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Perspective

Opening the OPK Assay Gatekeeper: Harnessing Multi-Modal Protection by Pneumococcal Vaccines

by
Ashleigh N. Riegler
1,
Beth Mann
2,
Carlos J. Orihuela
1 and
Elaine Tuomanen
2,*
1
Dept. of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
2
Dept. of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
*
Author to whom correspondence should be addressed.
Pathogens 2019, 8(4), 203; https://doi.org/10.3390/pathogens8040203
Submission received: 3 October 2019 / Revised: 14 October 2019 / Accepted: 21 October 2019 / Published: 23 October 2019
(This article belongs to the Special Issue Development of Pneumococcal Vaccines for the World)
Versions Notes

Abstract

:
Pneumococcal vaccine development is driven by the achievement of high activity in a single gatekeeper assay: the bacterial opsonophagocytic killing (OPK) assay. New evidence challenges the dogma that anti-capsular antibodies have only a single function that predicts success. The emerging concept of multi-modal protection presents an array of questions that are fundamental to adopting a new vaccine design process. If antibodies have hidden non-opsonic functions that are protective, should these be optimized for better vaccines? What would protein antigens add to protective activity? Are cellular immune functions additive to antibodies for success? Do different organs benefit from different modes of protection? Can vaccine activities beyond OPK protect the immunocompromised host? This commentary raises these issues at a time when capsule-only OPK assay-based vaccines are increasingly seen as a limiting strategy.

1. Introduction

The development of vaccines has historically placed great emphasis on three gold standard functional assays of antibody activity: the opsonophagocytic killing (OPK) and serum bactericidal assays for bacteria and the neutralization assay for viruses. The pneumococcal vaccine is no exception, and design has principally included only capsular antigens, which are held only to the OPK assay standard. This approach presents a narrow vision of both immunogen and antibody function. A growing body of evidence indicates that this single-minded approach is passé, and that not only can anti-polysaccharide antibodies do much more than enable OPK, but new protein antigens can also be protective even in the absence of neutrophils. This commentary addresses the question, “In an era recognizing a need for broader anti-pneumococcal vaccines that protect against old and newly recognized aspects of disease, should measuring vaccine efficacy be modified by adding other assays of functions of both capsules and proteins as immunogens?” We posit that capsular polysaccharide and protein immunogens have much broader bioactivities in terms of both quantity and quality of immune functions, which can be targeted and harnessed as better vaccines are developed.

2. Discussion

2.1. Multi-Modal Protection: Anti-Capsular Antibodies Are Not Just Active in OPK Assay

In a striking demonstration of the limitations of a single assay approach to predicting vaccine efficacy, Doyle and Pirofsky described two mouse monoclonal antibodies, 7A9 and 1E2, raised against a pneumococcal capsular polysaccharide [1]. 7A9 killed pneumococci in the OPK assay, but 1E2 did not. However, both antibodies protected equally well against lethal challenge in mice. This result clearly challenged dogma, and shouted loudly that it is not true that a “good” polysaccharide-based vaccine must be active in an OPK assay. If antibody function is complex, why focus on measuring only part of it? A clear clinical impact of non-opsonic antibody activities can be seen in the setting of neutropenia, such as in the growing population of patients undergoing cancer chemotherapy. Would the gaps in capsular vaccine protection in non-sepsis models be filled by these alternative activities?
In 1937, Harry Eagle described two dissociable activities of anti-pneumococcal horse serum: aggregation of bacteria vs. protection in animal models of sepsis [2]. As early efforts in vaccine design appropriately focused on preventing sepsis, which was reflected in OPK activity, agglutinating activity was rarely studied. Since 2000, the Pirofsky lab has examined the bioactivities of several protective, non-opsonic anti-capsular antibodies and showed that protection was correlated with the ability to agglutinate bacteria [3]. Agglutination, a feature of the state of natural transformation, modulates quorum sensing and specifically increases bacterial death by fratricide [4]. In 2017, it was recognized that anti-capsular antibodies that agglutinate bacteria interfere with pathogen shedding from the respiratory tract and subsequent transmission [5]. Mitsi et al. further demonstrated that the agglutinating activity of antibodies generated by vaccination with capsule were critical to protection against acquisition of carriage in a human challenge model [6]. An interesting twist to this emerging story is the recent demonstration that the influenza virus can hitchhike on aggregated pneumococci, and thus strongly enhance transmission of both pathogens [7]. It stands to reason that agglutinating activity could be a major predictor of the ability of antibodies to protect from spreading disease, and that distinguishing antibodies that protect in sepsis vs. colonization/transmission may require very different assays.
What else do capsules do that can be harnessed for vaccines? Although not tested as yet, a short list of possible modes of protection by anti-capsular antibodies can be generated by focusing on the multiple modes of bacterial clearance (Table 1). Antibodies could enhance the ability of neutrophil extracellular traps (NETS) to capture pneumococci [8,9]. Antibodies could counteract the ability of capsule to blunt the release of cytokines such as IL-6 and IL-8 from epithelial cells during the acute phase response [10]. Some non-opsonic, protective, anti-capsular monoclonal antibodies have been shown to decrease IL-8 secretion from leukocytes [11]. These examples suggest that protective activity in vivo not only can be, but most probably always is multi-modal, and can be recruited to expand vaccine efficacy even for the single polysaccharide capsule family of antigens.

