A novel pneumococcal surface protein K of nonencapsulated Streptococcus pneumoniae promotes transmission among littermates in an infant mouse model with influenza A virus co-infection

2022 ◽  
Author(s):  
Hideki Sakatani ◽  
Masamitsu Kono ◽  
Denisa Nanushaj ◽  
Daichi Murakami ◽  
Saori Takeda ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Mouse Model ◽  
Influenza A ◽  
Capsular Polysaccharide ◽  
Surface Protein ◽  
Nasal Colonization ◽  
Infant Mouse ◽  
Key Factor ◽  
Protective Strategy ◽  
New Hosts

We established an infant mouse model for colonization and transmission by nonencapsulated Streptococcus pneumoniae (NESp) strains to gain important information about its virulence among children. Invasive pneumococcal diseases have decreased dramatically since the worldwide introduction of pneumococcal capsular polysaccharide vaccines. Increasing prevalence of non-vaccine serotypes including NESp has been highlighted as a challenge in treatment strategy, but the virulence of NESp is not well understood. Protective strategy against NESp colonization and transmission between children require particularly urgent evaluation. NESp lacks capsules, a major virulent factor of pneumococci, but can cause a variety of infections in children and older people. PspK, a specific surface protein of NESp, is a key factor in establishing nasal colonization. In our infant mouse model for colonization and transmission by NESp strains, NESp could establish stable nasal colonization at the same level as encapsulated serotype 6A in infant mice, and could be transmitted between littermates. Transmission was promoted by NESp surface virulence factor PspK and influenza virus co-infection. However, PspK-deletion mutants lost the ability to colonize and transmit to new hosts. Promotion of NESp transmission by influenza was due to increased susceptibility of the new hosts. PspK was a key factor not only in establishment of nasal colonization, but also in transmission to new hosts. PspK may be targeted as a new candidate vaccine for NESp infection in children.

scholarly journals Capsule Type and Amount Affect Shedding and Transmission of Streptococcus pneumoniae

mBio ◽  
2017 ◽  
Vol 8 (4) ◽  
Author(s):  
M. Ammar Zafar ◽  
Shigeto Hamaguchi ◽  
Tonia Zangari ◽  
Michael Cammer ◽  
Jeffrey N. Weiser
Keyword(s):  
Streptococcus Pneumoniae ◽  
Mouse Model ◽  
Human Population ◽  
Capsular Polysaccharide ◽  
Upper Respiratory Tract ◽  
Wild Type ◽  
Infant Mouse ◽  
Capsule Type ◽  
Upper Respiratory ◽  
Epidemiology Studies

