See CDC
Introduction:
Pneumococcal disease is a name for any infection caused by bacteria called Streptococcus pneumoniae or pneumococcus. Bacteria called Streptococcus pneumoniae, or pneumococcus, can cause many types of infections. Some of these infections like pneumonia below can be life threatening. Today, the pneumococcus is thought to be responsible for at least half of all community-acquired pneumonia and otitis media and remains a significant cause of bacteremia and meningitis (together referred to as invasive pneumococcal disease [IPD])
Pneumococcal infections are caused by Streptococcus pneuonia (pneumococcus), a gram-positive, facultative anaerobic bacterium. Pneumococcus can colonize the upper respiratory tract, most commonly in young children, and is transmitted to others through contact with respiratory droplets from a person with pneumococcal colonization in the upper respiratory tract. Certain persons with pneumococcal colonization might develop invasive pneumococcal disease (IPD). IPD is infection of normally sterile sites, including pneumonia with bacteremia, meingitis, osteomyelitis, septic arthritis and bacteremica without a focus of infection. Examples of noninvasive disease include pneumonia without bacteremia, sinusitits, or otitis mediate. In adults, pneumococccal pneumonia is the most common type of pneumococcal disease, and pneumococccus is the most common bacterial cause of pneumonia that resutls in hospitalizaiton. (Kabayashi, “Pneumococcal vaccine for adults aged > 18 years: Recommendations of the advisory committe on immunization practices, United States, 2023”).
In adults, the risk for pneumococcal disease increased with age. Pneumococcal pneumonia is the most common form of pneumococcal disease in adults and is estimated to account for about 10% of hospitalized community acquired pneumonia. (Kabayashi, “Pneumococcal vaccine for adults aged > 18 years: Recommendations of the advisory committe on immunization practices, United States, 2023”).
Transmission:
The nasopharynx has been classed as the main reservoir of S. pneumoniae. This is due to the nasopharynx of hosts being colonized without any symptoms. Following colonization, the spreading of the disease depends on carriers coming into close contact with healthy individuals within the community. The CDC has declared that the main source of S. pneumoniae transmission is direct contact with secretions of the respiratory system of a carrier.
In addition to close contact with an S. pneumoniae carrier, the bacterium may also be transferred to healthy individuals via fomites. Chronic carriers of S. pneumoniae can contaminate inanimate objects with biofilms. S. pneumoniae biofilms are able to survive being in the environment because the biofilm’s structure provides protection from drying out. S. pneumoniae was found in high concentration on items within a daycare center following bacterial cultures. Pneumococcus can survive being in the environment for long periods of time (for example, up to 4 weeks). Because of this, fomites can serve as a reservoir. These findings indicate why it is important to improve hygiene and cleanliness in everyday-life, and at community-based facilities and daycare centers.
In 2020, a decline in IPD incidence was observed globally and the decline is thought to be a result of the introduction of nonpharmaceutical interventions to contain COVID-19 such as mask wearing and restrictions on indoor gathering.
Structure:
Streptococcus pneumonia (S.p.) or pneumococcus is a gram-positive, alpha-hemolytic member of the genus Streptococcus. Streptococcus pneumoniae, a gram-positive bacterium with over 90 serotypes, is the most common causative agent.
Streptococcus pneumoniae (S. pneumoniae, pneumococcus) is a Grampositive bacterium, which can colonize the surface of the nasopharynx. The carriage rate of bacterium in healthy adults is less than 10%, whereas the rate in children is between 27% and 65%.
Pneumococci are classified into seroptyes depending on their capsular polysaccharide, which is a main virulence factor for pneumococcus. At least 100 pneumococcal serotypes were documented as of 2020. During 2018-2019, about 60-75% of all IPD in adults was caused by the 24 pneumococcal serotypes that were included in formulations of commercially available polysaccharide conjugate vaccine (PCV) or pneumococcal polysaccharide vaccine (PPSV) vaccines (i.e., PCV13, PCV15, PCV20, and PPSV23). Current pneumococcal vaccines use the pneumococcal capsular polysaccharides as antigens to generate serotype specific antibodies, which facilitate serotype specific clearance of pneumococci through opsonophagocytosis. (Kabayashi, “Pneumococcal vaccine for adults aged > 18 years: Recommendations of the advisory committe on immunization practices, United States, 2023”).
