Autolysins promote colonization of nasopharyngeal cells due to the release of toxins such as pneumolysin during cell wall degradation Pneumococcal surface proteins: S. Pneumococcal surface proteins are categorized into four groups: CBPs, lipoproteins, non-classical proteins, and proteins that have an LPXTG motif X represents any amino acid and can be covalently bound through sortase cleavage of the motif 17 , CBPs: many of S. For example, pneumococcal surface proteins discussed below are also classified as CBPs 27 , 72 , 76 , These proteins are known for binding to PCho on S.
Some of these CBPs can also modify host cell surfaces to allow for binding interactions between to host cell receptors and S. PspA is very electronegative, and this characteristic can block complement binding, which prevents opsonization of S. PspA can also bind to host lactoferrin 22 , 27 , 51 , specifically apolactoferrin iron-free , which in turn provides protection to S.
PspC , also known as CbpA highly polymorphic , promotes adherence by binding to the polymeric immunoglobulin receptor 72 , It facilitates the colonization of S. This in turn interferes with opsonization of S. PspC exists in multiple allelic forms with most alleles containing a C-terminal cell wall choline-binding motif.
In addition, allelic variant PspC 4. LytA , an autolysin, was the first of three major lytic enzymes found in S. LytA degrades peptidoglycan by cleaving the N -acetyl-muramoyl- l -alanine bond 72 , This causes cell lysis and the release of pneumococcal antigens such as pneumolysin, peptidoglycan, and teichoic acids which are all harmful to host cells 72 , , The release of these harmful particles from S.
This is thought to be due to the fact that cells are already decomposed so phagocytic activity is no longer necessary , and acts as a form of immune system evasion by S. By blocking cell signaling via cytokine production, LytA has also been shown to hinder complement activation How exactly this blockade might be happening, still needs to be further researched.
LytB and LytC are two other lytic enzymes found in S. Their roles in S. Studies have shown that LytB is necessary for separating daughter cells , LytC on the other hand, is described as a lysozyme.
Ramos-Sevillano et al. Their results also suggest that LytC helps with evasion of the complement system via experiments with mutants. LytC mutants had larger amounts of C3b deposition and LytB and LytC double mutants all had a reduction in their ability to adhere to host cells These findings shed light on the roles of LytB and LytC. They aid in virulence by playing a role in colonization and evasion of host immune responses , In addition, LytC has also been described to play a role in cellular fratricide with LytA.
These enzymes are released to lyse non-competent pneumococci in close proximity of competent cells This is important for transformation of S. Competent cells are able to uptake and incorporate free DNA from the lysed cells , This promotes genetic exchange which in turn can improve bacterial survival. For example, the bacterium can take up genes for antibiotic resistance , CbpF , the most abundant protein on S.
These have not been studied as extensively as the main CBPs previously discussed. There is not much known about their structure or function. The CbpD is able to provide a substrate for LytC that is more accessible by binding to target cells and breaking down the cross-links of the peptidoglycan CbpG is necessary for adhesion and all others been reported to work as adhesins 77 , Lipoproteins: these proteins are necessary for substrate transport.
There are approximately 50 lipoproteins that have been characterized 72 , , The four main lipoproteins are the pneumococcal surface adhesin A PsaA , pneumococcal iron acquisition A PiaA , pneumococcal iron uptake A PiuA , and pneumococcal iron transporter PitA 17 , 72 , , ABC transporters transport substrates across membranes by utilizing energy generated from ATP binding and hydrolysis.
PsaA is involved in transporting magnesium and zinc into the cell 27 , 74 , , However, other studies on PsaA mutants have found that PsaA has no clear role in adhesion, but rather magnesium transport This particular characteristic of adhesion needs to be further investigated This indicates the importance of iron in the environment for growth.
Furthermore, Cheng et al. Cheng et al. On the other hand, PiuA binds to both hemin and hemoglobin but has greater affinity for hemin , PitA was later discovered and characterized to bind to ferric irons , , A novel iron transport was discovered in by Yang et al.
Using this mutant, they were able to identify potential iron transporters, such as putative protein SPD, which functions similarly to PitA via translatomics and proteomics These findings suggest that there are potentially more iron-binding proteins in S.
LPXTG cell wall bound proteins are recognized by the sortase of the cell wall 54 , , Sortase recognizes the LPXTG sequence, cleaves at this site, and anchors the proteins to the cell wall 54 , , Mutating the sortase gene srtA caused a decrease in S. Neuraminidase is an example of an LPXTG cell wall bound protein and is known for cleaving sialic acid from glycoproteins.