2.2. Multi-Modal Protection: Protein Functions Enter the Vaccine Efficacy Assay Repertoire

Introduction of protein antigens to the vaccine design discussion opens up a wide array of bioactivities that could be folded into standalone or existing vaccines to potentially improve prevention of disease (Table 1). Proteins with conserved sequences would build serotype-independent protection and interrupt more pathophysiological steps that would be expected to improve vaccine impact, than just OPK, especially outside of the bloodstream. It is well accepted that antibodies against bacterial surface proteins interfere with bacteria–host cell interactions, particularly on mucosal surfaces, and thus interrupt the progression of disease from site to site. This reasoning would support developing these antigens to improve vaccine-induced activity, especially against pneumonia, otitis media, and nasopharyngeal carriage.
A major hurdle for protein-based vaccines is the definition of an assay related to the protein’s function that would correlate to protection and predict improved vaccine efficacy. Particularly attractive would be activities in sites in which capsule-based vaccines show deficient protection: pneumonia, otitis media, or nasopharyngeal carriage. Many in vitro and in vivo assays have shown the bioactivities of many pneumococcal proteins, but adding them into vaccines requires assays that accurately correlate a functional assay with protection, often independent of prevention of sepsis. The difficulty of implementing this requirement was illustrated by a recent Phase II clinical trial of a combination of 10 polysaccharides with the histidine triad protein PhtD and a pneumolysin toxoid [12]. PhtD is believed to participate in zinc homeostasis in the nasopharynx, and the toxin pneumolysin causes damage to respiratory epithelial cells during pneumonia; both vaccine antigens decreased nasopharyngeal carriage in preclinical models [13,14]. However, the only functional assay developed to test sera after this combined vaccine was not directed to mucosal activity, but rather focused on assessment of complement-mediated killing by leukocytes [15]. This is essentially an OPK assay, which is not expected to be highly relevant to nasopharyngeal carriage. One trial in Gambian infants reported that the proteins produced high titer antibodies but failed to decrease nasopharyngeal carriage of any pneumococci (serotypes within or outside those in the vaccine) [12]. The key question remains: Did this failure arise because the antigens failed to generate antibodies (quality and quantity) directed to mucosal events in disease? Or were toxin neutralizing antibodies and anti-PhtD antibodies doing their jobs, but this approach was truly not effective in prevention? In the first case, the antigens have not really been tested; in the other, they are likely not useful vaccines. If they are not good vaccines, then this example of divergence in vaccine efficacy in preclinical animal models versus humans highlights the limits of animal models, and supports the continuation and expansion of human carriage trials for new vaccine candidates.
Noncapsular antigens can clearly protect against disease. For instance, virtually all respiratory bacterial pathogens display phosphorylcholine on their surfaces, and this decoration has been shown to enable several pathogens to interact with host cells via the platelet activating factor receptor [16,17]. C-reactive protein, a primordial member of the acute phase response, effectively counteracts this shared mechanism of invasion, illustrating non-capsule-based protection [18]. Similarly, shared motifs for the binding of bacteria to laminin receptors indicate that antibodies to a single bacterial protein can be broadly cross-protective against pathogens that use the same invasive strategy. This has been demonstrated using immunization with the pneumococcal laminin receptor binding protein, choline binding protein A (CbpA/PspC), resulting in protection against pneumococcal, Haemophilus, and meningococcal diseases [19,20,21,22]. Should this antigen strategy be developed into a vaccine, it is expected that the serum would need to be tested not just for high titer antibodies, but also for a high level of antibodies active in a functional assay reflecting CbpA binding to laminin receptor in vitro.
The process of shepherding protein-based vaccines through clinical trials will require reworking or replacing the OPK assay with functional assays for many other modes of defense. Revamping the OPK assay would be appropriate for testing whether blocking bacterial complement-binding proteins protects against activation of the complement cascade in phagocytosis. Complement-binding proteins of pneumococcus include the surface adhesin CbpA/PspC, which has been demonstrated to recruit Factor H from serum to inhibit amplification of C3b activation. Antibodies to CbpA/PspC block the interaction with Factor H, and thus allow complement fixation to continue [23,24,25].
For most activities of proteins in pathogenesis, new assays will need to be deployed in the clinic. Similarly to neutralization standards for viral vaccines, pneumolysin toxoid vaccines will need to be measured not only for the ability to neutralize pneumolysin-induced hemolysis, but also for prevention of the oligomerization required for pore formation [26]. Matrix-binding proteins, such as PavA, PavB, PfbA, RrgA, and CbpA/PspC, contribute to invasion of tissues, and inhibition of the progression of invasion by antibodies can be quantified by binding to fibronectin, vitronectin, and other matrix components [27,28,29,30]. A more complex approach is needed to ascertain effective blockade of the biofilm formation known to participate in nasopharyngeal colonization and otitis media. Many of the steps in biofilm formation cross over into bacterial aggregation (discussed above) [31,32]. It is clear that the physiology of biofilms and virulence extends to changes in bacterial behavior such as competence and fratricide [33,34,35,36]. Many proteins and signaling molecules, such as PsrP, GlpO, BriC, CbpD, LytC, and CbpF, can be targeted to interrupt the participation of these processes in biofilms and colonization. Others approaches involve distinguishing the features of bacteria shed from biofilms that then move on to produce disease in other organs or enhance transmission [7,37].

2.3. Multi-Modal Protection: Prevention of Disseminated Disease and Toxicity

Approximately 30% of adults hospitalized for pneumococcal pneumonia go on to develop bacteremia [38]. Critically, pneumococci in the bloodstream can disseminate and directly contribute to secondary organ damage independent of sepsis; some stark examples include neuronal damage in the central nervous system as result of meningitis and cardiomyocyte death following bacterial translocation into the myocardium [39,40]. Clinical epidemiological studies indicate that survivors of invasive pneumococcal disease are at greater risk for development of frailty, loss of independence, and a shortened lifespan [41]. Thus, an antibody that neutralizes the bacterial factors responsible for pneumococcal invasiveness and/or its toxicity would offer vital protection in a manner that is not covered by serotype-specific OPK.
Antibodies against a variety of pneumococcal adhesins have been demonstrated to reduce the ability to adhere to host cells and thus attenuate disease severity in murine models. Perhaps the best characterized, antibodies specific for CbpA/PspC have been shown to inhibit the ability of Streptococcus pneumoniae to bind polymeric immunoglobulin receptor, its ligand on mucosal epithelial cells, and 37 kDa laminin, its ligand on vascular endothelial cells [19,42]. As interactions with these receptors are involved in the uptake of pneumococci into endosomes and their translocation to the basolateral surface, immunization with CbpA inhibits the development of bacteremia, meningitis, and the formation of cardiac microlesions in animal models [19,43]. Targeting this organ-specific toxicity could be a significant upgrade to even existing capsule-based vaccines.
Pneumolysin is a pore-forming toxin produced by all clinical strains of S. pneumoniae [44]. It is thought to be responsible for much of the inflammation observed during pneumonia and the organ damage observed during disseminated infections. Briefly, pneumolysin has been directly implicated in hearing loss during otitis media, lung injury during pneumonia, neuron death during meningitis, and the killing of cardiomyocytes (Table 2) [14]. Being a pore-forming toxin, pneumolysin disrupts ion regulation. At low concentrations, this disrupts normal cell function, such as cardiomyocyte contraction and immune cell function, whereas higher concentrations kill host cells outright by various means, depending on exposure level and cell type [45,46,47]. Pneumolysin is not secreted by the bacteria, nor is it found on the bacterial surface at high concentrations. It is instead released from the bacteria as result of its death [48]. Thus, a neutralizing antibody against this toxin would have limited efficacy in an OPK assay. One emerging understanding is that this toxin plays a key role in instances where the pneumococcus is replicating in a fixed region within tissues. Along such lines, antibodies against pneumolysin have been demonstrated to protect against cell death in vitro and diminish the tissue damage that occurs during severe pneumococcal disease [49]. Pneumolysin also has other activities, such as activation of the classical complement cascade and binding to Toll-like receptor 4 to trigger inflammation [50,51]. Presumably, antibodies that block these interactions would also reduce the inflammatory damage that occurs during infection [51]. Importantly, the negative consequences of disseminated S. pneumoniae infection and pneumolysin toxicity are most likely already ongoing at the time of initial antimicrobial therapy in a patient care setting. Moreover, cell-wall-acting antimicrobials may worsen tissue injury, given the bolus of pneumolysin that would be released with bacterial death. Thus, immunization to protect against invasive disease caused by all serotypes of S. pneumoniae and to neutralize pneumolysin toxicity would be the protective method of choice.
Critically, molecular genetics allow the construction of hybrid molecules that contain both adhesin and toxin neutralizing epitopes. Multivalent pneumococcal protein vaccines that are composed of pneumolysin and fragments of key adhesins have been tested and shown to elicit strong and broad protection [69]. Such antibodies are thought to act by limiting the ability of pneumococci to attach to host cells and translocate, and, in addition, by neutralizing pneumolysin toxicity. Again, these are aspects of protection that would not be evident in a standard OPK assay.