ABSTRACT The capsular polysaccharide (CPS) of Streptococcus pneumoniae is characterized by its diversity, as it has over 95 known serotypes, and the variation in its thickness as it surrounds an organism. While within-host effects of CPS have been studied in detail, there is no information about its contribution to host-to-host transmission. In this study, we used an infant mouse model of intralitter transmission, together with isogenic capsule switch and cps promoter switch constructs, to explore the effects of CPS type and amount. The determining factor in the transmission rate in this model is the number of pneumococci shed in nasal secretions by colonized hosts. Two of seven capsule switch constructs showed reduced shedding. These constructs were unimpaired in colonization and expressed capsules similar in size to those of the wild-type strain. A cps promoter switch mutant expressing ~50% of wild-type amounts of CPS also displayed reduced shedding without a defect in colonization. Since shedding from the mucosal surface may require escape from mucus entrapment, a mucin-binding assay was used to compare capsule switch and cps promoter switch mutants. The CPS type or amount constructs that shed poorly were bound more robustly by immobilized mucin. These capsule switch and cps promoter switch constructs with increased mucin-binding affinity and reduced shedding also had lower rates of pup-to-pup transmission. Our results demonstrate that CPS type and amount affect transmission dynamics and may contribute to the marked differences in prevalence among pneumococcal types. IMPORTANCE Streptococcus pneumoniae, a leading cause of morbidity and mortality, is readily transmitted, especially among young children. Its structurally and antigenically diverse capsular polysaccharide is the target of currently licensed pneumococcal vaccines. Epidemiology studies show that only a subset of the >95 distinct serotypes are prevalent in the human population, suggesting that certain capsular polysaccharide types might be more likely to be transmitted within the community. Herein, we used an infant mouse model to show that both capsule type and amount are important determinants in the spread of pneumococci from host to host. Transmission rates correlate with those capsule types that are better at escaping mucus entrapment, a key step in exiting the host upper respiratory tract. Hence, our study provides a better mechanistic understanding of why certain pneumococcal serotypes are more common in the human population. IMPORTANCE Streptococcus pneumoniae, a leading cause of morbidity and mortality, is readily transmitted, especially among young children. Its structurally and antigenically diverse capsular polysaccharide is the target of currently licensed pneumococcal vaccines. Epidemiology studies show that only a subset of the >95 distinct serotypes are prevalent in the human population, suggesting that certain capsular polysaccharide types might be more likely to be transmitted within the community. Herein, we used an infant mouse model to show that both capsule type and amount are important determinants in the spread of pneumococci from host to host. Transmission rates correlate with those capsule types that are better at escaping mucus entrapment, a key step in exiting the host upper respiratory tract. Hence, our study provides a better mechanistic understanding of why certain pneumococcal serotypes are more common in the human population.

scholarly journals Infant Mouse Model for the Study of Shedding and Transmission during Streptococcus pneumoniae Monoinfection

2016 ◽  
Vol 84 (9) ◽  
pp. 2714-2722 ◽  
Author(s):  
M. Ammar Zafar ◽  
Masamitsu Kono ◽  
Yang Wang ◽  
Tonia Zangari ◽  
Jeffrey N. Weiser
Keyword(s):  
Streptococcus Pneumoniae ◽  
Mouse Model ◽  
Influenza A ◽  
Carrier State ◽  
High Ratio ◽  
New Host ◽  
Content Type ◽  
Infant Mouse ◽  
Colonization Density ◽  
Pneumococcal Colonization

One of the least understood aspects of the bacteriumStreptococcus pneumoniae(pneumococcus) is its transmission from host to host, the critical first step in both the carrier state and the disease state. To date, transmission models have depended on influenza A virus coinfection, which greatly enhances pneumococcal shedding to levels that allow acquisition by a new host. Here, we describe an infant mouse model that can be utilized to study pneumococcal colonization, shedding, and transmission during bacterial monoinfection. Using this model, we demonstrated that the level of bacterial shedding is highest in pups infected intranasally at age 4 days and peaks over the first 4 days postchallenge. Shedding results differed among isolates of five different pneumococcal types. Colonization density was found to be a major factor in the level of pneumococcal shedding and required expression of capsule. Transmission within a litter occurred when there was a high ratio of colonized “index” pups to uncolonized “contact” pups. Transmission was observed for each of the well-colonizing pneumococcal isolates, with the rate of transmission proportional to the level of shedding. This model can be used to examine bacterial and host factors that contribute to pneumococcal transmission without the effects of viral coinfection.

scholarly journals Increased Nasopharyngeal Bacterial Titers and Local Inflammation Facilitate Transmission of Streptococcus pneumoniae

mBio ◽  
2012 ◽  
Vol 3 (5) ◽  
Author(s):  
Kirsty R. Short ◽  
Patrick C. Reading ◽  
Nancy Wang ◽  
Dimitri A. Diavatopoulos ◽  
Odilia L. Wijburg
Keyword(s):  
Streptococcus Pneumoniae ◽  
Mouse Model ◽  
Influenza A ◽  
Pneumococcal Disease ◽  
Present Report ◽  
Bacterial Load ◽  
Disease Development ◽  
Proinflammatory Response ◽  
Content Type ◽  
Infant Mouse

