcal biofilms (Shak ,et al., 2013). PLY activates p38 in vitro (Ratner, et al., 2006) and the NLRP3 inflammasome in macrophages to encourage the production of type Iinterferons following pneumococcal phagocytosis (Koppe, et al., 2012).
In murine infection models, PLY-deficient mutants have reduced spread in whole blood , diminished capacity to colonize the nasopharynx, encourage less lung inflammation and neutrophil recruitment and are quickly cleared from the lung, compared with WT (Kadioglu, et al., 2000). Hereditarily inactivated PLY toxoids are immunogenic and protective against lethal pneumococcal challenge in mouse vaccination models (Kirkham, et al., 2006). Phase clinical trials demonstrated that PLY toxoid PlyD1 is safe and provokes functional neutralizing antibodies against the pneumococcus (Kamtchoua, et al., 2013).

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