Impaired Innate and Adaptive Immunity to
            <i>Streptococcus pneumoniae</i>
            and Its Effect on Colonization in an Infant Mouse Model

Bogaert, Debby; Weinberger, Daniel M; Thompson, Claudette M.; Lipsitch, Marc; Malley, Richard

doi:10.1128/iai.00871-08

Cited by 66 publications

(57 citation statements)

References 49 publications

(55 reference statements)

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“…In the ketamine-dependent adult mouse model, induction of IL-6 and MIP-2 was observed after wild-type infection (39), but there was no increase in NOS-2 or IL-17a. While many cytokines are reportedly reduced in neonates compared to adult mice, the anti-inflammatory cytokine IL-10 was increased (58,60). We did not see a detectable change in IL-10 in response to V. cholerae infection in neonatal mice, whereas a small but significant increase was observed in an adult mouse model (39).…”

Section: Discussionmentioning

confidence: 49%

“…This is rather surprising, as many neonatal innate immune responses have been shown to be lower than those in adult mice, including IL-6, IL-17a, and KC levels (58)(59)(60). However, this deficit does not apply to all situations, as one report showed elevated innate immune responses to high levels of LPS or to viral infection in neonates compared to adult mice (61).…”

Section: Discussionmentioning

confidence: 78%

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Vibrio cholerae-Induced Inflammation in the Neonatal Mouse Cholera Model

2014

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Vibrio cholerae is the causative agent of the acute diarrheal disease of cholera. Innate immune responses to V. cholerae are not a major cause of cholera pathology, which is characterized by severe, watery diarrhea induced by the action of cholera toxin. Innate responses may, however, contribute to resolution of infection and must be required to initiate adaptive responses after natural infection and oral vaccination. Here we investigated whether a well-established infant mouse model of cholera can be used to observe an innate immune response. We also used a vaccination model in which immunized dams protect their pups from infection through breast milk antibodies to investigate innate immune responses after V. cholerae infection for pups suckled by an immune dam. At the peak of infection, we observed neutrophil recruitment accompanied by induction of KC, macrophage inflammatory protein 2 (MIP-2), NOS-2, interleukin-6 (IL-6), and IL-17a. Pups suckled by an immunized dam did not mount this response. Accessory toxins RtxA and HlyA played no discernible role in neutrophil recruitment in a wild-type background. The innate response to V. cholerae deleted for cholera toxin-encoding phage (CTX) and part of rtxA was significantly reduced, suggesting a role for CTX-carried genes or for RtxA in the absence of cholera toxin (CTX). Two extracellular V. cholerae DNases were not required for neutrophil recruitment, but DNase-deficient V. cholerae caused more clouds of DNA in the intestinal lumen, which appeared to be neutrophil extracellular traps (NETs), suggesting that V. cholerae DNases combat NETs. Thus, the infant mouse model has hitherto unrecognized utility for interrogating innate responses to V. cholerae infection. Vibrio cholerae is the causative agent of cholera, which remains endemic in many regions of Africa and Asia (1). Sporadic outbreaks can devastate immunologically naïve populations, such as occurred in Haiti in 2010 (2). The O1 serogroup and, to a lesser degree, O139 are the major causes of cholera, and El Tor is currently the circulating O1 biotype (1). Cholera toxin (CTX), encoded by a lysogenic phage (3), is the major cause of the severe secretory diarrhea that is typical of cholera. Without rehydration therapy, cholera results in 25 to 50% mortality, but if treated, cholera will resolve in most patients (4). Unlike diseases such as shigellosis and Salmonella-induced gastroenteritis (5, 6), the pathology of cholera is not immune driven. However, innate immune responses have been observed in cholera patients during the acute phase of infection (7) and likely play a direct and/or indirect role in the resolution of disease. The majority of individuals who survive a bout of cholera will become immune to subsequent infection for at least 3 years (8-10), and some aspects of the observed innate immune response must be required to initiate this protective immunity.Many live attenuated vaccine candidate strains of V. cholerae have been developed in which ctxA, the gene encoding the catalytic subunit of cholera tox...

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Section: Discussionmentioning

confidence: 49%

Section: Discussionmentioning

confidence: 78%

Vibrio cholerae-Induced Inflammation in the Neonatal Mouse Cholera Model

2014

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“…The most plausible cause might be the polymorphic nature of S. pneumoniae and, to a lesser extent, S. aureus proteins, resulting in low cross-protectiveness of protein-specific antibodies among strains, which might be a serious problem for their use for future vaccine development (12,22). Therefore, it might not be surprising that results from murine models strongly suggest CD4 ϩ Th17-mediated immunity rather than antibody-mediated immunity to be the primary (natural) mechanism of protection against pneumococcal colonization, although this still needs to be confirmed in humans (5,20). Our immunogenicity data do not suggest cross-protection of S. aureus and S. pneumoniae anti-protein IgG against colonization with the heterologous bacterium, either (17).…”