ABSTRACTThe transmission of the bacteriumStreptococcus pneumoniae(the pneumococcus) marks the first step toward disease development. To date, our ability to prevent pneumococcal transmission has been limited by our lack of understanding regarding the factors which influence the spread of this pathogen. We have previously developed an infant mouse model of pneumococcal transmission which was strictly dependent on influenza A virus (IAV) coinfection of both the experimentally colonized “index mice” and the naive cohoused “contact mice.” Here, we sought to use this model to further elucidate the factors which facilitateS. pneumoniaetransmission. In the present report, we demonstrate that increasing the nasopharyngeal load ofS. pneumoniaein the colonized index mice (via the depletion of neutrophils) and inducing a proinflammatory response in the naive cohoused contact mice (as demonstrated by cytokine production) facilitatesS. pneumoniaetransmission. Thus, these data provide the first insights into the factors that help mediate the spread ofS. pneumoniaethroughout the community.IMPORTANCEStreptococcus pneumoniae(the pneumococcus) is a major cause of worldwide morbidity and mortality and is a leading cause of death among children under the age of five years. Transmission ofS. pneumoniaemarks the first step toward disease development. Therefore, understanding the factors that influence the spread of pneumococci throughout the community plays an essential role in preventing pneumococcal disease. We previously developed the first reproducible infant mouse model for pneumococcal transmission and showed that coinfection with influenza virus facilitates the spread ofS. pneumoniae. Here, we show that increasing the bacterial load in the nasal cavity of colonized individuals as well as inducing an inflammatory response in naive “contact cases” facilitates the spread of pneumococci. Therefore, this study helps to identify the factors which must be inhibited in order to successfully prevent pneumococcal disease.

scholarly journals Streptococcus pneumoniae Transmission Is Blocked by Type-Specific Immunity in an Infant Mouse Model

mBio ◽  
2017 ◽  
Vol 8 (2) ◽  
Author(s):  
Tonia Zangari ◽  
Yang Wang ◽  
Jeffrey N. Weiser
Keyword(s):  
Streptococcus Pneumoniae ◽  
Mouse Model ◽  
Pneumococcal Conjugate Vaccine ◽  
Herd Immunity ◽  
Mechanistic Explanation ◽  
Epidemiological Studies ◽  
Contributing Factors ◽  
Infant Mouse ◽  
Major Benefit

ABSTRACT Epidemiological studies on Streptococcus pneumoniae show that rates of carriage are highest in early childhood and that the major benefit of the pneumococcal conjugate vaccine (PCV) is a reduction in the incidence of nasopharyngeal colonization through decreased transmission within a population. In this study, we sought to understand how anti- S. pneumoniae immunity affects nasal shedding of bacteria, the limiting step in experimental pneumococcal transmission. Using an infant mouse model, we examined the role of immunity (passed from mother to pup) on shedding and within-litter transmission of S. pneumoniae by pups infected at 4 days of life. Pups from both previously colonized immune and PCV-vaccinated mothers had higher levels of anti- S. pneumoniae IgG than pups from non-immune or non-vaccinated mothers and shed significantly fewer S. pneumoniae over the first 5 days of infection. By setting up cross-foster experiments, we demonstrated that maternal passage of antibody to pups either in utero or post-natally decreases S. pneumoniae shedding. Passive immunization experiments showed that type-specific antibody to capsular polysaccharide is sufficient to decrease shedding and that the agglutinating function of immunoglobulin is required for this effect. Finally, we established that anti-pneumococcal immunity and anti-PCV vaccination block host-to-host transmission of S. pneumoniae . Moreover, immunity in either the donor or recipient pups alone was sufficient to reduce rates of transmission, indicating that decreased shedding and protection from acquisition of colonization are both contributing factors. Our findings provide a mechanistic explanation for the reduced levels of S. pneumoniae transmission between hosts immune from prior exposure and among vaccinated children. IMPORTANCE Rates of carriage of the bacterial pathogen Streptococcus pneumoniae are highest among young children, and this is the target group for the pneumococcal conjugate vaccine (PCV). Epidemiological studies have suggested that a major benefit of the PCV is a reduction in host-to-host transmission, which also protects the non-vaccinated population (“herd immunity”). In this study, we examined the role of anti-pneumococcal immunity on nasal shedding and transmission of the pathogen using an infant mouse model. We found that shedding is decreased and transmission is blocked by anti-pneumococcal immunity and PCV vaccination. Additionally, transmission rates decreased if either the infected or contact pups were immune, indicating that reduced shedding and protection from the establishment of colonization are both contributing factors. Our study provides a mechanistic explanation for the herd immunity effect seen after the introduction of PCV and identifies potential points of intervention, which may have implications for future vaccine development.