What it causes
Pneumonia: It is an important human pathogen that colonizes the upper respiratory tract. S pneumoniae is the most common etiologic agent in community acquired pneumonia, as well as bacterial meningitis, otitis media and sepsis. It is responsible for more than 500k cases of lower respiratory tract infection in the US each year. Despite the widespread use of antibiotics, the mortality rate from S.p remains highest during the first 48 hours of hospitalization and has not decreased appreciably over the past 30 years. Successful treatment has been hampered by the increasing prevalence of antibiotic resistant strains worldwide. The earliest stage is seldom recognized and is most likely to be found in patients who die after illness lasting only a short time period because of the very rapid progress of the disease.
Acute Otitis Media (Ear Infection):
Although the middle ear normally has no biota, bacteria can migrate along the eustachian tube form the upper respiratory tract. Wehn bacterai encounter mucus and fluid buildup in the middle ear, they multiply rapidy. Their presence increases the inflammatory response, leading to pus production and continued fluid secretion. Another condition, known as chronic otitis media occurs when fluid reamins in the middle ear.
The single most common bacterium seen in acute otitis media is Streptococcus pneumoniae, although new dat suggest that it is caused by a mixed biofilm of bacteria which are also less usceptible to antibiotics.
Pneumonia
Pneumonia is an inflammatory condition of the lung in which fluid fills the alveoli. It can be caused by a wide variety of different microorganisms but S pneumoniae accounts for up to 40% of community-acquired bacterial pneumonia cases.
Worldwide more children under the age of 5 die from pneumonia than any other infectious disease. In the US there are 2-3 million cases of pneumonia and more than 45,000 deaths eacy year. It is much more common in the winter.
Symptoms:
Histologically, the initial phase of pneumococcal pneumonia is characterized by acute lung injury (ALI) which is an inflammatory disorder of the lung, characterized by hypoxemia, diffuse biolateral infiltrate on chest radiograph and absence of atrial hypertension. Although numerous bacterial are present, few inflammatory cells are seen in serous exudates of these lesions because leukocytes have not had time to reach the alveoli in the advance edema zone.
Etiology:
Following adherence and colonization, Sp will infrequently cause more invasive disease such as pneumonia. The pneumococcus can gain access to the alveolar space and set in motion a series of events leading to inflammation and clinical pneumonia. Although the pneumococcus can bind to many epithelial cell types in the nasopharynx, it cannot adhere to the cilated epithelium lining the tracheo-bronchial tree and ultizes an entirely different set of cell surface receptors in the alveolus. How the pneumococcus changes from a passive colonizing agent in the nasopharynx to a destructive invader of the lower respiratory tract is incompletely understood. (McCullers, “Molecular Pathogenesis of Pneumococcal Pneumonia, Frontiers in Bioscience, 6, 2001).
1. Virulence Factors
–Toxins:
–—pneumolysis (PLY), a 53 kDa protein produced by virtually all clinical isolates of Sp, plays an important role in mortality by inducing hemorrhage. PLY is a member of a family of cholesterol-binding toxins (CBTs, known as cholesterol-dependent cytolysin), which also includes numerous toxins from four general of Gram-positive bacteria.
PLY, probably the most widely studied pneumococcal protein virulence factor, belongs to the family of pore-forming toxins produced by more than 20 species of Gram-positive bacteria, originally described as haemolysins. PLY is a 53-kDa protein made by almost all clinical isolates of the pneumococcus and expressed during the late log phase of growth. Initially, the toxin binds to membrane cholesterol; it then forms large pores (up to 30 nm in diameter) by the oligomerization of up to 50 toxin monomers. The role of PLY in the pathogenesis of infection has been studied in animal models, using mutants of the pneumococcus in which the gene for the toxin has been interrupted or deleted. Early experiments with PLY) strains showed that lack of the toxin reduces the virulence of the organism in both intranasal and systemic routes of infection. PLY has been shown to play a key role in brain damage induced during pneumococcal meningitis in the rabbit model of infection. See Mitchell
–Polysaccharide capsule: that surrounds Streptococcus pneumoniae (Spn) is one of its most important virulence determinants, serving to protect against phagocytosis. The reason for this is that capsule protects the bacterium from host clearance via inhibition of complement deposition and by obscuring bacterial surfaceattached host defense factors from their cognate receptors on immune cells (e.g., Fc portion of antibody), thereby blocking opsonophagocytosis. To date, 100 biochemical and antigenically distinct capsule types, i.e., serotypes, of Spn have been identified. Capsule enhances the escape rate of internalized pneumococci and protects Spn against intracellular killing by VEC and H2O2-mediated killing. See Orihuela
2. Protecting Factors:
CYLD: Studies have also shown that a deficiency of the deubiquitinating enzyme CYLD protects mice from Sp pneumonia pneumolysis induced ALI and lethality. CYLD was initially identified as a tumor suppressor because loss of its activity causes a benign human syndrome called cylindromatosis. In vitro studies have indicated that CYLD is a member of the deubiquitinating (cleavage of ubiquitin from protein) enzyme family. Transfection studies have that CYLD deubiquitinates TRAF2and TRAF6 and acts as a negative regulator for activation of NF-?B by tumor necrosis factor receptor and Toll-like receptor.
