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Interactions between blood-borne Streptococcus pneumoniae and the blood-brain barrier preceding meningitis.

Iovino F, Orihuela CJ, Moorlag HE, Molema G, Bijlsma JJ - PLoS ONE (2013)

Bottom Line: Interestingly, pneumococci were not detected in the choroid plexus till 8 hours-post infection.In contrast to the lungs, little to no leukocyte recruitment to the brain was observed over time, though Iba-1 and GFAP staining showed that microglia and astrocytes were activated as soon as 1 hour post-infection.These results provide new information on these two important steps towards the development of pneumococcal meningitis.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Microbiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

ABSTRACT
Streptococcus pneumoniae (the pneumococcus) is a Gram-positive bacterium and the predominant cause of bacterial meningitis. Meningitis is thought to occur as the result of pneumococci crossing the blood-brain barrier to invade the Central Nervous System (CNS); yet little is known about the steps preceding immediate disease development. To study the interactions between pneumococci and the vascular endothelium of the blood-brain barrier prior to meningitis we used an established bacteremia-derived meningitis model in combination with immunofluorescent imaging. Brain tissue of mice infected with S. pneumoniae strain TIGR4, a clinical meningitis isolate, was investigated for the location of the bacteria in relation to the brain vasculature in various compartments. We observed that S. pneumoniae adhered preferentially to the subarachnoid vessels, and subsequently, over time, reached the more internal cerebral areas including the cerebral cortex, septum, and choroid plexus. Interestingly, pneumococci were not detected in the choroid plexus till 8 hours-post infection. In contrast to the lungs, little to no leukocyte recruitment to the brain was observed over time, though Iba-1 and GFAP staining showed that microglia and astrocytes were activated as soon as 1 hour post-infection. Our results imply that i) the local immune system of the brain is activated immediately upon entry of bacteria into the bloodstream and that ii) adhesion to the blood brain barrier is spatiotemporally controlled at different sites throughout the brain. These results provide new information on these two important steps towards the development of pneumococcal meningitis.

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Leukocyte presence in the brain and lungs of mock treated and S.pneumoniae infected mice at different time points after infection.A. Immunofluorescent staining of the leukocyte common antigen CD45 (green) and nuclei (blue) in the subarachnoid space/cerebral cortex, septum and choroid plexus at 14 hours-post infection; total magnification 400X. The CD45 staining showed no influx of leukocytes in all the compartments of the brain in the early stages of infection (data not shown), and even 14 hours after infection the presence of leukocytes was minimal. For each time point of infection, brain sections from 3 mice were analyzed, and of each mouse 3 brain sections were used for the immunofluorescent detection. The images are representative of the situation observed in each mouse that was analyzed. B. Immunofluorescent staining of leukocyte common antigen CD45 (green) and nuclei (blue) in lungs of mock-treated and S. pneumoniae- infected mice; total magnification 630X. For each time point of infection, lungs from 3 mice were analyzed, and of each mouse 3 lung sections were used for the immunofluorescent detection. The images are representative of the situation observed in each mouse that was analyzed.
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pone-0068408-g006: Leukocyte presence in the brain and lungs of mock treated and S.pneumoniae infected mice at different time points after infection.A. Immunofluorescent staining of the leukocyte common antigen CD45 (green) and nuclei (blue) in the subarachnoid space/cerebral cortex, septum and choroid plexus at 14 hours-post infection; total magnification 400X. The CD45 staining showed no influx of leukocytes in all the compartments of the brain in the early stages of infection (data not shown), and even 14 hours after infection the presence of leukocytes was minimal. For each time point of infection, brain sections from 3 mice were analyzed, and of each mouse 3 brain sections were used for the immunofluorescent detection. The images are representative of the situation observed in each mouse that was analyzed. B. Immunofluorescent staining of leukocyte common antigen CD45 (green) and nuclei (blue) in lungs of mock-treated and S. pneumoniae- infected mice; total magnification 630X. For each time point of infection, lungs from 3 mice were analyzed, and of each mouse 3 lung sections were used for the immunofluorescent detection. The images are representative of the situation observed in each mouse that was analyzed.

Mentions: Inflammation is a crucial process in the defense mechanism against various infectious diseases, and leukocytes are the principal cellular mediators of inflammation. To evaluate the degree of inflammation in the brain and compare it to other tissue compartments such as the lungs, during the course of S. pneumoniae infection we studied tissue influx of leukocytes using the leukocyte common antigen marker CD45 [33], [34], [35]. As expected, in brain and lungs of mock treated mice no leukocytes were detected (Figure S4). The CD45 staining showed almost no influx of leukocytes in any compartment of the brain at the early stages of infection (Figure S4), and even at the later stages, the presence of leukocytes was minimal (Figure 6A). In contrast, in the lungs a different picture was observed. At all time points of pneumococcal infection, large numbers of leukocytes were present in the lungs, even as soon as after 1 hour (Figure 6B). These results reveal that intravenous injection of S. pneumoniae causes distinct tissue-specific responses. Furthermore, in contrast to the presence of large numbers of leukocytes in the lungs, no such infiltration was observed in the brain during the time course of our pneumococcal infection. Presumably, this would facilitate the replication of bacteria that are able to successfully translocate to the CNS.