scholarly journals Changes in Availability of Oxygen Accentuate Differences in Capsular Polysaccharide Expression by Phenotypic Variants and Clinical Isolates of Streptococcus pneumoniae

2001 ◽  
Vol 69 (9) ◽  
pp. 5430-5439 ◽  
Author(s):  
Jeffrey N. Weiser ◽  
Deborah Bae ◽  
Henry Epino ◽  
Stephen B. Gordon ◽  
Miki Kapoor ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Tyrosine Phosphorylation ◽  
Capsular Polysaccharide ◽  
Fold Increase ◽  
Growth Conditions ◽  
Inhibitory Effect ◽  
Invasive Infection ◽  
Environmental Concentration ◽  
Key Factor ◽  
Effect Of Oxygen

ABSTRACT Most isolates of Streptococcus pneumoniae are mixed populations of transparent (T) and opaque (O) colony phenotypes. Differences in the production of capsular polysaccharide (CPS) between O and T variants were accentuated by changes in the environmental concentration of oxygen. O variants demonstrated a 5.2- to 10.6-fold increase in amounts of CPS under anaerobic compared to atmospheric growth conditions, while CPS production remained low under all conditions for T variants. Increased amounts of CPS in O compared to T pneumococci were associated with increased expression ofcps-encoded proteins. The inhibitory effect of oxygen on expression of CPS in O variants correlated with decreased tyrosine phosphorylation of CpsD, a tyrosine kinase and regulator of CPS synthesis. Modulation of CpsD expression and its activity by tyrosine phosphorylation may allow the pneumococcus to adapt to the requirements of both colonization, where decreased CPS allows for adherence, and bacteremia, where increased CPS may be required to escape from opsonic clearance. In patients with invasive infection, paired isolates from the same patient were shown to have predominately a T colony phenotype without phosphotyrosine on CpsD when cultured from the nasopharynx, and an O phenotype that phosphorylates CpsD in response to oxygen when cultured from the blood. Differences in the availability of oxygen, therefore, may be a key factor in allowing for the selection of distinct phenotypes in these two host environments.

scholarly journals Type I Interferon Signaling Is a Common Factor Driving Streptococcus pneumoniae and Influenza A Virus Shedding and Transmission

mBio ◽  
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Tonia Zangari ◽  
Mila B. Ortigoza ◽  
Kristen L. Lokken-Toyli ◽  
Jeffrey N. Weiser
Keyword(s):  
Streptococcus Pneumoniae ◽  
Respiratory Tract ◽  
Influenza A Virus ◽  
Influenza A ◽  
Common Factor ◽  
Type I ◽  
Upper Respiratory Tract ◽  
Content Type ◽  
Infant Mouse ◽  
Upper Respiratory