2.4. nonIgG Immunological Correlates and Cellular Responses

For opportunistic mucosal pathogens like S. pneumoniae, secretory immunoglobulins play a pivotal role in pathogen control before the development of disease. While S. pneumoniae expresses an IgA protease that limits the impact of anti-pneumococcal IgA, previous work has shown that secretory IgA (sIgA), the polymeric form of the antibody, is capable of contributing to pathogen control through agglutination, as well as by facilitation of complement-mediated killing [70,71,72]. These systemic and site-specific IgA responses are not currently measured by the standard OPK assay and, we suggest, would be valuable measures of vaccine efficacy at the mucosal sites. Additional quantitation, such as a selective ELISA or agglutination efficacy of immunoglobulins from nasal and oral secretions, could provide valuable information on the site-specific responses elicited by the vaccine.
Another neglected aspect of potential vaccine-induced immunity against pathogens is the production of non-humoral cellular immunity at the interface of innate and adaptive responses. Activation of receptors on the surfaces of epithelial and immune cells at mucosal sites by pneumococcal proteins, such as TLR 2 interactions with cell wall–protein complexes or TLR 4 activation by pneumolysin, alter the inflammatory transcriptome of interacting cells, directly influencing the endocytosis of the pathogen [51,52,73]. The production of cytokines such as IL-1, IL-8, and thymic stromal lymphoprotein by epithelial cells when they encounter a foreign antigen has profound effects on the activation states of antigen-presenting cells such as dendritic cells, as well as the development of an antigen-specific T-cell repertoire [74,75,76]. Notably, it is now appreciated that CD4+ T cells specific to various pneumococcal protein antigens are vital in the initiation of a robust response within the respiratory tract and at other mucosal sites (reviewed by Reference [77]). CD4+ cellular responses to pneumococcal protein antigens have been shown in mice and humans to increase bacterial clearance from the airway through IL-17 mediated recruitment of macrophages and neutrophils [78,79] as well as by IL-10 and interferon-regulated mucosal antibody production [80,81]. The necessity for this CD4+, Th17-like response is supported by a decrease in incidence and severity of pneumococcal infections with age, independent of serum levels of anti-pneumococcal antibody [82], as well as the increased susceptibility to pulmonary infection in humans with deficient IL-17 signaling [83,84]. The possible side effects of the pro-inflammatory activity of Th17 cells, particularly on second challenge, remains a potential issue for vaccine safety. Additionally, mice deficient in B-cell antibody responses (uMT mice) clear primary pneumococcal colonization over time, while mice deficient in CD4+ T cells are susceptible to colonization and lack protection from re-colonization [73,85,86]. Re-stimulation of antigen-specific cells could be used to detect such Th17-like responses. While analysis of human B- and T-cell responses to vaccination are difficult to assess, requiring tissue collection and antigen activation assays ex vivo, in these instances, the above animal models provide valuable insight into the immune processes during infection and in response to vaccination which are not mediated by antibodies, and should be considered vital in the initial assessment of potential vaccine candidates.

3. Conclusion

As we begin to recognize the clinical limitations of current pneumococcal vaccines and consider approaches towards the rational design of an improved vaccine against S. pneumoniae, we suggest that the current standard of evaluating vaccine efficacy must also evolve beyond the OPK assay. For S. pneumoniae, a tremendous amount of data has shown that control and eradication of the bacteria during infection is reliant on many mechanisms, not simply the generation of opsonizing antibody. Antibodies that aggregate bacteria, impair bacterial–host cell binding, promote complement- mediated killing, disrupt bacterial signaling, enhance killing by NETs, and modulate immune cell responses are all potent mechanisms of potential vaccine-induced pathogen control which the OPK assay ignores. Knowing how each of these defense mechanisms applies to the many organs damaged by pneumococcal infection will also provide expanded avenues for designing better multi-modal vaccines.

Author Contributions

conceptualization, C.J.O. and E.T.; writing—original draft preparation, A.N.R., B.M., C.J.O., and E.T.; writing—review and editing, A.N.R., C.J.O., and E.T.

Funding

This research was funded by NIAID grant numbers AI128756 to E.T., AI114800 to C.J.O., AI007051 to A.N.R., and ALSAC.

Conflicts of Interest

E.T., B.M., and C.J.O. have rights for patents on protein-based pneumococcal vaccines. A.N.R, has no conflicts of interest to declare.