Type-1 plasminogen activator inhibitor-1 (PAI-1) deficient mice are hyper-susceptible to several Sp infection and exogenous administration of PAI-1 protects against alveolar hemorrhage and early lethality in mice (WO 2009/018010). PAI-1 is a principal inhibitor of tissue plasminogen activator (tPA) and urokinase (uPA), the activators of plasminogen and hence fibrinolysis (the physiological breakdown of blood clots). CYLD (above) has been shown to act as a negative regulator for PAI-1 expression. CYLD, highly induced by pneumolysin, negatively regulates MKK3-p38 MAPK-dependent expression of PAI-1 in lung tissue, which in turn leads to potentiation of lung hemorrhage and increased mortality.
Capsule: Streptococcus pneumoniae (the pneumococcus) virulence is largely due to its polysaccharide capsule, which shields it from the host immune system. Capsular PS is critical to pneumococcal survival by shielding the organism from complement and subsequent phagocytic killing. It is the virulence factor most necessary for invading the host and causing disease. Most protective antibodies are specific to serotypes or serogroups, and because of this, the famous immunologist Charles Janeway, Jr., stated, “from the point of view of the adaptive immune system, each serotype of S. pneumoniae represents a distinct organism”. Not all capsule types appear to be equally effective in shielding. Only 20 to 30 serotypes of the more than 90 show significant invasiveness. Most pneumococcal capsules are anionic which is thought to help prevent clearance by mucus. CAs pneumococcal vaccines provide serotype-specific protection, it is important that vaccines prevent disease caused by the most clinically relevant serotypes.
Thus, vaccines provide the greatest impetus for recognizing capsular diversity and serotype epidemiology. See Geno
Using unencapsulated serotype 2 and 4S. pneumoniaemutants, Hyams have confirmed that the capsule has several effects on complement activity. The capsule impaired bacterial opsonization with C3b/iC3b by both the alternative and classical complement pathways and also inhibited conversion of C3b bound to the bacterial surface to iC3b. There was increased binding of the classical pathway mediators immunoglobulin G (IgG) and C-reactive protein (CRP) to unencapsulatedS. pneumoniae, indicating that the capsule could inhibit classical pathway complement activity by masking antibody recognition of subcapsular antigens, as well as by inhibiting CRP binding. Cleavage of serum IgG by the enzyme IdeS reduced C3b/iC3b deposition on all of the strains, but there were still marked increases in C3b/iC3b deposition on unencapsulated TIGR4 and D39 strains compared to encapsulated strains, suggesting that the capsule inhibits both IgG-mediated and IgG-independent complement activity againstS. pneumoniae. Unencapsulated strains were more susceptible to neutrophil phagocytosis after incubation in normal serum, normal serum treated with IdeS, complement-deficient serum, and complement-deficient serum treated with IdeS or in buffer alone, suggesting that the capsule inhibits phagocytosis mediated by Fcγ receptors, complement receptors, and nonopsonic receptors. Overall, these data show that theS. pneumoniaecapsule affects multiple aspects of complement- and neutrophil-mediated immunity, resulting in a profound inhibition of opsonophagocytosis. See Hyams
3. Horizontal gene transfer (HGT) occurs between pneumococcal strains and strains of related species. HGT in pneumococcus can occur via transduction, conjugation, and transformation.