In the case of pathogenesis of S. Neuraminidase is secreted from S. It is also involved in colonization of the host and has been suggested to be involved with adhesion , They are also known as moonlighting proteins for having multiple functions 72 , 78 , NCSPs function as adhesins that are able to bind to host molecules which promotes pneumococcal host cell invasion PavA attaches to fibronectin and assists with adherence to host cells PavA also provides protection to pneumococci by controlling inflammation and inhibiting recognition by dendritic cells PavA mutants were more susceptible to recognition and phagocytosis by dendritic cells compared to wild type In addition to this, when the dendritic cells encountered PavA mutants there was a reduction in cytokine production, which affected the adaptive immune response.
Enolase is an anchorless protein found at the surface of S. It is important for proteolytic activity on the cell surface , which is necessary for the pathogenesis of S. Enolase also promotes complement system evasion by binding to the complement inhibitor C4b-binding protein In addition, studies suggest that enolase may cause host tissue damage by inducing the production of neutrophil extracellular traps by binding to neutrophils GADPH is suggested to also play a role in iron acquisition due to its ability to bind to hemoglobin and heme Pili : these hair-like structures are located on the cell surface of S.
They assist with S. These pili also help the bacteria avoid phagocytosis by host immune cells There are two main types of pili found on S. Studies have shown that piliated S. This suggests that pili are able to stimulate inflammatory responses of the host Pancotto et al.
High expression of pilus-1 is observed at early stages of colonization and reduced expression during later stages of infection. This downregulation may be necessary for avoiding host immune response but this needs to be further investigated as it is not clear why this might be happening This pilus is formed on the surface of the bacterial cell and contains the major pilin ComGC.
The structure of ComGC was recently discovered by Muschiol et al. Immunoglobulin A1 IgA1 protease : this enzyme is produced by S. These two isotypes differ in hinge regions—IgA1 has an extended hinge region because of an insertion into this region of a set of duplicated amino acids Hydrogen peroxide: S. However, this is only observed in strains with pyruvate oxidase activity SpxB gene , H 2 O 2 production also has bactericidal effects.
In addition, pneumococcal H 2 O 2 induces an innate immune response by enhancing the release of pro-inflammatory cytokines, and targets cellular stress responses These radicals are often harmful to bacteria but do not affect S.
This is because of S. SpxB mutants produced no H 2 O 2 and were less resistant In addition, S. Pathogenicity islands PAIs : these are parts of pathogenic bacterial genomes that were acquired via horizontal gene transfer The genes on PAIs aid in the virulence of the pathogen PAIs can code for iron-uptake systems and proteins involved in cell attachment For example, the first PAI discovered in S.
In addition, the pilus-1 is encoded by another PAI, known as the rlrA islet However, this PAI is not found in all of the S. Pilus-2 is also encoded by a PAI, pilus islet 2 Another important adhesin, pneumococcal serine-rich repeat protein PsrP , is also coded for by a PAI.
PsrP is important for S. High PsrP production is also linked to biofilm growth PAIs promote genetic variation in species, and this may affect current treatment and vaccine targets. Biofilms : these are structured communities that consist of aggregated microbial cells surrounded by an extracellular matrix of polysaccharides that attach to surfaces 47 , The extracellular matrix provides protection and enhances S.
Biofilms are formed in response to stress and harsh conditions to promote bacterial survival 47 , , To promote biofilm formation and competence, S. Within biofilms, horizontal gene transfer rates increase due to close cell proximity 47 , , , Studies indicate that S.
We have discussed above the virulence factors that aid in ensuring S. On the other hand, there are several host defenses that recognize S. Protection from S. Age plays a role in how successful the immune system will be at clearing the infection by S. Children under the age of five and the elderly are at higher risk for contracting pneumococcal diseases Figure 2. A variety of immune cells are involved in the innate first-line of defense and adaptive immune responses.
The most important immune cellular and humoral components for defending against pneumococcal infections Figure 7 are summarized in the following sections including how aging may affect their ability to defend the host. Figure 7. Host surface and intracellular receptors necessary for immune response to Streptococcus pneumoniae. Highlighted in this figure are the major pathogen recognition receptors necessary for binding to pneumococcal ligands and eliciting an immune response. Upon binding to the ligands, receptors and signaling pathways are activated, which leads to the overall production of inflammatory cytokines and recruitment of immune cells.