References

  1. Doyle, C.R.; Pirofski, L.A. Reduction of Streptococcus pneumoniae colonization and dissemination by a nonopsonic capsular polysaccharide antibody. MBio 2016, 7, e02260-15. [Google Scholar] [CrossRef] [PubMed]
  2. Eagle, H. Some effects of formaldehyde on horse antipneumococcus serum and diphtheria antitoxin, and their significance for the theory of antigen-antibody aggregation. J. Exp. Med. 1938, 67, 495–514. [Google Scholar] [CrossRef] [PubMed]
  3. Fabrizio, K.; Manix, C.; Guimaraes, A.J.; Nosanchuk, J.D.; Pirofski, L.A. Aggregation of Streptococcus pneumoniae by a pneumococcal capsular polysaccharide-specific human monoclonal IgM correlates with antibody efficacy in vivo. Clin. Vaccine Immunol. 2010, 17, 713–721. [Google Scholar] [CrossRef] [PubMed]
  4. Yano, M.; Gohil, S.; Coleman, J.R.; Manix, C.; Pirofski, L.A. Antibodies to Streptococcus pneumoniae capsular polysaccharide enhance pneumococcal quorum sensing. Mbio 2011, 2. [Google Scholar] [CrossRef] [PubMed]
  5. Zangari, T.; Wang, Y.; Weiser, J.N. Streptococcus pneumoniae transmission is blocked by type-specific immunity in an infant mouse model. Mbio 2017, 8. [Google Scholar] [CrossRef]
  6. Mitsi, E.; Roche, A.M.; Reine, J.; Zangari, T.; Owugha, J.T.; Pennington, S.H.; Gritzfeld, J.F.; Wright, A.D.; Collins, A.M.; van Selm, S.; et al. Agglutination by anti-capsular polysaccharide antibody is associated with protection against experimental human pneumococcal carriage. Mucosal Immunol. 2017, 10, 385–394. [Google Scholar] [CrossRef]
  7. Rowe, H.M.; Karlsson, E.; Echlin, H.; Chang, T.C.; Wang, L.; van Opijnen, T.; Pounds, S.B.; Schultz-Cherry, S.; Rosch, J.W. Bacterial factors required for transmission of Streptococcus pneumoniae in mammalian hosts. Cell Host Microbe 2019, 25, 884–891. [Google Scholar] [CrossRef]
  8. Brinkmann, V.; Zychlinsky, A. Beneficial suicide: why neutrophils die to make NETs. Nat. Rev. Microbiol. 2007, 5, 577–582. [Google Scholar] [CrossRef]
  9. Storisteanu, D.M.; Pocock, J.M.; Cowburn, A.S.; Juss, J.K.; Nadesalingam, A.; Nizet, V.; Chilvers, E.R. Evasion of neutrophil extracellular traps by respiratory pathogens. Am. J. Respir. Cell Mol. Biol. 2017, 56, 423–431. [Google Scholar] [CrossRef]
  10. Kung, E.; Coward, W.R.; Neill, D.R.; Malak, H.A.; Muhlemann, K.; Kadioglu, A.; Hilty, M.; Hathaway, L.J. The pneumococcal polysaccharide capsule and pneumolysin differentially affect CXCL8 and IL-6 release from cells of the upper and lower respiratory tract. PLoS ONE 2014, 9, e92355. [Google Scholar] [CrossRef]
  11. Burns, T.; Zhong, Z.; Steinitz, M.; Pirofski, L.A. Modulation of polymorphonuclear cell interleukin-8 secretion by human monoclonal antibodies to type 8 pneumococcal capsular polysaccharide. Infect. Immun. 2003, 71, 6775–6783. [Google Scholar] [CrossRef] [PubMed]
  12. Odutola, A.; Ota, M.O.C.; Antonio, M.; Ogundare, E.O.; Saidu, Y.; Foster-Nyarko, E.; Owiafe, P.K.; Ceesay, F.; Worwui, A.; Idoko, O.T.; et al. Efficacy of a novel, protein-based pneumococcal vaccine against nasopharyngeal carriage of Streptococcus pneumoniae in infants: A phase 2, randomized, controlled, observer-blind study. Vaccine 2017, 35, 2531–2542. [Google Scholar] [CrossRef] [PubMed]
  13. Eijkelkamp, B.A.; Pederick, V.G.; Plumptre, C.D.; Harvey, R.M.; Hughes, C.E.; Paton, J.C.; McDevitt, C.A. The first histidine triad motif of PhtD is critical for zinc homeostasis in Streptococcus pneumoniae. Infect. Immun. 2016, 84, 407–415. [Google Scholar] [CrossRef] [PubMed]
  14. Anderson, R.; Feldman, C. Pneumolysin as a potential therapeutic target in severe pneumococcal disease. J. Infect. 2017, 74, 527–544. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Visan, L.; Rouleau, N.; Proust, E.; Peyrot, L.; Donadieu, A.; Ochs, M. Antibodies to PcpA and PhtD protect mice against Streptococcus pneumoniae by a macrophage- and complement-dependent mechanism. Hum. Vaccin. Immunother. 2018, 14, 489–494. [Google Scholar] [CrossRef] [PubMed]
  16. Cundell, D.R.; Gerard, N.P.; Gerard, C.; Idanpaan-Heikkila, I.; Tuomanen, E.I. Streptococcus pneumoniae anchor to activated human cells by the receptor for platelet-activating factor. Nature 1995, 377, 435–438. [Google Scholar] [CrossRef]
  17. Clark, S.E.; Weiser, J.N. Microbial modulation of host immunity with the small molecule phosphorylcholine. Infect. Immun. 2013, 81, 392–401. [Google Scholar] [CrossRef]
  18. Gould, J.M.; Weiser, J.N. The inhibitory effect of C-reactive protein on bacterial phosphorylcholine platelet-activating factor receptor-mediated adherence is blocked by surfactant. J. Infect. Dis. 2002, 186, 361–371. [Google Scholar] [CrossRef]
  19. Orihuela, C.J.; Mahdavi, J.; Thornton, J.; Mann, B.; Wooldridge, K.G.; Abouseada, N.; Oldfield, N.J.; Self, T.; Ala’Aldeen, D.A.; Tuomanen, E.I. Laminin receptor initiates bacterial contact with the blood brain barrier in experimental meningitis models. J. Clin. Invest. 2009, 119, 1638–1646. [Google Scholar] [CrossRef] [Green Version]
  20. Chen, A.; Mann, B.; Gao, G.; Heath, R.; King, J.; Maissoneuve, J.; Alderson, M.; Tate, A.; Hollingshead, S.K.; Tweten, R.K.; et al. Multivalent pneumococcal protein vaccines comprising pneumolysoid with epitopes/fragments of CbpA and/or PspA elicit strong and broad protection. Clin. Vaccine Immunol. 2015, 22, 1079–1089. [Google Scholar] [CrossRef]
