Pneumococcal Surface Protein A Contributes to Secondary<i>Streptococcus pneumoniae</i>Infection after Influenza Virus Infection

King, Quinton O.; Lei, Benfang; Harmsen, Allen G.

doi:10.1086/600871

Cited by 28 publications

(29 citation statements)

References 47 publications

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“…Indeed, we show that while coinfection with IAV increases the levels of both nasal colonization and middle ear infection by NanA-deficient pneumococci, it is not to wild-type levels. Interestingly, this contrasts somewhat with the findings of King et al, who observed that NanA was not involved in the outgrowth of pneumococci in the lungs during IAV coinfection (48). This difference is likely tissue niche specific, particularly as NanA has been shown to be expressed at levels between 15-and 22-fold higher in the nasopharynx than in the lungs (36).…”

Section: Discussioncontrasting

confidence: 61%

Pneumococcal Neuraminidase A (NanA) Promotes Biofilm Formation and Synergizes with Influenza A Virus in Nasal Colonization and Middle Ear Infection

et al. 2017

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Even in the vaccine era, Streptococcus pneumoniae (the pneumococcus) remains a leading cause of otitis media, a significant public health burden, in large part because of the high prevalence of nasal colonization with the pneumococcus in children. The primary pneumococcal neuraminidase, NanA, which is a sialidase that catalyzes the cleavage of terminal sialic acids from host glycoconjugates, is involved in both of these processes. Coinfection with influenza A virus, which also expresses a neuraminidase, exacerbates nasal colonization and disease by S. pneumoniae, in part via the synergistic contributions of the viral neuraminidase. The specific role of its pneumococcal counterpart, NanA, in this interaction, however, is less well understood. We demonstrate in a mouse model that NanA-deficient pneumococci are impaired in their ability to cause both nasal colonization and middle ear infection. Coinfection with neuraminidase-expressing influenza virus and S. pneumoniae potentiates both colonization and infection but not to wild-type levels, suggesting an intrinsic role of NanA. Using in vitro models, we show that while NanA contributes to both epithelial adherence and biofilm viability, its effect on the latter is actually independent of its sialidase activity. These data indicate that NanA contributes both enzymatically and nonenzymatically to pneumococcal pathogenesis and, as such, suggest that it is not a redundant bystander during coinfection with influenza A virus. Rather, its expression is required for the full synergism between these two pathogens.

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Section: Discussioncontrasting

confidence: 61%

Pneumococcal Neuraminidase A (NanA) Promotes Biofilm Formation and Synergizes with Influenza A Virus in Nasal Colonization and Middle Ear Infection

et al. 2017

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“…immunization with PspA administered in the presence of cholera toxin B subunit as an adjuvant or with polyinosinic-poly(C), a Toll-like receptor 3 agonist, reduced the bacterial load of pneumococci in the lungs of influenza A virus-infected mice. Yet neither strategy eradicated the pneumococci in the lungs (24,25). While these studies did not examine nasopharyngeal colonization, previous research suggested that mucosal immunization with PspA was protective against colonization of the nasopharynx (34,44).…”

Section: Discussionmentioning

confidence: 94%

“…PspA is an important virulence factor that is expressed by all clinical pneumococcal isolates and is essential for full virulence during local and invasive disease although its role during colonization is less clear (16)(17)(18)(19). Other studies have revealed that PspA, when employed as an immunogen in mouse models, protects against primary pneumococcal infection (20-23) and against pneumococcal challenge subsequent to a viral infection (24,25). The vast majority of these investigations, however, examined the protection offered by PspA immunization against invasive disease caused by challenge with planktonic, broth-grown pneumococci, which do not represent either the biofilm community of S. pneumoniae normally found residing in the nasopharynx prior to contact with IAV or the bacteria released from biofilms in response to virus infection (4).…”

mentioning

confidence: 99%

Novel Strategy To Protect against Influenza Virus-Induced Pneumococcal Disease without Interfering with Commensal Colonization

Greene

Marks

et al. 2016

Infect Immun

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dStreptococcus pneumoniae commonly inhabits the nasopharynx as a member of the commensal biofilm. Infection with respiratory viruses, such as influenza A virus, induces commensal S. pneumoniae to disseminate beyond the nasopharynx and to elicit severe infections of the middle ears, lungs, and blood that are associated with high rates of morbidity and mortality. Current preventive strategies, including the polysaccharide conjugate vaccines, aim to eliminate asymptomatic carriage with vaccinetype pneumococci. However, this has resulted in serotype replacement with, so far, less fit pneumococcal strains, which has changed the nasopharyngeal flora, opening the niche for entry of other virulent pathogens (e.g., Streptococcus pyogenes, Staphylococcus aureus, and potentially Haemophilus influenzae). The long-term effects of these changes are unknown. Here, we present an attractive, alternative preventive approach where we subvert virus-induced pneumococcal disease without interfering with commensal colonization, thus specifically targeting disease-causing organisms. In that regard, pneumococcal surface protein A (PspA), a major surface protein of pneumococci, is a promising vaccine target. Intradermal (i.d.) immunization of mice with recombinant PspA in combination with LT-IIb(T13I), a novel i.d. adjuvant of the type II heat-labile enterotoxin family, elicited strong systemic PspA-specific IgG responses without inducing mucosal anti-PspA IgA responses. This response protected mice from otitis media, pneumonia, and septicemia and averted the cytokine storm associated with septic infection but had no effect on asymptomatic colonization. Our results firmly demonstrated that this immunization strategy against virally induced pneumococcal disease can be conferred without disturbing the desirable preexisting commensal colonization of the nasopharynx.