There are 10 toll-like receptors TLRs that have been discovered in humans—TLRs involved in pneumococcal disease are depicted in the figure. Innate immunity involves non-specific immune responses—cells and receptors recognize foreign particles and elicit immune responses to eliminate the invaders that can be harmful to the host 16 , , Cell-related innate immune responses against pneumococcal infection include:.
Mucosa and respiratory epithelial cells : epithelial cells provide a protective barrier for tissues and organs In this case, they line the respiratory tract and protect against pneumococcus There are epithelial cells known as goblet cells, which secrete mucus The negatively charged mucus is necessary for maintaining moisture and trapping foreign particles and pathogens.
In addition, ciliated epithelial cells function simultaneously with the mucus to clear pathogens. This process is known as mucociliary clearance Once the pathogen is trapped in the mucus, the cilia hair-like structures move together to direct the trapped pathogen and the mucus to the mouth, for expelling the pathogen via coughing or swallowing The respiratory epithelial cells can recruit other cells by producing and releasing cytokines and chemokines 22 , They also can directly kill pneumococcus by secreting antimicrobial peptides such as defensins, human apolactoferrin, and lysozyme Figure 8 22 , , Human apolactoferrin sequesters iron and lyses cells.
Lysozyme also lyses cells and acts as a bactericidal The negatively charged capsule also promotes evasion of mucus via electrostatic repulsion Mouse model experiments showed that encapsulated S. This again was due to the negatively charged capsule. In addition to this, S. This modification promotes resistance of S.
Another impressive method of evasion by S. The thick capsule is necessary to avoid entrapment in mucus, and the thin capsule is necessary for binding directly to epithelial cells , Once the thin capsule is expressed, adhesins are exposed for binding to the glycoconjugates on epithelial cells , Infants and the elderly both are challenged with mucociliary clearance due to different reasons: in infants, immature submucosal glands, surface epithelial secretory cells, and low numbers of ciliated epithelial cells can result in poor mucociliary clearance In the elderly, as the host ages there is a deterioration of mucociliary clearance, with reduced mucin and slower cilia beat frequencies 28 , , which promotes dissemination of the bacteria Neutrophils : these are found in larger concentrations compared to any other white blood cells WBC , and they are generally the first to travel to the infection , Neutrophils are phagocytic cells that also produce granules, which break down the cell walls of pathogens ultimately killing them Primary granules include defensins whereas secondary granules include enzymes necessary for digestion, such as lysosomes.
Neutrophils can also trap S. Neutrophil response changes with age: infants experience minimal protection by neutrophils in their early days of life due to poor bactericidal function, impaired phagocytotic activity, low response to inflammatory signals, and reduced chemotaxis — With age, neutrophil activity improves and strengthens in young adults but later starts to deteriorate. Elderly populations experience impaired chemotaxis, which may lead to the overproduction of proteases by neutrophils.
This causes an increase in inflammation levels in older subjects 15 , Neutrophil extracellular traps generation, phagocytosis, and killing diminishes with age 15 , Macrophages : macrophages are derived from monocytes and function as phagocytic cells that engulf and directly kill S.
These cells can recruit other immune cells, such as neutrophils via cytokine signaling , and remove dead neutrophils , and other cells via phagocytosis and apoptosis. The macrophage receptor with collagenous structure MARCO , found on the surface of macrophages, aids with the phagocytosis of non-opsonized antigens Macrophage activation due to S. For example, toll-like receptors TLRs 2 and 4 work together to activate macrophages in the presence of pneumococci Within days post birth, macrophage levels and function improve to reach adult levels By contrast, with old age alveolar macrophage concentrations are depleted, cytokine production and phagocytotic activity are reduced, and lowered expression of MARCO contributes to poor killing of S.
PAMPs are structures found in bacteria and viruses. Many of these are necessary for virulence in pathogens. There are currently 10 identified TLRs in humans TLR2 is necessary in pneumococcal infection because it recognizes bacterial cell wall constituents.