  21. Mann, B.; Thornton, J.; Heath, R.; Wade, K.R.; Tweten, R.K.; Gao, G.; El Kasmi, K.; Jordan, J.B.; Mitrea, D.M.; Kriwacki, R.; et al. Broadly protective protein-based pneumococcal vaccine composed of pneumolysin toxoid-CbpA peptide recombinant fusion protein. J. Infect. Dis. 2014, 209, 1116–1125. [Google Scholar] [CrossRef] [PubMed]
  22. Rowe, H.M.; Mann, B.; Iverson, A.; Poole, A.; Tuomanen, E.; Rosch, J.W. A Cross-reactive protein vaccine combined with PCV-13 prevents Streptococcus pneumoniae- and Haemophilus influenzae-mediated acute otitis media. Infect. Immun. 2019. [Google Scholar] [CrossRef] [PubMed]
  23. Pathak, A.; Bergstrand, J.; Sender, V.; Spelmink, L.; Aschtgen, M.S.; Muschiol, S.; Widengren, J.; Henriques-Normark, B. Factor H binding proteins protect division septa on encapsulated Streptococcus pneumoniae against complement C3b deposition and amplification. Nat. Commun. 2018, 9, 3398. [Google Scholar] [CrossRef] [PubMed]
  24. Dave, S.; Carmicle, S.; Hammerschmidt, S.; Pangburn, M.K.; McDaniel, L.S. Dual roles of PspC, a surface protein of Streptococcus pneumoniae, in binding human secretory IgA and factor H. J. Immunol. 2004, 173, 471–477. [Google Scholar] [CrossRef]
  25. Moreno, A.T.; Oliveira, M.L.; Ho, P.L.; Vadesilho, C.F.; Palma, G.M.; Ferreira, J.M., Jr.; Ferreira, D.M.; Santos, S.R.; Martinez, M.B.; Miyaji, E.N. Cross-reactivity of antipneumococcal surface protein C (PspC) antibodies with different strains and evaluation of inhibition of human complement factor H and secretory IgA binding via PspC. Clin. Vaccine Immunol. 2012, 19, 499–507. [Google Scholar] [CrossRef]
  26. Lawrence, S.L.; Feil, S.C.; Morton, C.J.; Farrand, A.J.; Mulhern, T.D.; Gorman, M.A.; Wade, K.R.; Tweten, R.K.; Parker, M.W. Crystal structure of Streptococcus pneumoniae pneumolysin provides key insights into early steps of pore formation. Sci. Rep. 2015, 5, 14352. [Google Scholar] [CrossRef]
  27. Kanwal, S.; Jensch, I.; Palm, G.J.; Bronstrup, M.; Rohde, M.; Kohler, T.P.; Somplatzki, D.; Tegge, W.; Jenkinson, H.F.; Hammerschmidt, S. Mapping the recognition domains of pneumococcal fibronectin-binding proteins PavA and PavB demonstrates a common pattern of molecular interactions with fibronectin type III repeats. Mol. Microbiol. 2017, 105, 839–859. [Google Scholar] [CrossRef] [Green Version]
  28. Suits, M.D.; Boraston, A.B. Structure of the Streptococcus pneumoniae surface protein and adhesin PfbA. PLoS ONE 2013, 8, e67190. [Google Scholar] [CrossRef]
  29. Becke, T.D.; Ness, S.; Gurster, R.; Schilling, A.F.; di Guilmi, A.M.; Sudhop, S.; Hilleringmann, M.; Clausen-Schaumann, H. Single molecule force spectroscopy reveals two-domain binding mode of pilus-1 tip protein RrgA of Streptococcus pneumoniae to fibronectin. ACS Nano 2018, 12, 549–558. [Google Scholar] [CrossRef]
  30. Voss, S.; Hallstrom, T.; Saleh, M.; Burchhardt, G.; Pribyl, T.; Singh, B.; Riesbeck, K.; Zipfel, P.F.; Hammerschmidt, S. The choline-binding protein PspC of Streptococcus pneumoniae interacts with the C-terminal heparin-binding domain of vitronectin. J. Biol. Chem. 2013, 288, 15614–15627. [Google Scholar] [CrossRef]
  31. Brown, L.R.; Caulkins, R.C.; Schartel, T.E.; Rosch, J.W.; Honsa, E.S.; Schultz-Cherry, S.; Meliopoulos, V.A.; Cherry, S.; Thornton, J.A. Increased zinc availability enhances initial aggregation and biofilm formation of Streptococcus pneumoniae. Front. Cell. Infect. Microbiol. 2017, 7, 233. [Google Scholar] [CrossRef] [PubMed]
  32. Schulte, T.; Mikaelsson, C.; Beaussart, A.; Kikhney, A.; Deshmukh, M.; Wolniak, S.; Pathak, A.; Ebel, C.; Lofling, J.; Fogolari, F.; et al. The BR domain of PsrP interacts with extracellular DNA to promote bacterial aggregation; structural insights into pneumococcal biofilm formation. Sci. Rep. 2016, 6, 32371. [Google Scholar] [CrossRef] [PubMed]
  33. Aggarwal, S.D.; Eutsey, R.; West-Roberts, J.; Domenech, A.; Xu, W.; Abdullah, I.T.; Mitchell, A.P.; Veening, J.W.; Yesilkaya, H.; Hiller, N.L. Function of BriC peptide in the pneumococcal competence and virulence portfolio. PLoS Pathog. 2018, 14, e1007328. [Google Scholar] [CrossRef] [PubMed]
  34. Shen, P.; Lees, J.A.; Bee, G.C.W.; Brown, S.P.; Weiser, J.N. Pneumococcal quorum sensing drives an asymmetric owner-intruder competitive strategy during carriage via the competence regulon. Nat. Microbiol. 2019, 4, 198–208. [Google Scholar] [CrossRef] [PubMed]
  35. Trappetti, C.; Potter, A.J.; Paton, A.W.; Oggioni, M.R.; Paton, J.C. LuxS mediates iron-dependent biofilm formation, competence, and fratricide in Streptococcus pneumoniae. Infect. Immun. 2011, 79, 4550–4558. [Google Scholar] [CrossRef]
  36. Eldholm, V.; Johnsborg, O.; Straume, D.; Ohnstad, H.S.; Berg, K.H.; Hermoso, J.A.; Havarstein, L.S. Pneumococcal CbpD is a murein hydrolase that requires a dual cell envelope binding specificity to kill target cells during fratricide. Mol. Microbiol. 2010, 76, 905–917. [Google Scholar] [CrossRef]