Section: Discussionmentioning

confidence: 99%

Nasopharyngeal Colonization Elicits Antibody Responses to Staphylococcal and Pneumococcal Proteins That Are Not Associated with a Reduced Risk of Subsequent Carriage

et al. 2012

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Knowledge of the immunological correlates of Staphylococcus aureus and Streptococcus pneumoniae colonization is required for the search for future protein vaccines. We evaluated natural antibody levels against pneumococcal and staphylococcal proteins in relation to previous bacterial colonization with both pathogens. In a randomized controlled trial, nasopharyngeal samples were obtained from children at 1.5, 6, 12, 18, and 24 months and cultured for S. aureus and S. pneumoniae. Approximately 50% of the children were PCV7 vaccinated. Serum IgG against 18 pneumococcal and 40 staphylococcal proteins was semiquantified by Luminex technology from 111 12 month olds and 158 24 month olds. Previous culture-proven S. aureus colonization was associated with higher IgG levels against 6/40 staphylococcal proteins (ClfB, ClfA, Efb, CHIPS, LukD, and LukF [P < 0.001]) compared to noncarriers. Previous pneumococcal colonization was associated with increased IgG levels against 12/18 pneumococcal proteins compared to noncarriers (P < 0.003). Increasing age was associated with higher levels of antibodies to most pneumococcal proteins and lower levels of antibodies to over half the staphylococcal proteins, reflecting natural colonization dynamics. Anti-S. pneumoniae and anti-S. aureus protein antibodies at the age of 12 months were not negatively correlated with subsequent colonization with the homologous species in the following year and did not differ between PCV7-vaccinated and nonvaccinated children. Colonization with S. aureus and S. pneumoniae induces serum IgG against many proteins, predominantly proteins with immune-modulating functions, irrespective of PCV7 vaccination. None of them appeared to be protective against new acquisition with both pathogens, possibly due to the polymorphic nature of those proteins in the circulating bacterial population.

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“…Protein vaccine antigen-specific CD4 ϩ T cells of adult mice are mature and can participate in clearance of colonization more effectively even in the absence of antibodies (39)(40)(41). However, the function of CD4 ϩ T cells in infancy vis-à-vis clearance of colonization could be impaired significantly in the light of their immature and less well developed immune systems (35,(42)(43)(44). Therefore, the role of protein antigen-specific antibodies and CD4 ϩ T cells appears to be important in the context of the infant immune system and its ability to clear colonization in contrast to adult mice, where CD4 ϩ T cells are sufficient.…”

Section: Phtd Vaccination Prevents Pneumococcal Invasionmentioning

confidence: 99%

“…Humans and mice have a less mature immune response during infancy than in adulthood (35)(36)(37)(38). Human infants will be a primary vulnerable population targeted for next-generation PPVs.…”

Section: Phtd Vaccination Prevents Pneumococcal Invasionmentioning

confidence: 99%

Protection against Streptococcus pneumoniae Invasive Pathogenesis by a Protein-Based Vaccine Is Achieved by Suppression of Nasopharyngeal Bacterial Density during Influenza A Virus Coinfection

Khan

Pichichero

2017

Infect Immun

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An increase in Streptococcus pneumoniae nasopharynx (NP) colonization density during a viral coinfection initiates pathogenesis. To mimic natural S. pneumoniae pathogenesis, we commensally colonized the NPs of adult C57BL/6 mice with S. pneumoniae serotype (ST) 6A or 8 and then coinfected them with mouseadapted H1N1 influenza A virus (PR/8/34). S. pneumoniae established effective commensal colonization, and influenza virus coinfection caused S. pneumoniae NP density to increase, resulting in bacteremia and mortality. We then studied histidine triad protein D (PhtD), an S. pneumoniae adhesin vaccine candidate, for its ability to prevent invasive S. pneumoniae disease in adult and infant mice. In adult mice, the efficacy of PhtD vaccination was compared with that of PCV13. Vaccination with PCV13 led to a greater reduction of S. pneumoniae NP density (Ͼ2.5 log units) than PhtD vaccination (ϳ1-log-unit reduction). However, no significant difference was observed with regard to the prevention of S. pneumoniae bacteremia, and there was no difference in mortality. Depletion of CD4 ϩ T cells in PhtD-vaccinated adult mice, but not PCV13-vaccinated mice, caused a loss of vaccine-induced protection. In infant mice, passive transfer of antisera or CD4 ϩ T cells from PhtD-vaccinated adult mice led to a nonsignificant reduction in NP colonization density, whereas passive transfer of antisera and CD4 ϩ T cells was needed to cause a significant reduction in NP colonization density. For the first time, these data show an outcome with regard to prevention of invasive S. pneumoniae pathogenesis with a protein vaccine similar to that which occurs with a glycoconjugate vaccine despite a less robust reduction in NP bacterial density.

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Impaired Innate and Adaptive Immunity to Streptococcus pneumoniae and Its Effect on Colonization in an Infant Mouse Model

Cited by 66 publications

References 49 publications

Vibrio cholerae-Induced Inflammation in the Neonatal Mouse Cholera Model

Vibrio cholerae-Induced Inflammation in the Neonatal Mouse Cholera Model

Nasopharyngeal Colonization Elicits Antibody Responses to Staphylococcal and Pneumococcal Proteins That Are Not Associated with a Reduced Risk of Subsequent Carriage

Protection against Streptococcus pneumoniae Invasive Pathogenesis by a Protein-Based Vaccine Is Achieved by Suppression of Nasopharyngeal Bacterial Density during Influenza A Virus Coinfection

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