However, TLR2 is now found to be binding to pneumococcal lipoproteins and peptidoglycan , , TLR2 also has a role in transmission of pneumococci. Mouse models with deficient TLR2 had increased inflammation and shedding TLR4 was the first TLR to be characterized and is needed for recognition of pneumococcal pneumolysin 51 , , TLR9 binds to CpG motifs on the DNA, and when activated it also has signaling pathways which result in the release of cytokines , MYD88 is an intracellular protein necessary for signal transduction and activation of TLR signaling pathways , In addition to cytokine production, the activation of these TLRs facilitates the secretion of co-stimulatory molecules which are necessary for activating T cells Thus, the functions of these TLRs also play a role in adaptive immunity Figure 9 , , Aging greatly affects TLR function.
Expression of TLR1 is reduced with age TLR4 expression appears to remain normal but experiences a reduction of function 15 , This association has been made in mice, due to macrophages having a lowered production of pro-interleukin-1B 15 , 28 , , Overall TLR cell signaling impairment causes a reduction in cytokines produced, leading to poor defense against S.
This NLR recognizes muramyl-dipeptide which is a fragment of bacterial peptidoglycan in the cytosol 16 , It promotes the production of cytokines and activation of nucleotide-binding domain and leucine-rich-repeat-containing protein 3 NLRP3 genes For example, when NOD2 senses peptidoglycan, CCL2 is made and that recruits macrophages and monocytes to the infection This is dependent on the lysozyme producing these peptidoglycan fragments NLRs expression decreases with age and responses to S.
It has been reported that, in the case of pneumococcal infections, CD14 promotes growth and dissemination of the bacteria 22 , Previous studies have found CD14 to be beneficial and protective to hosts against Gram-negative infections, but as for Gram-positive pathogens such as pneumococci, it instead enhances the pathogenesis of the bacteria and facilitates infection Figure 8.
Two types of epithelial cells are depicted: goblet cells and ciliated epithelial cells. The cilia on the epithelial cells together with the mucus produced by goblet cells clear the pathogen via mucociliary clearance. Epithelial cells can also secrete antimicrobial peptides that directly kill S.
Figure 9. Toll-like receptors TLRs assist in the activation of adaptive immune cells. Upon activation, TLR2 secretes cytokines and co-stimulatory molecules. These co-stimulatory molecules are essential for co-stimulation and activation of T cells. Adaptive immune responses transpire a few to several days post-infection.
The cells involved in adaptive immune responses respond to specific antigens from pathogens. Adaptive immunity can also be broken down into two types of responses: humoral and cell-mediated Humoral immunity involves B cells that are activated by antigens, and production of antibodies that are specific to antigens. Cell-mediated immunity also involves T cells, including T cell activation and T cell-mediated recruitment, which involves the activation of other immune cells that can directly kill pathogenic cells These immune cells are formed in the bone marrow—B cells mature in the bone marrow into plasma cells that make antigen-specific antibodies Infections at mucosal sites are controlled by the pneumococcal specific IgA antibody.
IgA is observed in mucosal areas of the nose and saliva following S. Secretory IgA is important for opsonizing S. This blocks opsonization.
Following cleaving, the remaining Fab fragment binds to the cell wall , This exposes CBPs, decreases negative charge of the capsule and increases cell adhesion , Studies suggest that the Fab neutralizes the negative charge of the capsule and instead promotes cell adhesion , Furthermore, the complement C3 activates B cells.
Class switching produces other immunoglobulins needed for clearing the infection Antigen-presenting cells APCs paired with the major histocompatibility complex MHC proteins present antigens specifically, peptides to T cells to stimulate an immune response Upon activation, helper T cells differentiate into Th1 and Th2 cells Figure 9. Th2 helper cells release IL-4 cytokines, and are geared toward facilitating a humoral immune response by interacting with B cells and aiding in antibody production Cytotoxic T cells directly kill infected cells Furthermore, upon activation of T and B cells, they can differentiate into memory B and T cells that can provide quicker clearance in reoccurring infection Similarly, natural killer T-cells are also important for clearance of pneumococci 16 , T-helper 17 Th17 and regulatory T cells Tregs are also very important for pneumococcal infections.
Th17 cells release the cytokine IL which is pro-inflammatory. IL is needed for recruiting and activating macrophages, monocytes, and neutrophils to sites of infection and promotes clearance of S.
Increased production of IL has been connected to reduced S. Imbalance between Tregs and Th17 cells can lead to autoimmune disease due to over inflammation Infants experience poor T cell responses to foreign antigens because their exposure to non-maternal antigens was restricted prior to birth Infants also display a skewed Th2 response to foreign antigens.