  37. Li, Y.; Hill, A.; Beitelshees, M.; Shao, S.; Lovell, J.F.; Davidson, B.A.; Knight, P.R., 3rd; Hakansson, A.P.; Pfeifer, B.A.; Jones, C.H. Directed vaccination against pneumococcal disease. Proc. Natl. Acad Sci. USA 2016, 113, 6898–6903. [Google Scholar] [CrossRef] [Green Version]
  38. Centers for Disease Control and Prevention. Pneumococcal disease. In Epidemiology and Prevention of Vaccine Preventable Diseases, 13th ed.; Hamborsky, J., Kroger, A., Wolfe, C., Eds.; Publich Health Foundation: Washington, DC, USA, 2015; pp. 279–296. [Google Scholar]
  39. Reyes, L.F.; Restrepo, M.I.; Hinojosa, C.A.; Soni, N.J.; Anzueto, A.; Babu, B.L.; Gonzalez-Juarbe, N.; Rodriguez, A.H.; Jimenez, A.; Chalmers, J.D.; et al. Severe pneumococcal pneumonia causes acute cardiac toxicity and subsequent cardiac remodeling. Am. J. Respir. Crit. Care Med. 2017, 196, 609–620. [Google Scholar] [CrossRef]
  40. van de Beek, D.; Brouwer, M.; Hasbun, R.; Koedel, U.; Whitney, C.G.; Wijdicks, E. Community-acquired bacterial meningitis. Nat. Rev. Dis. Primers 2016, 2, 16074. [Google Scholar] [CrossRef]
  41. Ajayi, O.O.; Norton, N.B.; Gress, T.W.; Stanek, R.J.; Mufson, M.A. Three decades of follow-up of adults after recovery from invasive pneumococcal pneumonia. Am. J. Med. Sci. 2017, 353, 445–451. [Google Scholar] [CrossRef]
  42. Zhang, J.R.; Mostov, K.E.; Lamm, M.E.; Nanno, M.; Shimida, S.; Ohwaki, M.; Tuomanen, E. The polymeric immunoglobulin receptor translocates pneumococci across human nasopharyngeal epithelial cells. Cell 2000, 102, 827–837. [Google Scholar] [CrossRef]
  43. Brown, A.O.; Mann, B.; Gao, G.; Hankins, J.S.; Humann, J.; Giardina, J.; Faverio, P.; Restrepo, M.I.; Halade, G.V.; Mortensen, E.M.; et al. Streptococcus pneumoniae translocates into the myocardium and forms unique microlesions that disrupt cardiac function. PLoS Pathog. 2014, 10, e1004383. [Google Scholar] [CrossRef]
  44. Vogele, M.; Bhaskara, R.M.; Mulvihill, E.; van Pee, K.; Yildiz, O.; Kuhlbrandt, W.; Muller, D.J.; Hummer, G. Membrane perforation by the pore-forming toxin pneumolysin. Proc. Natl. Acad. Sci. USA 2019, 116, 13352–13357. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Alhamdi, Y.; Neill, D.R.; Abrams, S.T.; Malak, H.A.; Yahya, R.; Barrett-Jolley, R.; Wang, G.; Kadioglu, A.; Toh, C.H. Circulating pneumolysin is a potent inducer of cardiac injury during pneumococcal infection. PLoS Pathog. 2015, 11, e1004836. [Google Scholar] [CrossRef] [PubMed]
  46. Gonzalez-Juarbe, N.; Bradley, K.M.; Riegler, A.N.; Reyes, L.F.; Brissac, T.; Park, S.S.; Restrepo, M.I.; Orihuela, C.J. Bacterial pore-forming toxins promote the activation of caspases in parallel to necroptosis to enhance alarmin release and inflammation during pneumonia. Sci. Rep. 2018, 8, 5846. [Google Scholar] [CrossRef] [PubMed]
  47. Gonzalez-Juarbe, N.; Gilley, R.P.; Hinojosa, C.A.; Bradley, K.M.; Kamei, A.; Gao, G.; Dube, P.H.; Bergman, M.A.; Orihuela, C.J. Pore-forming toxins induce macrophage necroptosis during acute bacterial pneumonia. PLoS Pathog. 2015, 11, e1005337. [Google Scholar] [CrossRef]
  48. Martner, A.; Dahlgren, C.; Paton, J.C.; Wold, A.E. Pneumolysin released during Streptococcus pneumoniae autolysis is a potent activator of intracellular oxygen radical production in neutrophils. Infect. Immun. 2008, 76, 4079–4087. [Google Scholar] [CrossRef]
  49. Shenoy, A.T.; Brissac, T.; Gilley, R.P.; Kumar, N.; Wang, Y.; Gonzalez-Juarbe, N.; Hinkle, W.S.; Daugherty, S.C.; Shetty, A.C.; Ott, S.; et al. Streptococcus pneumoniae in the heart subvert the host response through biofilm-mediated resident macrophage killing. PLoS Pathog. 2017, 13, e1006582. [Google Scholar] [CrossRef]
  50. Paton, J.C.; Rowan-Kelly, B.; Ferrante, A. Activation of human complement by the pneumococcal toxin pneumolysin. Infect. Immun. 1984, 43, 1085–1087. [Google Scholar] [Green Version]
  51. Malley, R.; Henneke, P.; Morse, S.C.; Cieslewicz, M.J.; Lipsitch, M.; Thompson, C.M.; Kurt-Jones, E.; Paton, J.C.; Wessels, M.R.; Golenbock, D.T. Recognition of pneumolysin by Toll-like receptor 4 confers resistance to pneumococcal infection. Proc. Natl. Acad. Sci. USA 2003, 100, 1966–1971. [Google Scholar] [CrossRef] [Green Version]
  52. Zafar, M.A.; Wang, Y.; Hamaguchi, S.; Weiser, J.N. Host-to-host transmission of Streptococcus pneumoniae is driven by its inflammatory toxin, pneumolysin. Cell Host Microbe 2017, 21, 73–83. [Google Scholar] [CrossRef] [PubMed]
  53. Riegler, A.N.; Brissac, T.; Gonzalez-Juarbe, N.; Orihuela, C.J. Necroptotic cell death promotes adaptive immunity against colonizing pneumococci. Front. Immunol. 2019, 10, 615. [Google Scholar] [CrossRef] [PubMed]
  54. Grimwood, K.; Anderson, P.; Anderson, V.; Tan, L.; Nolan, T. Twelve year outcomes following bacterial meningitis: further evidence for persisting effects. Arch. Dis. Child. 2000, 83, 111–116. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Rubins, J.B.; Duane, P.G.; Clawson, D.; Charboneau, D.; Young, J.; Niewoehner, D.E. Toxicity of pneumolysin to pulmonary alveolar epithelial cells. Infect. Immun. 1993, 61, 1352–1358. [Google Scholar] [PubMed]
  56. Garcia-Suarez Mdel, M.; Florez, N.; Astudillo, A.; Vazquez, F.; Villaverde, R.; Fabrizio, K.; Pirofski, L.A.; Mendez, F.J. The role of pneumolysin in mediating lung damage in a lethal pneumococcal pneumonia murine model. Respir. Res. 2007, 8, 3. [Google Scholar] [CrossRef]
