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. 2003 Nov 25;100(24):14363-7.
doi: 10.1073/pnas.2235844100. Epub 2003 Nov 10.

Pneumococcal carriage results in ganglioside-mediated olfactory tissue infection

Frederik W van Ginkel  1 , Jerry R McGhee, James M Watt, Antonio Campos-Torres, Lindsay A Parish, David E Briles
Affiliations

Pneumococcal carriage results in ganglioside-mediated olfactory tissue infection

Frederik W van Ginkel et al. Proc Natl Acad Sci U S A. .

Erratum in

  • Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6834

Abstract

Streptococcus pneumoniae cause considerable morbidity and mortality, with persistent neurological sequelae, particularly in young children and the elderly. It is widely assumed that carriage occurs through direct mucosal colonization from the environment whereas meningitis results from invasion from the blood. However, the results of published studies can be interpreted that pneumococci may enter the brain directly from the nasal cavity by axonal transport through olfactory nerves. This hypothesis is based on findings that (i) teichoic acid of the pneumococcal cell wall interact with gangliosides (GLS), (ii) the interaction of GLS with cholera toxin leads to axonal transport through the olfactory nerves into the brain, and (iii) viruses enter the brain through axonal transport into olfactory nerves. After nasal inoculation, we observe high numbers of pneumococci in nasal washes and the olfactory nerves and epithelium. Significant numbers of pneumococci also infected the olfactory bulbs, brain, and the trigeminal ganglia. The absence of bacteremia in this model makes it unlikely that the bacteria entered the brain from the blood stream. Recovery of colony-forming units from the brain, lungs, olfactory nerves, and epithelium and nasal washes was inhibited by incubating pneumococci with GLS before nasal inoculation. These findings, confirmed by PCR and immunohistochemistry, support a GLS-mediated process of infection and are consistent with pneumococci reaching the brain through retrograde axonal transport.

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Figures

Fig. 1.
Fig. 1.
Nasal delivery of 3 × 106 cfu of either the nonencapsulated R36A strain or the virulent EF3030 strain of S. pneumoniae to xid mice. The neuronal tissues (ON/E, OB, and brain) and the lymphoid tissues (NALT, CLN, and lungs) were collected, minced, and analyzed for the presence of live pneumococci at 1 and 4 days after nasal challenge. Indicated is the mean of log10 cfu ± 1 SE. The 0 value on the y-axis represents the absence of detectable cfu. Indicated are the mean cfu ± SE of five mice per group; data are representative of three different experiments.
Fig. 2.
Fig. 2.
The kinetics of organ distribution of S. pneumoniae strain EF3030 cfu after nasal challenge. The ON/E, OB, brain, blood, NW, NALT, CLN, and lung tissues were collected on days 4, 11, 18, 25, and 39 and were analyzed for the presence of S. pneumoniae. An aliquot of 3 × 106 cfu of S. pneumoniae resulted in the colonization of the nasal tract and a subsequent infection of the OB. The 0 value on the y-axis represents the absence of detectable cfu. Indicated are the mean cfu ± SE of three separate experiments. Each time point represents 10 mice with the exception of day 39, which represents 5 mice.
Fig. 3.
Fig. 3.
The distribution of S. pneumoniae strain EF3030 after preincubation with GLS. Aliquots (3 × 107 cfu) of S. pneumoniae were incubated for 30 min with 20 μg of asialo-GM1 (a-GM1) or 125 μg of mixed GLS (MG) before nasal application. The ON/E, OB, and brain and the NW, NALT, and lungs were collected 4 days later and analyzed for numbers of S. pneumoniae. The 0 value on the y-axis represents the absence of detectable cfu. Indicated are the mean ± 1 SE of five mice, and the P values were obtained after statistical analysis. The data are representative of two separate experiments.
Fig. 4.
Fig. 4.
Detection of the TIGR4 strain of S. pneumoniae in the OB after nasal challenge. An aliquot of 5 × 105 cfu was given nasally, and the blood, NW, ON/E, OB, and brain tissues were analyzed for colonization 1 week after challenge (A and B). These tissues (10 μg of DNA) were also analyzed for the presence of the pneumolysin gene by PCR (C). In addition, the S. pneumoniae were visualized by immunofluorescence with PspA-specific Abs in the OB of control (D) or S. pneumoniae-challenged mice (E and F). Indicated are the mean ± 1 SE. The data are representative of three separate experiments.
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