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“…Strains of various capsule and PspA types can be protected against by immunizing with a single PspA (7). Recombinant alpha-helical regions of PspAs of different alphahelical PspA families are cross-reactive and can be cross-protective (6,7,21,24,34), but the strongest protection in mice against some challenge strains is often observed when the immunizing and challenge PspAs are of the same alpha-helical PspA family (13,38).A gap in our knowledge of PspA and PspC immunogenicity exists, because with few exceptions, the published active and passive immunization experiments focused on immunity to the N-terminal alpha-helical regions of the protein or monoclonal antibodies (MAb) directed at the same alpha-helical regions. Although protection-eliciting sites exist within the N-terminal regions of PspA and PspC, these regions are diverse in their sequences and antigenic epitopes (8,21,23,32).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

The Proline-Rich Region of Pneumococcal Surface Proteins A and C Contains Surface-Accessible Epitopes Common to All Pneumococci and Elicits Antibody-Mediated Protection against Sepsis

et al. 2010

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Pneumococcal surface protein A (PspA) and PspC of Streptococcus pneumoniae are surface virulence proteins that interfere with complement deposition and elicit protective immune responses. The C-terminal halves of PspA and PspC have some structural similarity and contain highly cross-reactive proline-rich (PR) regions. In many PR regions of PspA and PspC, there exists an almost invariant nonproline block (NPB) of about 33 amino acids. Neither the PR regions nor their NPB exhibit the alpha-helical structure characteristic of much of the protection-eliciting N-terminal portions of PspA and PspC. Prior studies of PspA and PspC as immunogens focused primarily on the alpha-helical regions of these molecules that lack the PR and NPB regions. This report shows that immunization with recombinant PR (rPR) molecules and passive immunization with monoclonal antibodies reactive with either NPB or PR epitopes are protective against infection in mice. PR regions of both PspA and PspC were antibody accessible on the pneumococcal surface. Our results indicate that while PspA could serve as a target of these protective antibodies in invasive infections, PspC might not. When antibody responses to rPR immunogens were evaluated by using flow cytometry to measure antibody binding to live pneumococci, it was observed that the mice that survived subsequent challenge produced significantly higher levels of antibodies reactive with exposed PR epitopes than the mice that became moribund. Due to their conservation and cross-reactivity, the PR regions and NPB regions represent potential vaccine targets capable of eliciting cross-protection immunity against pneumococcal infection.Pneumonia is the leading cause of mortality for children under the age of 5 years worldwide, and its most common etiology is Streptococcus pneumoniae (42). S. pneumoniae also cause otitis media and life-threatening meningitis. A 7-valent pneumococcal conjugate vaccine (PCV7) was introduced in the United States in 2000. PCV7 use reduced the number of cases of infections with vaccine capsular types in both immunized children (43) and nonimmunized individuals (18) in the same communities. But less than 5 years after the implementation of PCV7, reports of serotype replacement (increases in the number of invasive infections caused by strains of capsular serotypes not covered by the vaccine) began to appear (20,22,25,40). The observation of this serotype replacement within a few years after vaccine implementation and the fact that there are at least 91 capsular types (36) raise concerns about the long-term effectiveness of capsule-based vaccines and stress the need for continued development of effective, noncapsular serotype-dependent pneumococcal vaccines (2, 39).Surface proteins of pneumococci are important nonpolysaccharide vaccine candidates. Two of the more promising vaccine candidates are pneumococcal surface protein A (PspA) and pneumococcal surface protein C (PspC; also called CbpA). These two proteins have some similar structural features, and both proteins have ...

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Pneumococcal Surface Protein A Contributes to SecondaryStreptococcus pneumoniaeInfection after Influenza Virus Infection

Cited by 28 publications

References 47 publications

Pneumococcal Neuraminidase A (NanA) Promotes Biofilm Formation and Synergizes with Influenza A Virus in Nasal Colonization and Middle Ear Infection

Pneumococcal Neuraminidase A (NanA) Promotes Biofilm Formation and Synergizes with Influenza A Virus in Nasal Colonization and Middle Ear Infection

Novel Strategy To Protect against Influenza Virus-Induced Pneumococcal Disease without Interfering with Commensal Colonization

The Proline-Rich Region of Pneumococcal Surface Proteins A and C Contains Surface-Accessible Epitopes Common to All Pneumococci and Elicits Antibody-Mediated Protection against Sepsis

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