  57. Gonzalez-Juarbe, N.; Bradley, K.M.; Shenoy, A.T.; Gilley, R.P.; Reyes, L.F.; Hinojosa, C.A.; Restrepo, M.I.; Dube, P.H.; Bergman, M.A.; Orihuela, C.J. Pore-forming toxin-mediated ion dysregulation leads to death receptor-independent necroptosis of lung epithelial cells during bacterial pneumonia. Cell Death Differ. 2017. [Google Scholar] [CrossRef]
  58. Anderson, V.; Anderson, P.; Grimwood, K.; Nolan, T. Cognitive and executive function 12 years after childhood bacterial meningitis: effect of acute neurologic complications and age of onset. J. Pediatr. Psychol. 2004, 29, 67–81. [Google Scholar] [CrossRef]
  59. Loeffler, J.M.; Ringer, R.; Hablutzel, M.; Tauber, M.G.; Leib, S.L. The free radical scavenger alpha-phenyl-tert-butyl nitrone aggravates hippocampal apoptosis and learning deficits in experimental pneumococcal meningitis. J. Infect. Dis. 2001, 183, 247–252. [Google Scholar] [CrossRef]
  60. Bedford, H.; de Louvois, J.; Halket, S.; Peckham, C.; Hurley, R.; Harvey, D. Meningitis in infancy in England and Wales: follow up at age 5 years. BMJ 2001, 323, 533–536. [Google Scholar] [CrossRef]
  61. van de Beek, D.; Schmand, B.; de Gans, J.; Weisfelt, M.; Vaessen, H.; Dankert, J.; Vermeulen, M. Cognitive impairment in adults with good recovery after bacterial meningitis. J. Infect. Dis. 2002, 186, 1047–1052. [Google Scholar] [CrossRef]
  62. Braun, J.S.; Sublett, J.E.; Freyer, D.; Mitchell, T.J.; Cleveland, J.L.; Tuomanen, E.I.; Weber, J.R. Pneumococcal pneumolysin and H(2)O(2) mediate brain cell apoptosis during meningitis. J. Clin. Invest. 2002, 109, 19–27. [Google Scholar] [CrossRef] [PubMed]
  63. Braun, J.S.; Hoffmann, O.; Schickhaus, M.; Freyer, D.; Dagand, E.; Bermpohl, D.; Mitchell, T.J.; Bechmann, I.; Weber, J.R. Pneumolysin causes neuronal cell death through mitochondrial damage. Infect. Immun. 2007, 75, 4245–4254. [Google Scholar] [CrossRef] [PubMed]
  64. Littmann, M.; Albiger, B.; Frentzen, A.; Normark, S.; Henriques-Normark, B.; Plant, L. Streptococcus pneumoniae evades human dendritic cell surveillance by pneumolysin expression. EMBO Mol. Med. 2009, 1, 211–222. [Google Scholar] [CrossRef] [PubMed]
  65. Nel, J.G.; Theron, A.J.; Durandt, C.; Tintinger, G.R.; Pool, R.; Mitchell, T.J.; Feldman, C.; Anderson, R. Pneumolysin activates neutrophil extracellular trap formation. Clin. Exp. Immunol. 2016, 184, 358–367. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  66. Bewley, M.A.; Naughton, M.; Preston, J.; Mitchell, A.; Holmes, A.; Marriott, H.M.; Read, R.C.; Mitchell, T.J.; Whyte, M.K.; Dockrell, D.H. Pneumolysin activates macrophage lysosomal membrane permeabilization and executes apoptosis by distinct mechanisms without membrane pore formation. Mbio 2014, 5, e01710–01714. [Google Scholar] [CrossRef] [PubMed]
  67. Gilley, R.P.; Gonzalez-Juarbe, N.; Shenoy, A.T.; Reyes, L.F.; Dube, P.H.; Restrepo, M.I.; Orihuela, C.J. Infiltrated macrophages die of pneumolysin-mediated necroptosis following pneumococcal myocardial invasion. Infect. Immun. 2016, 84, 1457–1469. [Google Scholar] [CrossRef]
  68. Subramanian, K.; Neill, D.R.; Malak, H.A.; Spelmink, L.; Khandaker, S.; Dalla Libera Marchiori, G.; Dearing, E.; Kirby, A.; Yang, M.; Achour, A.; et al. Pneumolysin binds to the mannose receptor C type 1 (MRC-1) leading to anti-inflammatory responses and enhanced pneumococcal survival. Nat. Microbiol. 2019, 4, 62–70. [Google Scholar] [CrossRef]
  69. Lynch, J.P., 3rd; Zhanel, G.G. Streptococcus pneumoniae: epidemiology and risk factors, evolution of antimicrobial resistance, and impact of vaccines. Curr. Opin. Pulm. Med. 2010, 16, 217–225. [Google Scholar] [CrossRef]
  70. Roche, A.M.; Richard, A.L.; Rahkola, J.T.; Janoff, E.N.; Weiser, J.N. Antibody blocks acquisition of bacterial colonization through agglutination. Mucosal Immunol. 2015, 8, 176–185. [Google Scholar] [CrossRef] [PubMed]
  71. van der Pol, W.; Vidarsson, G.; Vile, H.A.; van de Winkel, J.G.; Rodriguez, M.E. Pneumococcal capsular polysaccharide-specific IgA triggers efficient neutrophil effector functions via FcalphaRI (CD89). J. Infect. Dis. 2000, 182, 1139–1145. [Google Scholar] [CrossRef] [PubMed]
  72. Janoff, E.N.; Fasching, C.; Orenstein, J.M.; Rubins, J.B.; Opstad, N.L.; Dalmasso, A.P. Killing of Streptococcus pneumoniae by capsular polysaccharide-specific polymeric IgA, complement, and phagocytes. J. Clin. Invest. 1999, 104, 1139–1147. [Google Scholar] [CrossRef] [PubMed]
  73. Zhang, Z.; Clarke, T.B.; Weiser, J.N. Cellular effectors mediating Th17-dependent clearance of pneumococcal colonization in mice. J. Clin. Invest. 2009, 119, 1899–1909. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Liu, Y.J.; Soumelis, V.; Watanabe, N.; Ito, T.; Wang, Y.H.; Malefyt Rde, W.; Omori, M.; Zhou, B.; Ziegler, S.F. TSLP: an epithelial cell cytokine that regulates T cell differentiation by conditioning dendritic cell maturation. Annu. Rev. Immunol. 2007, 25, 193–219. [Google Scholar] [CrossRef] [PubMed]