As for B cells, in infants there is a limited response to antigens due to low expression of co-receptors Infants also experience incomplete class switching for immunoglobulins and lower somatic hypermutations compared to adults Immunoglobulin protection against S. At birth, maternal IgG antibodies protect infants until 27 days of age based on the half-life of IgG 28 , By contrast, IgM has been detected in infants following S.
Encountering the pathogen again, also promotes antibody production similar to booster effects in vaccines discussed below With development, the adaptive immune cells mature, develop memory, and the incidence of S.
In elderly populations, the efficacy of the adaptive immune cells diminishes. Aging leads to reduced production of antibodies, immunoglobulin class switching, and cell maturation, which promotes S. Antibodies specific for capsular polysaccharides decrease with age Previously Th17 levels were described to increase in elderly populations whereas most recently, in , van der Geest et al.
Diminished responses from the adaptive immune cells explain the higher incidence rates of pneumococcal diseases in these high-risk age groups. These are signaling molecules released by innate and adaptive immune cells and receptors to direct other immune cells to the infected tissues , Chemokines are examples of cytokines that attract cells to the infected site. In addition to recruiting cells, they promote inflammation , The phagocyte-activating cytokines are suggested to be inhibited by autolysin activity in pneumococci The elderly experience chronic low-grade age-associated inflammation inflammaging Inflammaging induces the expression of host proteins which enhances S.
This is a protein complex that consists of a sensor protein, caspase 1, and an apoptosis-associated Speck-like protein with a caspase recruitment domain ASC The inflammasome is used by the host for indirectly recognizing bacterial or pathogenic molecules and DNA Upon recognition, the inflammasome regulates cytokine production NLRP3 plays a role in identifying pneumococcal infection, activating macrophages and has been shown to directly interact with pneumolysin during pneumococcal infection Although inflammasomes may aid in the recognition of pathogens, the activation of inflammasomes promote inflammation and this can be harmful to the host Cho et al.
Ensuring that NLRP3 is activated appropriately in the elderly population will promote stronger immune defenses against S. This is comprised of a set of small proteins that enhance the ability of antibodies and phagocytic cells to clear microbes and damaged cells These proteins can mark antigens and cells by coating them with opsonins 16 , Complement activation involves three cascade pathways: classical, mannose-lectin, and alternative pathways.
In the classical pathway, the complement proteins bind to an antibody-antigen complex , whereas the alternate and mannose-lectin pathways, bind directly to PAMPs and cell surface components. Which pathway plays the main role in response to pneumococcus has been debated. Brown et al. On the other hand, in Ali et al. However, irrespective of the specific pathway, the complement proteins also help to fight infections by pathogens such as pneumococcus by promoting inflammation, attacking pathogens, and rupturing their cell walls 16 , 22 , For example, mice deficient in complement C3 infected with S.
PspA inhibits C1q binding and polyhistidine triad proteins are suggested to degrade C3. The effects of aging on the complement system are complex. Previous studies suggest that complement levels are low in infants , In , Grumach et al. Studies have also indicated that complement activity is greater in the elderly compared to young adults 15 , , These proteins increase in concentration within the blood during an acute inflammatory infection These proteins work to alleviate infections and can recognize and bind to bacterial surfaces Acute phase proteins are made as a result of cytokine production from innate cells such as macrophages As for MBL, there are conflicting reports about its role in pneumococcus infection as discussed above in the description of the complement system.
It has been shown to recognize and attach to sugars on the cell surface of S. Currently, there are several methods utilized in pneumococcal disease diagnostics. Traditionally, diagnosis begins with physicians performing a physical exam. For example, in the case of an ear infection, an otoscope 24 is used to confirm infection, whereas for pneumonia physicians monitor breathing for cracking sounds and wheezing 1 , , More specifically, for pneumonia, based on the results of the physical exam, physicians can conduct a chest X-ray to examine the lungs and monitor inflammation to confirm the presence of infection , This X-ray is also performed following signs of respiratory distress , Blood oxygen levels are also measured via pulse oximetry in both children and adults to assess the severity of the infection 1 , , Pulse oximetry at the primary care level should be the future, and future technological developments might add respiratory rate and work of breathing to the parameters measured by oximetry Body fluids are also processed to assess whether or not pneumococcus is present, and to confirm its identity 1 , — , These fluids include blood, urine, cerebrospinal fluid, and saliva 1 , — , The blood test allows physicians to examine complete blood cell count.
