Abstract
Citrobacter koseri (C. koseri) is a Gram-negative bacterium that can cause a highly aggressive form of neonatal meningitis, which often progresses to establish multi-focal brain abscesses. The roles of Toll-like receptor 4 (TLR4) and its signaling adaptor MyD88 during CNS C. koseri infection have not yet been examined, which is important since recent evidence indicates that innate immune responses are tailored towards specific pathogen classes. Here TLR4 WT (C3H/FeJ) and TLR4 mutant (C3H/HeJ) mice as well as MyD88 KO animals were infected intracerebrally with live C. koseri, resulting in meningitis and ventriculitis with accompanying brain abscess formation. MyD88 KO mice were exquisitely sensitive to C. koseri, demonstrating enhanced mortality rates and significantly elevated bacterial burdens compared to WT animals. Interestingly, although early proinflammatory mediator release (i.e. 12 h) was MyD88-dependent, a role for MyD88-independent signaling was evident at 24 h, revealing a compensatory response to CNS C. koseri infection. In contrast, TLR4 did not significantly impact bacterial burdens or proinflammatory mediator production in response to C. koseri. Similar findings were obtained with primary astrocytes, where MyD88-dependent pathways were essential for chemokine release in response to intact C. koseri, whereas TLR4 was dispensable; implicating the involvement of alternative TLRs since highly enriched astrocytes did not produce IL-1 upon bacterial exposure, which also signals via MyD88. Collectively, these findings demonstrate the importance of MyD88-dependent mechanisms in eliciting maximal proinflammatory responses, astrocyte activation, and bacterial containment during CNS C. koseri infection, as well as a late-phase MyD88-independent signaling pathway for cytokine/chemokine production.
Highlights
Citrobacter koseri is a Gram-negative bacillus with a predilection for causing meningitis and multi-focal brain abscesses in human neonates [1,2]
myeloid differentiation factor 88 (MyD88)-dependent signals are critical for bacterial containment and inflammatory mediator production during C. koseri brain infection To evaluate the functional importance of MyD88-dependent pathways for CNS immune responses to C. koseri, we employed a mouse model of meningitis and brain abscess formation using a C. koseri clinical isolate [20]
MyD88 KO mice were exquisitely sensitive to intracerebral C. koseri, with the majority of animals succumbing to infection within 24-36 h following bacterial exposure
Summary
Citrobacter koseri (formerly known as C. diversus) is a Gram-negative bacillus with a predilection for causing meningitis and multi-focal brain abscesses in human neonates [1,2]. Lipoproteins and LPS contained in the outer cell wall of Gram-negative bacteria are agonists for TLR2 and TLR4, respectively; flagellin, which is the main component of bacterial flagella, engages TLR5; and bacterial DNA containing unmethylated CpG motifs binds to TLR9. But are not limited to, lipoproteins, flagellin, and bacterial DNA that are recognized by TLR2, TLR5, and TLR9, respectively All of these TLRs could conceivably contribute to activation of the host inflammatory response during CNS C. koseri infection and since they all utilize the common adaptor molecule myeloid differentiation factor 88 (MyD88) [11,12], we examined responses to bacterial challenge in MyD88 KO mice
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