  75. Schmitz, J.; Owyang, A.; Oldham, E.; Song, Y.; Murphy, E.; McClanahan, T.K.; Zurawski, G.; Moshrefi, M.; Qin, J.; Li, X.; et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 2005, 23, 479–490. [Google Scholar] [CrossRef] [PubMed]
  76. Whitsett, J.A.; Alenghat, T. Respiratory epithelial cells orchestrate pulmonary innate immunity. Nat. Immunol. 2015, 16, 27–35. [Google Scholar] [CrossRef]
  77. Wilson, R.; Cohen, J.M.; Jose, R.J.; de Vogel, C.; Baxendale, H.; Brown, J.S. Protection against Streptococcus pneumoniae lung infection after nasopharyngeal colonization requires both humoral and cellular immune responses. Mucosal Immunol. 2015, 8, 627–639. [Google Scholar] [CrossRef]
  78. van Rossum, A.M.; Lysenko, E.S.; Weiser, J.N. Host and bacterial factors contributing to the clearance of colonization by Streptococcus pneumoniae in a murine model. Infect. Immun. 2005, 73, 7718–7726. [Google Scholar] [CrossRef]
  79. Lu, Y.J.; Gross, J.; Bogaert, D.; Finn, A.; Bagrade, L.; Zhang, Q.; Kolls, J.K.; Srivastava, A.; Lundgren, A.; Forte, S.; et al. Interleukin-17A mediates acquired immunity to pneumococcal colonization. PLoS Pathog. 2008, 4, e1000159. [Google Scholar] [CrossRef]
  80. Zhang, Q.; Bernatoniene, J.; Bagrade, L.; Paton, J.C.; Mitchell, T.J.; Hammerschmidt, S.; Nunez, D.A.; Finn, A. Regulation of production of mucosal antibody to pneumococcal protein antigens by T-cell-derived gamma interferon and interleukin-10 in children. Infect. Immun. 2006, 74, 4735–4743. [Google Scholar] [CrossRef]
  81. Wang, Y.; Jiang, B.; Guo, Y.; Li, W.; Tian, Y.; Sonnenberg, G.F.; Weiser, J.N.; Ni, X.; Shen, H. Cross-protective mucosal immunity mediated by memory Th17 cells against Streptococcus pneumoniae lung infection. Mucosal Immunol. 2017, 10, 250–259. [Google Scholar] [CrossRef]
  82. Lipsitch, M.; Whitney, C.G.; Zell, E.; Kaijalainen, T.; Dagan, R.; Malley, R. Are anticapsular antibodies the primary mechanism of protection against invasive pneumococcal disease? PLoS Med. 2005, 2, e15. [Google Scholar] [CrossRef] [PubMed]
  83. Li, J.; Casanova, J.L.; Puel, A. Mucocutaneous IL-17 immunity in mice and humans: host defense vs. excessive inflammation. Mucosal Immunol. 2018, 11, 581–589. [Google Scholar] [CrossRef] [PubMed]
  84. Levy, R.; Okada, S.; Beziat, V.; Moriya, K.; Liu, C.; Chai, L.Y.; Migaud, M.; Hauck, F.; Al Ali, A.; Cyrus, C.; et al. Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency. Proc. Natl. Acad. Sci. USA 2016, 113, E8277–E8285. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Trzcinski, K.; Thompson, C.; Malley, R.; Lipsitch, M. Antibodies to conserved pneumococcal antigens correlate with, but are not required for, protection against pneumococcal colonization induced by prior exposure in a mouse model. Infect. Immun. 2005, 73, 7043–7046. [Google Scholar] [CrossRef] [PubMed]
  86. Malley, R.; Srivastava, A.; Lipsitch, M.; Thompson, C.M.; Watkins, C.; Tzianabos, A.; Anderson, P.W. Antibody-independent, interleukin-17A-mediated, cross-serotype immunity to pneumococci in mice immunized intranasally with the cell wall polysaccharide. Infect. Immun. 2006, 74, 2187–2195. [Google Scholar] [CrossRef] [PubMed]
Table
Table 1. Non-opsonic activities of antibodies that could improve prevention by vaccines.
Table 1. Non-opsonic activities of antibodies that could improve prevention by vaccines.
Anti-Capsule ActivityAnti-Protein Activity
Increase agglutinationIncrease agglutination
Enhance NETSNeutralize toxin
Increase cytokinesBlock adherence to cells, matrix
Block biofilm components, competence
Enhance fratricide
Block metabolism, e.g. uptake of metals, sugars
Table
Table 2. Tissue damage attributed to pneumolysin during Streptococcus pneumoniae infection.
Table 2. Tissue damage attributed to pneumolysin during Streptococcus pneumoniae infection.
Affected SiteTargeted cellConsequence Ref.
NasopharynxMucosal epithelial cellsEpithelial cell sloughing[52,53]
Middle earCochlear hair cellHearing loss[54]
Lower respiratory tractBronchial epithelial cells
Alveolar epithelial cells		Inhibited mucociliary
clearance,
lung consolidation, pulmonary fibrosis		[46,55,56,57]
Central nervous systemNeurons,
brain endothelial cells, ependymal cells		Cognitive impairment[58,59,60,61,62,63]
HeartCardiomyocytesImpaired contractility, cardiac remodeling[43,45]
Immune systemMacrophages, neutrophils,
dendritic cells		Reduced clearance, dampened immune signaling,
enhanced pneumococcal survival		[64,65,66,67,68]

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Riegler, A.N.; Mann, B.; Orihuela, C.J.; Tuomanen, E. Opening the OPK Assay Gatekeeper: Harnessing Multi-Modal Protection by Pneumococcal Vaccines. Pathogens 2019, 8, 203. https://doi.org/10.3390/pathogens8040203

AMA Style

Riegler AN, Mann B, Orihuela CJ, Tuomanen E. Opening the OPK Assay Gatekeeper: Harnessing Multi-Modal Protection by Pneumococcal Vaccines. Pathogens. 2019; 8(4):203. https://doi.org/10.3390/pathogens8040203

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Riegler, Ashleigh N., Beth Mann, Carlos J. Orihuela, and Elaine Tuomanen. 2019. "Opening the OPK Assay Gatekeeper: Harnessing Multi-Modal Protection by Pneumococcal Vaccines" Pathogens 8, no. 4: 203. https://doi.org/10.3390/pathogens8040203

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