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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

IFN-γ specific monoclonal antibody treatment. Mice were infected by the intracranial route with 3 × 104 CFU of S. pneumoniae TIGR4 and administered with a neutralizing anti-IFN-γ antibody (black) or with an isotype control antibody (white) at the time of the bacteria inoculum. To analyze the role of IFN-γ in pneumococcal meningitis, animals were monitored up to 4 days post infection. Data are from two independent experiments with 4 mice/group. (A) Kaplan-Meier curve of mouse survival. Results were expressed as percentage of survival over time. (B) Clinical score was evaluated using a scale for severity of disease, from 0 (normal) to 5 (moribund), and reported as mean value ± SEM. (C) Bacterial load estimation in brain of mice 48 h post infection. Mean values ± SEM are reported.
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Figure 5: IFN-γ specific monoclonal antibody treatment. Mice were infected by the intracranial route with 3 × 104 CFU of S. pneumoniae TIGR4 and administered with a neutralizing anti-IFN-γ antibody (black) or with an isotype control antibody (white) at the time of the bacteria inoculum. To analyze the role of IFN-γ in pneumococcal meningitis, animals were monitored up to 4 days post infection. Data are from two independent experiments with 4 mice/group. (A) Kaplan-Meier curve of mouse survival. Results were expressed as percentage of survival over time. (B) Clinical score was evaluated using a scale for severity of disease, from 0 (normal) to 5 (moribund), and reported as mean value ± SEM. (C) Bacterial load estimation in brain of mice 48 h post infection. Mean values ± SEM are reported.

Mentions: The involvement of IFN-γ produced in the brain during meningitis with S. pneumoniae TIGR4 was further confirmed by IFN-γ antibody-mediated neutralization. Anti-IFN-γ antibody was administered by the intracranial route at the time of infection and survival was analyzed. As control, a group of mice was infected with bacteria and administered with the isotype control. Two independent experiments were performed, each with 4 mice/group. Two days post infection all mice infected with TIGR4 and treated with the anti-IFN-γ antibody survived, whereas only the 33% of animals treated with the isotype control survived (P = 0.019, Figure 5A). Eighty-three percent of mice treated with the IFN-γ neutralizing antibody survived 3 and 4 days post infection, while the survival rates of isotype control treated mice didn't change, with 33% of survived animals (Figure 5A). Differences of mice survival between the two groups were reduced at day 8, where 33% of mice treated with anti-IFN-γ antibody and 17% of mice in the control group survived, respectively (data not shown). All infected mice were monitored for clinical signs (Figure 5B) up to 4 days post infection. Interestingly, the inoculum of anti-IFN-γ antibody caused minor clinical symptoms, compared to control group, supporting the survival data collected at this early time point.


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)

IFN-γ specific monoclonal antibody treatment. Mice were infected by the intracranial route with 3 × 104 CFU of S. pneumoniae TIGR4 and administered with a neutralizing anti-IFN-γ antibody (black) or with an isotype control antibody (white) at the time of the bacteria inoculum. To analyze the role of IFN-γ in pneumococcal meningitis, animals were monitored up to 4 days post infection. Data are from two independent experiments with 4 mice/group. (A) Kaplan-Meier curve of mouse survival. Results were expressed as percentage of survival over time. (B) Clinical score was evaluated using a scale for severity of disease, from 0 (normal) to 5 (moribund), and reported as mean value ± SEM. (C) Bacterial load estimation in brain of mice 48 h post infection. Mean values ± SEM are reported.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4664635&req=5

Figure 5: IFN-γ specific monoclonal antibody treatment. Mice were infected by the intracranial route with 3 × 104 CFU of S. pneumoniae TIGR4 and administered with a neutralizing anti-IFN-γ antibody (black) or with an isotype control antibody (white) at the time of the bacteria inoculum. To analyze the role of IFN-γ in pneumococcal meningitis, animals were monitored up to 4 days post infection. Data are from two independent experiments with 4 mice/group. (A) Kaplan-Meier curve of mouse survival. Results were expressed as percentage of survival over time. (B) Clinical score was evaluated using a scale for severity of disease, from 0 (normal) to 5 (moribund), and reported as mean value ± SEM. (C) Bacterial load estimation in brain of mice 48 h post infection. Mean values ± SEM are reported.
Mentions: The involvement of IFN-γ produced in the brain during meningitis with S. pneumoniae TIGR4 was further confirmed by IFN-γ antibody-mediated neutralization. Anti-IFN-γ antibody was administered by the intracranial route at the time of infection and survival was analyzed. As control, a group of mice was infected with bacteria and administered with the isotype control. Two independent experiments were performed, each with 4 mice/group. Two days post infection all mice infected with TIGR4 and treated with the anti-IFN-γ antibody survived, whereas only the 33% of animals treated with the isotype control survived (P = 0.019, Figure 5A). Eighty-three percent of mice treated with the IFN-γ neutralizing antibody survived 3 and 4 days post infection, while the survival rates of isotype control treated mice didn't change, with 33% of survived animals (Figure 5A). Differences of mice survival between the two groups were reduced at day 8, where 33% of mice treated with anti-IFN-γ antibody and 17% of mice in the control group survived, respectively (data not shown). All infected mice were monitored for clinical signs (Figure 5B) up to 4 days post infection. Interestingly, the inoculum of anti-IFN-γ antibody caused minor clinical symptoms, compared to control group, supporting the survival data collected at this early time point.

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