This test confirms whether or not an infection is present by giving an estimate of the percentage of WBC that are circulating 1 , — , A large concentration of WBC is indicative of an infection 1 , — , This is expected in infection response.
However, Gardner et al. Studies have also shown that poor prognosis has been associated with low WBC These conflicting results indicate that WBC count alone should not be used to diagnose pneumonia and should be better investigated as key indicator of pneumonia. Bacterial cultures and Gram-staining tests using body fluids are important for determining the strain of bacteria and confirming its identity 1 , — , Currently, physicians are investigating other means of diagnosing pneumococcal infections due to the poor yield and quality of sample when conducting cultures.
This process is also dependent on bacterial growth which can be time consuming. One useful tool that is being developed is the urinary antigen detection test , which is only currently used in adults. This test monitors the levels of the C-polysaccharide antigen of pneumococcus in the urine. It appears to be quicker, can allow for targeted treatment with better results than culture-based methods of diagnosis 1 , , , In addition to testing for pneumococcus, physicians also test for other bacteria which may be causing the infection, and other viruses such as influenza which can coinfect patients Once all the tests confirm the presence of an infection, the cause of the infection and the severity of the disease patients are treated accordingly.
Currently, thoracic ultrasounds are being investigated as a method for diagnosing CAP When compared to chest X-rays, thoracic ultrasounds identified Lung ultrasound has been tested for its diagnostic potential and it was found to be a sensitive tool for confirming CAP in children Chest computed tomography is not used for children due to radiation Recently, a computer-aided differential diagnosis system was tested for distinguishing types of pneumonia, using high-resolution computed tomography.
For example, high levels of CRP and procalcitonin accompanied by unilateral hyperventilation and grunting were associated with pneumonia On the other hand, children with no clinical signs of pneumonia and low CRP results were at a lower risk for pneumonia. The use of PCR for diagnosis is also being developed.
A positive blood pneumococcal PCR can more accurately confirm the diagnosis of pneumonia PCR has been used to detect pneumolysin in whole blood samples By contrast, assessment of quantitative real-time PCR indicated that it is more successful in achieving greater speed, specificity, and sensitivity compared to multiplex PCR The two main modes of preventing pneumococcal infections are using antibiotics and vaccinations against pneumococcus Antibiotics are essential in reducing bacterial load Such treatment can work by killing the bacteria or hindering their growth The first antibiotic to be created was penicillin which was discovered in by Alexander Fleming , and antibiotics have been used widely since.
However, misuse of antibiotics can cause bacteria to become resistant 39 , , Resistant bacteria are then able to survive post antibiotic treatment and they can grow, multiply, and share antibiotic-resistant genes with each other. Pneumococcal strains that were penicillin-resistant were first recorded in the s Currently, penicillin-resistant strains have spread worldwide with pneumococcus also being resistant to other types of antibiotics: erythromycin, tetracycline, and chloramphenicol Mutations in penicillin-binding proteins pbp affect binding of penicillin which acts by blocking cell wall synthesis Erythromycin resistance gene erm B blocks the binding of macrolides antibiotics targeting protein synthesis and mefA and mefE genes produce an efflux pump which regulates entry of the antibiotics — Resistant S.
This resistance increases the number of doctor visits and hospitalizations For example, the CDC reports that the resistance can lead to 1,, more illness and 7, deaths annually This reduction in ability to treat and clear the pathogen led to the development of vaccines that would provide protection prior to infection and thus reduce the need for antibiotics Currently, there are two types of inactivated vaccinations that protect against S.
The pneumococcal polysaccharide vaccine 23 PPSV23 uses purified capsular polysaccharides and is routinely given to adults who are 65 and older — It protects against 23 serotypes of S. This vaccine works in a T-cell independent manner. The polysaccharide antigens are recognized by B cells which differentiate into plasma cells that produce antibodies specific for the polysaccharide antigens PPSV23 provides T-cell-independent immunity and requires revaccination 5 years after the first vaccination because the immunity is transient , The pneumococcal conjugate vaccine PCV was developed after noticing the low efficacy and poor immunogenicity of PPSV23 in infants and young children 91 , In the conjugate vaccine, the purified polysaccharides covalently conjugated to a carrier protein, specifically CRM , This elicits a T-cell-dependent response which provides mucosal immunity and immunologic memory in children PCV13 provides long-lasting immunity by causing B and T cells to interact B cells recognize and process the carrier protein The MHCII needed for antigen-presentation to T cells, binds to the peptide produced following B cell breakdown of the carrier protein When it comes to high-risk individuals, the CDC recommends the prime-boost method of vaccination.
