Double deficiency of toll-like receptors 2 and 4 alters long-term neurological sequelae in mice cured of pneumococcal meningitis

Too, Lay Khoon, Yau, Belinda, Baxter, Alan G., McGregor, Iain S., and Hunt, Nicholas H. (2019) Double deficiency of toll-like receptors 2 and 4 alters long-term neurological sequelae in mice cured of pneumococcal meningitis. Scientific Reports, 9. 16189.

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Toll-like receptor (TLR) 2 and 4 signalling pathways are central to the body's defence against invading pathogens during pneumococcal meningitis. Whereas several studies support their importance in innate immunity, thereby preventing host mortality, any role in protecting neurological function during meningeal infection is ill-understood. Here we investigated both the acute immunological reaction and the long-term neurobehavioural consequences of experimental pneumococcal meningitis in mice lacking both TLR2 and TLR4. The absence of these TLRs significantly impaired survival in mice inoculated intracerebroventricularly with Streptococcus pneumoniae. During the acute phase of infection, TLR2/4-deficient mice had lower cerebrospinal fluid concentrations of interleukin-1 beta, and higher interferon-gamma, than their wild-type counterparts. After antibiotic cure, TLR2/4 double deficiency was associated with aggravation of behavioural impairment in mice, as shown by diurnal hypolocomotion throughout the adaptation phases in the Intellicage of TLR-deficient mice compared to their wild-type counterparts. While TLR2/4 double deficiency did not affect the cognitive ability of mice in a patrolling task, it aggravated the impairment of cognitive flexibility. We conclude that TLR2 and TLR4 are central to regulating the host inflammatory response in pneumococcal meningitis, which may mediate diverse compensatory mechanisms that protect the host not only against mortality but also long-term neurological complications.

Item ID: 61071
Item Type: Article (Research - C1)
ISSN: 2045-2322
Keywords: Animal behaviour, Infection, Meningitis, Neuroimmunology
Copyright Information: © The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit
Funders: Australian National Health and Medical Research Council (NHMRC), Ministry of Science, Technology and Innovation, Malaysia
Date Deposited: 27 Nov 2019 07:31
FoR Codes: 32 BIOMEDICAL AND CLINICAL SCIENCES > 3209 Neurosciences > 320903 Central nervous system @ 50%
32 BIOMEDICAL AND CLINICAL SCIENCES > 3204 Immunology > 320402 Applied immunology (incl. antibody engineering, xenotransplantation and t-cell therapies) @ 50%
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