ABSTRACT The dynamics underlying respiratory contagion (the transmission of infectious agents from the airways) are poorly understood. We investigated host factors involved in the transmission of the leading respiratory pathogen Streptococcus pneumoniae. Using an infant mouse model, we examined whether S. pneumoniae triggers inflammatory pathways shared by influenza A virus (IAV) to promote nasal secretions and shedding from the upper respiratory tract to facilitate transit to new hosts. Here, we show that amplification of the type I interferon (IFN-I) response is a critical host factor in this process, as shedding and transmission by both IAV and S. pneumoniae were decreased in pups lacking the common IFN-I receptor (Ifnar1−/− mice). Additionally, providing exogenous recombinant IFN-I to S. pneumoniae-infected pups was sufficient to increase bacterial shedding. The expression of IFN-stimulated genes (ISGs) was upregulated in S. pneumoniae-infected wild-type (WT) but not Ifnar1−/− mice, including genes involved in mucin type O-glycan biosynthesis; this correlated with an increase in secretions in S. pneumoniae- and IAV-infected WT compared to Ifnar1−/− pups. S. pneumoniae stimulation of ISGs was largely dependent on its pore-forming toxin, pneumolysin, and coinfection with IAV and S. pneumoniae resulted in synergistic increases in ISG expression. We conclude that the induction of IFN-I signaling appears to be a common factor driving viral and bacterial respiratory contagion. IMPORTANCE Respiratory tract infections are a leading cause of childhood mortality and, globally, Streptococcus pneumoniae is the leading cause of mortality due to pneumonia. Transmission of S. pneumoniae primarily occurs through direct contact with respiratory secretions, although the host and bacterial factors underlying transmission are poorly understood. We examined transmission dynamics of S. pneumoniae in an infant mouse model and here show that S. pneumoniae colonization of the upper respiratory tract stimulates host inflammatory pathways commonly associated with viral infections. Amplification of this response was shown to be a critical host factor driving shedding and transmission of both S. pneumoniae and influenza A virus, with infection stimulating expression of a wide variety of genes, including those involved in the biosynthesis of mucin, a major component of respiratory secretions. Our findings suggest a mechanism facilitating S. pneumoniae contagion that is shared by viral infection.

scholarly journals Conjugation of PspA4Pro with Capsular Streptococcus pneumoniae Polysaccharide Serotype 14 Does Not Reduce the Induction of Cross-Reactive Antibodies

2017 ◽  
Vol 24 (8) ◽  
Author(s):  
Míriam A. da Silva ◽  
Thiago R. Converso ◽  
Viviane M. Gonçalves ◽  
Luciana C. C. Leite ◽  
Martha M. Tanizaki ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Capsular Polysaccharide ◽  
Vaccine Coverage ◽  
Protein A ◽  
Surface Protein ◽  
Cross Reactivity ◽  
Carrier Protein ◽  
Content Type ◽  
Clade 1 ◽  
The Impact

ABSTRACT Current pneumococcal vaccines are composed of bacterial polysaccharides as antigens, plain or conjugated to carrier proteins. While efficacious against vaccine serotypes, epidemiologic data show an increasing incidence of infections caused by nonvaccine serotypes of Streptococcus pneumoniae. The use of pneumococcal surface protein A (PspA) as a carrier protein in a conjugate vaccine could help prevent serotype replacement by increasing vaccine coverage and reducing selective pressure of S. pneumoniae serotypes. PspA is present in all pneumococcal strains, is highly immunogenic, and is known to induce protective antibodies. Based on its sequence, PspA has been classified into three families and six clades. A PspA fragment derived from family 2, clade 4 (PspA4Pro), was shown to generate antibodies with a broad range of cross-reactivity, across clades and families. Here, PspA4Pro was modified and conjugated to capsular polysaccharide serotype 14 (PS14). We investigated the impact of conjugation on the immune response induced to PspA4Pro and PS14. Mice immunized with the PS14-mPspA4Pro conjugate produced higher titers of anti-PS14 antibodies than the animals that received coadministered antigens. The conjugate induced antibodies with opsonophagocytic activity against PS14-carrying strains, as well as against a panel of strains bearing PspAs from five clades (encompassing families 1 and 2) bearing a non-PS14 serotype. Furthermore, mice immunized with PS14-mPspA4Pro were protected against nasal colonization with a nonrelated S. pneumoniae strain bearing PspA from clade 1, serotype 6B. These results demonstrate that the cross-reactivity mediated by PspA4Pro is retained following conjugation, supporting the use of PspA4 as a carrier protein in order to enhance pneumococcal vaccine coverage and encourage its further investigation as a candidate in future vaccine designs.