This involves priming the immune system to a specific antigen, and enhancing this antigen-specific immune response by re-administering the antigen The prime-boost strategy increases immunity to antigens and is recommended for high-risk individuals , There are two ways to prime and boost the immune system: homologous, in which the same vaccine is received twice, and heterologous, which utilizes different types of vaccines The heterologous method has been shown to be more immunogenic Currently, children and adults who are at high risk for pneumococcal disease and have pre-existing conditions undergo the prime-boost strategy prevention by receiving the PCV13 followed by the PPSV23 , Prime-boost vaccinated HIV-infected groups have been shown to be more likely to display a twofold increase in IgG geometric mean concentrations PCV13 provides a longer and stronger level of protection against S.
Despite the availability of pneumococcal vaccines, it is important to note that these vaccinations are both serotype and age dependent 23 , 91 , — , Understanding the role that age plays in host immune system activation is essential for better prognosis and treatment of diseases. As stated previously, young children and the elderly are at higher risk for contracting pneumococcal diseases This is due to immunosenescence within the elderly population, whereas for infants, it is due to their underdeveloped immune systems In addition to age recommendations, the CDC also recommends the use of either vaccine in high-risk individuals with pre-existing health conditions.
For example, both vaccines are recommended in young children and adults ages 19—64 with pre-existing health conditions 23 , 24 , These vaccine recommendations are reevaluated regularly based on vaccine efficacy and changes within the bacteria serotypes , Vaccines have drastically reduced invasive pneumococcal diseases, especially CAP in young children and adults Table 2 However, these vaccines have pitfalls.
The current vaccines only protect against S. Some studies suggest that there is little evidence that PPSV23 protects against non-invasive pneumococcal diseases, which are more prevalent in adults Weinberger et al.
These researchers argue that PPSV23 does not show a real benefit to the elderly As for, PCV13 they argue that it is already used in children and thus adults should be partially protected from serotypes in PCV13 due to herd immunity They also state that herd immunity should provide partial protection and thus will lead to reduction of efficacy of PCV13 Other studies also discuss herd immunity from PCV13 due to infants and toddlers being vaccinated , This becomes a problem because of serotype replacement.
The serotypes that are not in the vaccine can colonize young children and spread to adults , In addition, with serotype vaccines, the serotypes that are popular and commonly cause CAP and other diseases may not necessarily do so in the future and so these vaccines would need to be reevaluated. Recently researchers at Merck Sharp and Dohme Corp. Current vaccines are ineffective against non-encapsulated S.
Further developments of vaccinations are vital for eliminating the burden of S. Following pneumococcal diseases such as pneumonia, high-risk individuals may experience longer recovery times and complications due to the disease 1 , , About 1.
According to the CDC, there were over 50, deaths within the US during 29 and the majority of these deaths were seen in the elderly Older adults have lower survival rates than other age groups 94 , The elderly may recover from pneumococcal diseases such as CAP, but they face higher death rates due to the high possibility of developing other health problems and the reoccurrence of the disease 1 , 94 , Infants and young children who recover from CAP have an increased risk for developing respiratory problems For example, research indicates that young children face a greater risk for reduced lung function and developing chronic obstructive pulmonary disease 44 , In some cases, increased death rates and complications are due to delays in diagnosis.
Such delays in turn hamper timely treatment, which also increases the severity of the disease. For example, meningitis can progress quickly and cause permanent disabilities such as brain damage, hearing loss, and seizures 24 , 52 , Timely treatment can reduce the risk of neurological damage and death due to this infection In addition, ear and sinus infections can lead to hearing loss and respiratory problems respectively The environment also plays a role in affecting recovery rates and reoccurrence of the disease especially for smokers and those residing in nursing homes and crowded areas 1.
Furthermore, Tiewsoh et al. Nutrition also plays a vital role in how well someone will recover from these diseases Some complications due to pneumococcal pneumonia include respiratory failure, lowered oxygen levels, and collapsed lungs 4. It is also possible for the lungs to fill with fluid and this fluid can become infected. This is called bacteremia which is the most common complication for pneumonia 4 , Pneumonia and other pneumococcal diseases are classified as invasive if the bacteria migrate to the blood.
