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Microglial Activation by Citrobacter koseri Is Mediated by TLR4- and MyD88-Dependent Pathways¹

Shuliang Liu,^* and Tammy Kielian²

^*Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205; and Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198

Citrobacter koseri is a Gram-negative bacterium that can cause a highly aggressive form of neonatal meningitis, which often progresses to establish multifocal brain abscesses. Despite its tropism for the brain parenchyma, microglial responses to C. koseri have not yet been examined. Microglia use TLRs to recognize invading pathogens and elicit proinflammatory mediator expression important for infection containment. In this study, we investigated the importance of the LPS receptor TLR4 and MyD88, an adaptor molecule involved in the activation of the majority of TLRs in addition to the IL-1 and IL-18 receptors, for their roles in regulating microglial activation in response to C. koseri. Proinflammatory mediator release was significantly reduced in TLR4 mutant and MyD88 knockout microglia compared with wild-type cells following exposure to either live or heat-killed C. koseri, indicating a critical role for both TLR4- and MyD88-dependent pathways in microglial responses to this pathogen. However, residual proinflammatory mediator expression was still observed in TLR4 mutant and MyD88 KO microglia following C. koseri exposure, indicating a contribution of TLR4- and MyD88-independent pathway(s) for maximal pathogen recognition. Interestingly, C. koseri was capable of surviving intracellularly in both primary microglia and macrophages, suggesting that these cells may serve as a reservoir for the pathogen during CNS infections. These results demonstrate that microglia respond to C. koseri with the robust expression of proinflammatory molecules, which is dictated, in part, by TLR4- and MyD88-dependent signals.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the National Institute of Neurological Disorders and Stroke, National Institutes of Health Grant R01 NS055385 (to T.K.) and the National Institute of Neurological Disorders and Stroke supported Core Facility at UAMS (P30 NS047546). S.L. was the recipient of a Graduate Student Research Funds award from the University of Arkansas for Medical Sciences Graduate School.

² Address correspondence and reprint requests to Dr. Tammy Kielian, University of Nebraska Medical Center, Department of Pathology and Microbiology, 985900 Nebraska Medical Center, Omaha, NE 68198-5900. E-mail address: tkielian{at}unmc.edu

³ Abbreviations used in this paper: PRR, pattern recognition receptor; CSF, cerebrospinal fluid; GPA, gentamicin protection assay; KO, knockout; MOI, multiplicity of infection; WT, wild type.