scholarly journals Immunization with Pneumococcal Surface Protein K of Nonencapsulated Streptococcus pneumoniae Provides Protection in a Mouse Model of Colonization

2015 ◽  
Vol 22 (11) ◽  
pp. 1146-1153 ◽  
Author(s):  
Lance E. Keller ◽  
Xiao Luo ◽  
Justin A. Thornton ◽  
Keun-Seok Seo ◽  
Bo Youn Moon ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Mouse Model ◽  
Pneumococcal Disease ◽  
Surface Protein ◽  
Antibody Isotype ◽  
Content Type ◽  
Mouse Immunization ◽  
Escape Mutants

ABSTRACTCurrent vaccinations are effective against encapsulated strains ofStreptococcus pneumoniae, but they do not protect against nonencapsulatedStreptococcus pneumoniae(NESp), which is increasing in colonization and incidence of pneumococcal disease. Vaccination with pneumococcal proteins has been assessed for its ability to protect against pneumococcal disease, but several of these proteins are not expressed by NESp. Pneumococcal surface protein K (PspK), an NESp virulence factor, has not been assessed for immunogenic potential or host modulatory effects. Mammalian cytokine expression was determined in anin vivomouse model and in anin vitrocell culture system. Systemic and mucosal mouse immunization studies were performed to determine the immunogenic potential of PspK. Murine serum and saliva were collected to quantitate specific antibody isotype responses and the ability of antibody and various proteins to inhibit epithelial cell adhesion. Host cytokine response was not reduced by PspK. NESp was able to colonize the mouse nasopharynx as effectively as encapsulated pneumococci. Systemic and mucosal immunization provided protection from colonization by PspK-positive (PspK+) NESp. Anti-PspK antibodies were recovered from immunized mice and significantly reduced the ability of NESp to adhere to human epithelial cells. A protein-based pneumococcal vaccine is needed to provide broad protection against encapsulated and nonencapsulated pneumococci in an era of increasing antibiotic resistance and vaccine escape mutants. We demonstrate that PspK may serve as an NESp target for next-generation pneumococcal vaccines. Immunization with PspK protected against pneumococcal colonization, which is requisite for pneumococcal disease.

scholarly journals Evaluation of Pneumococcal Surface Protein A as a Vaccine Antigen against Secondary Streptococcus pneumoniae Challenge during Influenza A Infection

Vaccines ◽  
2019 ◽  
Vol 7 (4) ◽  
pp. 146
Author(s):  
Sean Roberts ◽  
Clare M. Williams ◽  
Sharon L. Salmon ◽  
Jesse L. Bonin ◽  
Dennis W. Metzger ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Influenza A Virus ◽  
Influenza A ◽  
Influenza Infection ◽  
Protein A ◽  
Surface Protein ◽  
Vaccine Antigen ◽  
High Dose ◽  
Pneumococcal Surface Protein A ◽  
Relevant Dose

Secondary bacterial pneumonia is responsible for significant morbidity and mortality during seasonal and pandemic influenza. Due to the unpredictability of influenza A virus evolution and the time-consuming process of manufacturing strain-specific influenza vaccines, recent efforts have been focused on developing anti-Streptococcus pneumoniae immunity to prevent influenza-related illness and death. Bacterial vaccination to prevent viral-bacterial synergistic interaction during co-infection is a promising concept that needs further investigation. Here, we show that immunization with pneumococcal surface protein A (PspA) fully protects mice against low-dose, but not high-dose, secondary bacterial challenge using a murine model of influenza A virus-S. pneumoniae co-infection. We further show that immunization with PspA is more broadly protective than the pneumococcal conjugate vaccine (Prevnar). These results demonstrate that PspA is a promising vaccine target that can provide protection against a physiologically relevant dose of S. pneumoniae following influenza infection.

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