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Differential effect of p47phox and gp91phox deficiency on the course of Pneumococcal Meningitis

Manuela Schaper1, Stephen L Leib, Damian N Meli

  • 1Institute for Infectious Diseases, University of Berne, 3010 Berne, Switzerland.

Infection and Immunity
|June 24, 2003
PubMed

Insights

Reactive oxygen species (ROS) generated by NADPH oxidase are crucial for fighting pneumococcal meningitis. Mice lacking the p47 subunit showed impaired host defense, leading to increased bacterial load and inflammation.

Area of Science:

  • Immunology
  • Neuroscience
  • Microbiology

Background:

  • Bacterial meningitis, a severe central nervous system inflammation, involves significant granulocyte infiltration into cerebrospinal fluid (CSF).
  • NADPH oxidase-derived reactive oxygen species (ROS) play a role in inflammatory responses and host defense against bacterial infections.

Purpose of the Study:

  • To investigate the specific role of NADPH oxidase-derived ROS in the pathogenesis of pneumococcal meningitis.
  • To determine the contribution of different NADPH oxidase subunits (gp91 and p47) to the host's inflammatory response and bacterial clearance.

Main Methods:

  • Mice deficient in gp91 or p47 NADPH oxidase subunits were intracisternally infected with live Streptococcus pneumoniae.
  • Disease parameters, including CSF bacterial titers, inflammation markers (interleukin-1 beta, tumor necrosis factor alpha), blood-brain barrier integrity, and matrix metalloproteinase 9 levels, were measured.
  • Responses to heat-inactivated pneumococci were also assessed to differentiate between direct bacterial effects and host immune responses.

Main Results:

  • Mice lacking the gp91 subunit showed no significant differences in disease parameters compared to wild-type mice.
  • Mice lacking the p47 subunit exhibited exacerbated subarachnoid and ventricular inflammation, blood-brain barrier disruption, and elevated inflammatory mediators.
  • p47(-/-) mice had significantly higher CSF bacterial titers (approx. 10-fold) and impaired inflammatory response to heat-inactivated bacteria, suggesting a defect in host defense.

Conclusions:

  • ROS generated by a gp91-independent NADPH oxidase are essential for an effective inflammatory response against pneumococcal meningitis.
  • The p47 subunit of NADPH oxidase plays a critical role in host defense mechanisms crucial for controlling pneumococcal infection in the central nervous system.
  • Targeting ROS-producing enzymes may offer therapeutic strategies for bacterial meningitis.

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