In addition, individuals with this disease can develop pericarditis which is inflammation of the sac around the heart, lung abscess, empyema, and blockage of airways 4 , It is also highly probable for coinfections to occur when suffering with pneumonia. Most of these health complications are seen in elderly subjects, and this also points to the increasing importance of improved diagnostics, treatments, and vaccinations for this age group.
Pneumococcal diseases cause millions of deaths worldwide 36 , In this review, we have characterized S. We have discussed the host defenses against S. We have also indicated that young children, elders, and individuals who are immunocompromised all have an increased risk for contracting pneumococcal diseases.
The majority of previous efforts have provided an extensive characterization of S. However, in terms of treatment and prevention there remain substantial open questions that need to be addressed as discussed below. There are a variety of methods available for pneumococcal disease diagnostics. Many of the current tests needed to confirm S. Culture-independent methods that take advantage of the latest technologies are being developed, such as the use of a lung ultrasound to assess pneumonia Chavez et al.
Similarly, the use of mass spectrometry to examine metabolites from the saliva , breath , and urine , of patients being tested for pneumococcal diseases is under development. The urine antigen test discussed above also provides rapid results that will allow for quicker diagnosis and treatment once S.
With diagnostic methods improving, pneumococcal disease treatments are also being updated. Antibiotics are available to reduce the colonization of S. Broad-spectrum antibiotics are no longer as effective , Inhaled therapeutics are underdeveloped but can be beneficial for treating pneumonia and other pneumococcal diseases. This method can provide a mode of delivering antibiotics and antimicrobials in a more targeted manner, improve mucociliary clearance via hypertonic saline solutions and inhalation of cytokines to stimulate the immune system On the other hand, to also reduce the effect of antibiotic resistance, S.
Treatment and prevention of pneumonia and other pneumococcal diseases are of major concern for the clinical field due to the high death rates and low efficacy of current vaccines due to aging differences and serotype replacement. Some alternative vaccination methods have been proposed and are also being developed.
For instance, Weinberger et al. Some researchers have proposed creating a conjugate vaccine that targets all or more of the identified serotypes of S.
However, the impact on the immune system and immunogenicity of this vaccine would need to be thoroughly investigated This vaccine would also need to demonstrate better efficacy than existing vaccines In addition, observing how pneumococcal disease incidence rates are changing as more and more people are getting vaccinated will lead to accurate assessment of pneumococcal disease burden and vaccine efficacy Vaccination policies and cost-effect analyses can benefit from information on vaccine disease reduction Serotype-independent vaccines are also being investigated.
These include protein, protein and polysaccharide combination, and whole cell vaccines , , , Protein vaccines would contain surface proteins that are highly conserved in S.
For example, PspA and inactivated pneumolysin have been tested in phase 1 clinical trials as protein antigens PspA is considered an ideal protein candidate because reports indicate that PspA family 2 is commonly found in S. For example, in Pakistan most strains of pneumococci have PspA genes These protein vaccines can provide an extra preventative method once developed and will require thorough analysis of regulation and what regulatory issues may be faced In addition, as a form of combination therapy, a vaccine with protein antigens as well as conjugated polysaccharide antigens may also provide a broader range of protection against pneumococcal diseases , On the other hand, whole cell vaccinations would introduce a dead S.
HogenEsch et al. This exposed the host to multiple parts of S. They found that the vaccine led to the productions of antibodies and IL which defend against S. Researchers have also started developing live attenuated pneumococcal vaccines , The SPY1 strain is a live attenuated strain of pneumococci that does not have a capsule Xu et al.
More recently, Zhang et al. This modified SPY1 vaccine led to higher stability, more production of IgG, and an overall increase in protection when compared to the SPY1 vaccine Additional concerns of serotype-independent vaccines include determining if the vaccines will be immunogenic in all ages, whether or not the vaccines would elicit a strong immune response, and ensuring that they can induce a pro-inflammatory state while not leading to an over activation of the immune system.
All of these novel methods show great promise, but they require further assessments. Overall, there has been progress in our understanding of pneumococcal diseases over the last three decades, however, the diseases still constitute a big burden on health care. There has been a great decrease in pneumococcal diseases since the implementation of purified polysaccharide and polysaccharide conjugate vaccines, but over time due to serotype replacement, antibiotic resistance, and changes in immunity with age, the treatments, and vaccines in place may prove ineffective.
Therefore, ongoing research to improve vaccinations and treatments must continue toward alleviating the ill effects of S.
All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. GM is funded by Jean P. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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