Interactions between blood-borne Streptococcus pneumoniae and the blood-brain barrier preceding meningitis.

Iovino F, Orihuela CJ, Moorlag HE, Molema G, Bijlsma JJ - PLoS ONE (2013)

Leukocyte presence in the brain and lungs of mock treated and S.pneumoniae infected mice at different time points after infection.A. Immunofluorescent staining of the leukocyte common antigen CD45 (green) and nuclei (blue) in the subarachnoid space/cerebral cortex, septum and choroid plexus at 14 hours-post infection; total magnification 400X. The CD45 staining showed no influx of leukocytes in all the compartments of the brain in the early stages of infection (data not shown), and even 14 hours after infection the presence of leukocytes was minimal. For each time point of infection, brain sections from 3 mice were analyzed, and of each mouse 3 brain sections were used for the immunofluorescent detection. The images are representative of the situation observed in each mouse that was analyzed. B. Immunofluorescent staining of leukocyte common antigen CD45 (green) and nuclei (blue) in lungs of mock-treated and S. pneumoniae- infected mice; total magnification 630X. For each time point of infection, lungs from 3 mice were analyzed, and of each mouse 3 lung sections were used for the immunofluorescent detection. The images are representative of the situation observed in each mouse that was analyzed.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3713044&req=5

pone-0068408-g006: Leukocyte presence in the brain and lungs of mock treated and S.pneumoniae infected mice at different time points after infection.A. Immunofluorescent staining of the leukocyte common antigen CD45 (green) and nuclei (blue) in the subarachnoid space/cerebral cortex, septum and choroid plexus at 14 hours-post infection; total magnification 400X. The CD45 staining showed no influx of leukocytes in all the compartments of the brain in the early stages of infection (data not shown), and even 14 hours after infection the presence of leukocytes was minimal. For each time point of infection, brain sections from 3 mice were analyzed, and of each mouse 3 brain sections were used for the immunofluorescent detection. The images are representative of the situation observed in each mouse that was analyzed. B. Immunofluorescent staining of leukocyte common antigen CD45 (green) and nuclei (blue) in lungs of mock-treated and S. pneumoniae- infected mice; total magnification 630X. For each time point of infection, lungs from 3 mice were analyzed, and of each mouse 3 lung sections were used for the immunofluorescent detection. The images are representative of the situation observed in each mouse that was analyzed.
Mentions: Inflammation is a crucial process in the defense mechanism against various infectious diseases, and leukocytes are the principal cellular mediators of inflammation. To evaluate the degree of inflammation in the brain and compare it to other tissue compartments such as the lungs, during the course of S. pneumoniae infection we studied tissue influx of leukocytes using the leukocyte common antigen marker CD45 [33], [34], [35]. As expected, in brain and lungs of mock treated mice no leukocytes were detected (Figure S4). The CD45 staining showed almost no influx of leukocytes in any compartment of the brain at the early stages of infection (Figure S4), and even at the later stages, the presence of leukocytes was minimal (Figure 6A). In contrast, in the lungs a different picture was observed. At all time points of pneumococcal infection, large numbers of leukocytes were present in the lungs, even as soon as after 1 hour (Figure 6B). These results reveal that intravenous injection of S. pneumoniae causes distinct tissue-specific responses. Furthermore, in contrast to the presence of large numbers of leukocytes in the lungs, no such infiltration was observed in the brain during the time course of our pneumococcal infection. Presumably, this would facilitate the replication of bacteria that are able to successfully translocate to the CNS.

Bottom Line: Interestingly, pneumococci were not detected in the choroid plexus till 8 hours-post infection.In contrast to the lungs, little to no leukocyte recruitment to the brain was observed over time, though Iba-1 and GFAP staining showed that microglia and astrocytes were activated as soon as 1 hour post-infection.These results provide new information on these two important steps towards the development of pneumococcal meningitis.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Microbiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

ABSTRACT
Streptococcus pneumoniae (the pneumococcus) is a Gram-positive bacterium and the predominant cause of bacterial meningitis. Meningitis is thought to occur as the result of pneumococci crossing the blood-brain barrier to invade the Central Nervous System (CNS); yet little is known about the steps preceding immediate disease development. To study the interactions between pneumococci and the vascular endothelium of the blood-brain barrier prior to meningitis we used an established bacteremia-derived meningitis model in combination with immunofluorescent imaging. Brain tissue of mice infected with S. pneumoniae strain TIGR4, a clinical meningitis isolate, was investigated for the location of the bacteria in relation to the brain vasculature in various compartments. We observed that S. pneumoniae adhered preferentially to the subarachnoid vessels, and subsequently, over time, reached the more internal cerebral areas including the cerebral cortex, septum, and choroid plexus. Interestingly, pneumococci were not detected in the choroid plexus till 8 hours-post infection. In contrast to the lungs, little to no leukocyte recruitment to the brain was observed over time, though Iba-1 and GFAP staining showed that microglia and astrocytes were activated as soon as 1 hour post-infection. Our results imply that i) the local immune system of the brain is activated immediately upon entry of bacteria into the bloodstream and that ii) adhesion to the blood brain barrier is spatiotemporally controlled at different sites throughout the brain. These results provide new information on these two important steps towards the development of pneumococcal meningitis.

Show MeSH
Related in: MedlinePlus