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Interferon-γ from Brain Leukocytes Enhances Meningitis by Type 4 Streptococcus pneumoniae.

Pettini E, Fiorino F, Cuppone AM, Iannelli F, Medaglini D, Pozzi G - Front Microbiol (2015)

Bottom Line: The amount of lymphocytes, NK cells, neutrophils, monocytes and macrophages in the brain increased 48 h post infection.Pro-inflammatory cytokines such as IL-1β and TNF-α, and TLR2 were also upregulated.This study shows that IFN-γ produced during meningitis by type 4 S. pneumoniae enhances bacterial pathogenesis exerting a negative effect on the disease outcome.

View Article: PubMed Central - PubMed

Affiliation: Laboratorio di Microbiologia Molecolare e Biotecnologia, Dipartimento di Biotecnologie Mediche, Università degli Studi di Siena Siena, Italy.

ABSTRACT
Streptococcus pneumoniae is the leading cause of bacterial meningitis. Pneumococcal meningitis is a life-threatening disease with high rates of mortality and neurological sequelae. Immune targeting of S. pneumoniae is essential for clearance of infection; however, within the brain, the induced inflammatory response contributes to pathogenesis. In this study we investigate the local inflammatory response and the role of IFN-γ in a murine model of pneumococcal meningitis induced by intracranial injection of type 4 S. pneumoniae. Lymphoid and myeloid cell populations involved in meningitis, as well as cytokine gene expression, were investigated after infection. Animals were treated with a monoclonal antibody specific for murine IFN-γ to evaluate its role in animal survival. Intracranial inoculation of 3 × 10(4) colony-forming units of type 4 strain TIGR4 caused 75% of mice to develop meningitis within 4 days. The amount of lymphocytes, NK cells, neutrophils, monocytes and macrophages in the brain increased 48 h post infection. IFN-γ mRNA levels were about 240-fold higher in brains of infected mice compared to controls. Pro-inflammatory cytokines such as IL-1β and TNF-α, and TLR2 were also upregulated. In vivo treatment with anti-IFN-γ antibody increased survival of infected mice. This study shows that IFN-γ produced during meningitis by type 4 S. pneumoniae enhances bacterial pathogenesis exerting a negative effect on the disease outcome.

No MeSH data available.


Related in: MedlinePlus

Murine model of meningitis by S. pneumoniae. C57BL/6J mice were infected by the intracranial route with 3 × 104 CFU of S. pneumoniae strain TIGR4 (filled circles) or injected with bacterial growth medium (control, open circles). Data are from two independent experiments with 8 mice/group, and animals were monitored up to 8 days post infection. (A) Kaplan-Meier curve of mouse survival. Results were expressed as percentage of survival over time, and statistical differences were evaluated between infected mice and control group using Log-Rank test. Asterisks indicate statistical significance (***P < 0.0001). (B) Clinical score analysis was evaluated using a scale for severity of disease, from 0 (normal) to 5 (moribund), and values were reported as mean value ± SEM.
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Figure 1: Murine model of meningitis by S. pneumoniae. C57BL/6J mice were infected by the intracranial route with 3 × 104 CFU of S. pneumoniae strain TIGR4 (filled circles) or injected with bacterial growth medium (control, open circles). Data are from two independent experiments with 8 mice/group, and animals were monitored up to 8 days post infection. (A) Kaplan-Meier curve of mouse survival. Results were expressed as percentage of survival over time, and statistical differences were evaluated between infected mice and control group using Log-Rank test. Asterisks indicate statistical significance (***P < 0.0001). (B) Clinical score analysis was evaluated using a scale for severity of disease, from 0 (normal) to 5 (moribund), and values were reported as mean value ± SEM.

Mentions: The amount of type 4 S. pneumoniae chosen for intracranial challenge experiments was 3 × 104 CFU/mouse. Groups of 8 mice were infected with S. pneumoniae TIGR4 or injected with bacterial growth medium. Three days post infection with TIGR4, 56% of infected mice survived and values decreased until 8 days post infection (Figure 1A), when about 6% of mice survived. Median survival time of mice challenged with TIGR4 was 96 h. On the contrary, all mice of the control group, injected by the intracranial route with the bacterial growth medium, survived with no signs of disease. Survival analysis was supported by daily clinical parameters observation, in terms of weight and clinical score. A decrease of about 25% of initial weight was estimated starting from 3 days post infection (data not shown). The clinical score of infected mice gradually increased following infection, while all control mice showed no signs of illness and no differences in clinical score compared to initial condition (Figure 1B).