–-Transformation is traditionally defined as the uptake of naked DNA from the environment, often derived from lysed pneumococcal cells. Transformation is initiated by the autoinducing competence stimulating peptide (CSP). CSP activates a two-component system (ComD and ComE), leading to changes in the expression of over 5% of genes in the pneumococcal genome. A critical phenotypic consequence of CSP induction is the assembly of the transformasome, a multi-protein complex that imports single-stranded DNA from the immediate extracellular environment and delivers it to RecA for recombination. In this manner, CSP initiates the process by which cells can take up such DNA, a state known as competence. Transformation is active during chronic mucosal infection and colonization events. Multiple studies on the pneumococcus have demonstrated that this bacterium secretes extracellular vesicles EVs. Pneumococcal EVs (pEVs) are internalized by host cells and interact and influence multiple components of the mammalian immune response including the complement system, dendritic cells, macrophages, and neutrophil extracellular traps. It has also been shown that pEVs serve as DNA donors to pneumococcal cells. one study demonstrates that genomic DNA associates with the external surfaces of pEVs. This DNA can serve as a source for transformation but requires CSP signaling and transformation machinery on the recipient cell. The pEVs apparently deliver DNA to the cell via the transformation machinery and not through EV-fusion to the recipient cell membrane nor by EVs transport into the recipient cell. See Hiller
Expression of competence for natural genetic transformation in S. pneumoniae is a transient phenotype. Typically, laboratory cultures growing in a competence-promoting medium will spontaneously induce this phenotype at an OD550 nm of 0.15–0.2. However, after c. 30 min of competence, the ability to take up DNA is rapidly lost. The exact nature of the secreted competence factor and the mechanism by which it would induce competence remained elusive until the mid-1990s, when the inducing molecule was purified and identified as an unmodified peptide termed competence-stimulating peptide (CSP). See havarstein
A prominent characteristic of the bacterium is a natural ability to take up exogenous DNA from its environment. If the exogenous DNA is integrated into the genome, the bacterium is said to be transformed. Such transformation depends on development of a specialized physiological state, termed competence, development of which is coordinated within a culture by a quorum-sensing (QS) mechanism encoded by two genetic loci, comAB and comCDE . Both loci are transcribed at a basal level by the “housekeeping” sigma factor. The competence-stimulating peptide (CSP), a product of the comC gene, is secreted by an ABC transporter/protease encoded by comA and comB. CSP is sensed by a histidine kinase receptor, ComD, which phosphorylates a cognate response regulator, ComE. Phosphorylated ComE activates the promoters of eight operons comprising 13 genes transcribed specifically at competence by binding a direct repeat centered at 40, the ComE box. They are designated early competence genes and include both the comAB and comCDE operons. This organization creates a positivefeedback loop, ensuring a rapid increase in the level of CSP that can cause all the cells in a culture to become competent simultaneously. See Morrison
Extracellular vesicles (EVs) secreted by the human pathogen Streptococcus pneumoniae (pneumococcus) are associated with bacterial DNA on their surface and can deliver this DNA to the transformation machinery of competent cells. These findings suggest that EVs contribute to gene transfer in Gram-positive bacteria and, in doing so, may promote the spread of drug resistance genes in the population. See Hiller
Metabolism:
The pneumococcus is a lactic acid bacterium and consequently ferments carbohydrates to lactic acid in order to harvest energy, although it is also capable of mixed acid fermentation where ethanol and acetate are formed in addition to lactic acid. Because it lives primarily in the respiratory airways where free carbohydrates are scarce, the pneumococcus has evolved to become capable of metabolizing a wide range of carbohydrates that allows it to colonize its host. Its sources of carbohydrate include surface-exposed carbohydrates on host cells, mucus components and other glycoproteins in the respiratory environment. It may even be able to utilize carbohydrates from the host diet when it resides in the oropharynx. In the lungs, where the pneumococcus can cause pneumonia, it adheres to and degrades the glycogen stores inside the type II alveolar cells after it has invaded the lung epithelium. See Engholm
Prevention and Treatment:
Vaccination:
To reduce mortality rates worldwide, vaccination with the pneumococcal vaccine is highly recommended because S. pneumoniae is the most common causative agent of pneumonia
The pneumococcal vaccine is divided into whole cell vaccine and subunit. Whole cell vaccine included live attenuated vaccine and inactivated vaccine, and subunit vaccine included polysaccharide vaccine, conjugate vaccine and protein based vaccine.
–Live Attenuated Virus: An attenuated or weakened form of the pathogen is used as a vaccine. Currently available live vaccines are the most cost effective
–Inactivated Virus: The inactivated vaccine is made by treating pathogens with chemicals or physical processes. Compared to live attenuated vaccines, inactivated vaccines are safer
–Polysaccharide vaccine: The polysaccharide capsule from encapsulated bacteria is a major virulence factor and can be used as an antigen. However, the polysaccharide antigen interacts with B cells and directly induces antibody production without a T cell response. Infants have a particularly immature B cell response, and so vaccines that do not also induce a T cell response cannot provide adequate protection against pneumococcal infection. See Rhee
–Conjugate vaccine: This vaccine uses polysaccharide antigens conjugated with carrier proteins. In contrast to polysaccharide vaccines, the conjugate vaccine can elicit T cell response, resulting in superior immunogenicity.