Interferon-γ from Brain Leukocytes Enhances Meningitis by Type 4 Streptococcus pneumoniae.

Pettini E, Fiorino F, Cuppone AM, Iannelli F, Medaglini D, Pozzi G - Front Microbiol (2015)

Murine model of meningitis by S. pneumoniae. C57BL/6J mice were infected by the intracranial route with 3 × 104 CFU of S. pneumoniae strain TIGR4 (filled circles) or injected with bacterial growth medium (control, open circles). Data are from two independent experiments with 8 mice/group, and animals were monitored up to 8 days post infection. (A) Kaplan-Meier curve of mouse survival. Results were expressed as percentage of survival over time, and statistical differences were evaluated between infected mice and control group using Log-Rank test. Asterisks indicate statistical significance (***P < 0.0001). (B) Clinical score analysis was evaluated using a scale for severity of disease, from 0 (normal) to 5 (moribund), and values were reported as mean value ± SEM.
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Figure 1: Murine model of meningitis by S. pneumoniae. C57BL/6J mice were infected by the intracranial route with 3 × 104 CFU of S. pneumoniae strain TIGR4 (filled circles) or injected with bacterial growth medium (control, open circles). Data are from two independent experiments with 8 mice/group, and animals were monitored up to 8 days post infection. (A) Kaplan-Meier curve of mouse survival. Results were expressed as percentage of survival over time, and statistical differences were evaluated between infected mice and control group using Log-Rank test. Asterisks indicate statistical significance (***P < 0.0001). (B) Clinical score analysis was evaluated using a scale for severity of disease, from 0 (normal) to 5 (moribund), and values were reported as mean value ± SEM.
Mentions: The amount of type 4 S. pneumoniae chosen for intracranial challenge experiments was 3 × 104 CFU/mouse. Groups of 8 mice were infected with S. pneumoniae TIGR4 or injected with bacterial growth medium. Three days post infection with TIGR4, 56% of infected mice survived and values decreased until 8 days post infection (Figure 1A), when about 6% of mice survived. Median survival time of mice challenged with TIGR4 was 96 h. On the contrary, all mice of the control group, injected by the intracranial route with the bacterial growth medium, survived with no signs of disease. Survival analysis was supported by daily clinical parameters observation, in terms of weight and clinical score. A decrease of about 25% of initial weight was estimated starting from 3 days post infection (data not shown). The clinical score of infected mice gradually increased following infection, while all control mice showed no signs of illness and no differences in clinical score compared to initial condition (Figure 1B).

Bottom Line: The amount of lymphocytes, NK cells, neutrophils, monocytes and macrophages in the brain increased 48 h post infection.Pro-inflammatory cytokines such as IL-1β and TNF-α, and TLR2 were also upregulated.This study shows that IFN-γ produced during meningitis by type 4 S. pneumoniae enhances bacterial pathogenesis exerting a negative effect on the disease outcome.

View Article: PubMed Central - PubMed

Affiliation: Laboratorio di Microbiologia Molecolare e Biotecnologia, Dipartimento di Biotecnologie Mediche, Università degli Studi di Siena Siena, Italy.

ABSTRACT
Streptococcus pneumoniae is the leading cause of bacterial meningitis. Pneumococcal meningitis is a life-threatening disease with high rates of mortality and neurological sequelae. Immune targeting of S. pneumoniae is essential for clearance of infection; however, within the brain, the induced inflammatory response contributes to pathogenesis. In this study we investigate the local inflammatory response and the role of IFN-γ in a murine model of pneumococcal meningitis induced by intracranial injection of type 4 S. pneumoniae. Lymphoid and myeloid cell populations involved in meningitis, as well as cytokine gene expression, were investigated after infection. Animals were treated with a monoclonal antibody specific for murine IFN-γ to evaluate its role in animal survival. Intracranial inoculation of 3 × 10(4) colony-forming units of type 4 strain TIGR4 caused 75% of mice to develop meningitis within 4 days. The amount of lymphocytes, NK cells, neutrophils, monocytes and macrophages in the brain increased 48 h post infection. IFN-γ mRNA levels were about 240-fold higher in brains of infected mice compared to controls. Pro-inflammatory cytokines such as IL-1β and TNF-α, and TLR2 were also upregulated. In vivo treatment with anti-IFN-γ antibody increased survival of infected mice. This study shows that IFN-γ produced during meningitis by type 4 S. pneumoniae enhances bacterial pathogenesis exerting a negative effect on the disease outcome.

No MeSH data available.


Related in: MedlinePlus