Before October 2024, the Advisory Committee on Immunization Practices (ACIP) recommended use of a pneumococcal conjugate vaccine (PCV) for all adults aged ≥65 years, as well as for those aged 19–64 years with risk conditions for pneumococcal disease who have not received a PCV or whose vaccination history is unknown. Options included either 20-valent PCV (PCV20; Prevnar20; Wyeth Pharmaceuticals) or 21-valent PCV (PCV21; CAPVAXIVE; Merck Sharp & Dohme) alone or 15-valent PCV (PCV15; VAXNEUVANCE; Merck Sharp & Dohme) in series with 23-valent pneumococcal polysaccharide vaccine (PPSV23; Pneumovax23; Merck Sharp & Dohme). On October 23, 2024, ACIP recommended a single dose of PCV for all PCV-naïve adults aged ≥50 years. See CDC
Widespread use of pneumococcal conjugate vaccine (PCV) in children reduced the incidence of pneumococcal disease, both among children through direct effects and among older children and adults who have not received PCV through indirect effects (i.e., reduction in disease incidence in the population because of decreased transmission of pneumococcus from children).
The PPSV and PCV vaccines induce immune responses in different ways. Studies in mice have found that the polysaccharide vaccine induces a T cell independent immune response and stimulated immediate B cell resposes. As a result, B cells differentiate to plasma cells that produce antibodies. However, a T cell independent immune response does not result in creation of serotope specific memory cells. On the other hand, conjugate vaccines induce a T cell dependent response. The polysaccharide antigen binds to the B cells, and the peptides form the carrier protein are presented to carrier peptide specific helper T cells which enhance the immune response by the B cells and memory Beclls are also created. All PCVs use CRM197 (genetically detoxified diphteria toxin) as a carrier protein. (Kabayashi, “Pneumococcal vaccine for adults aged > 18 years: Recommendations of the advisory committe on immunization practices, United States, 2023”).
Use of azithromycin, benzathine penicillin G, amoxicillin or levofloxacin has been reported in recent outbreaks to prevent additional cases. If an exposed person has received vaccines that contain the serotype of the circulating pneumococcus, they are expected to have longer term protection against pneumococcal disease than if they were to receive antimicrobial chemoprophylaxis. PCVs have advantages offer PPSV23 because these vaccines can induce high levels of serotype specific iIgG to help protect vaccinated persons from vaccine type pneumococcal carriage. (Kabayashi, “Pneumococcal vaccine for adults aged > 18 years: Recommendations of the advisory committe on immunization practices, United States, 2023”).
Treatment:
The current treatment recommendation for uncomplicated acute otitis media with a fewer below 104F is “watchful waiting” for 72 hours to allow the body to clear the infection, avoiding the use of antibiotics.
Since the introduction of sulfonamides and penicilin in the first half of the 20th century, antibiotic therpay has been the primary treatment. However, antibotic resistance could be detected in clinical isolates as early as 1941, 12 years after the discvoery of penicillin.
Innate Immune Response:
Inflammasome:
nflammasomes are multimeric protein complexes that accumulate in the cytosol upon detection of PAMP or DAMP and whose key role is to regulate caspase-1 activation. They are multi-protein complexes composed mainly of protein receptors of the NLR or ALR family, with apoptosis-associated speck-like proteins containing a C-terminal caspase recruitment domain (CARD). The role of NLRP3, NLRC4 and AIM2 inflammasomes in infections and diseases of various backgrounds has been demonstrated.
The inflammasome 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. Pneumolysin can directly activate NLRP3 tion (225). Pneumolysin can directly activate NLRP3 (281), and when activated, inflammasomes secrete IL-1β and IL-18.
Acute Phase Serum Proteins: These proteins increase in concentration within the blood during an acute inflammatory infection. The three main proteins that have been investigated and associated with pneumococcal infection include C-reactive protein (CRP), serum amyloid P (SAP), and mannose-binding lectin (MBL). 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. For example, CRP production by the liver is increased in response to IL-6. CRP and SAP bind to PCho which is part of the S. pneumoniae’s cell wall. Once bound to the PCho, CRP and SAP activate the complement deposition on the bacteria via the classical pathway. 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. pneumoniae.
Adaptive Immune Responses:
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.