Neurobrucellosis

Madkour, M. Monir; Al-Moutaery, Khalaf R.; Al-Deeb, Saleh M.; Al-Swailem, R.; Al-Okaily, F.

doi:10.1007/978-3-642-59533-2_15

Cited by 6 publications

(1 citation statement)

References 58 publications

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“…Although the clinical and diagnostic aspects of BBB alteration during neurobrucellosis have been widely described (3,(13)(14)(15), the pathogenic mechanisms involved in activation of the BBB caused by Brucella have not been investigated at the molecular and cellular levels. For this, we designed a minimal in vitro model of the interaction of B. abortus with cells of the BBB by using HBMEC (16).…”

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Glial Cell–Elicited Activation of Brain Microvasculature in Response to Brucella abortus Infection Requires ASC Inflammasome–Dependent IL-1β Production

Miraglia

Franco

Rodrı́guez

et al. 2016

The Journal of Immunology

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Blood–brain barrier activation and/or dysfunction are a common feature of human neurobrucellosis, but the underlying pathogenic mechanisms are largely unknown. In this article, we describe an immune mechanism for inflammatory activation of human brain microvascular endothelial cells (HBMEC) in response to infection with Brucella abortus. Infection of HBMEC with B. abortus induced the secretion of IL-6, IL-8, and MCP-1, and the upregulation of CD54 (ICAM-1), consistent with a state of activation. Culture supernatants (CS) from glial cells (astrocytes and microglia) infected with B. abortus also induced activation of HBMEC, but to a greater extent. Although B. abortus–infected glial cells secreted IL-1β and TNF-α, activation of HBMEC was dependent on IL-1β because CS from B. abortus–infected astrocytes and microglia deficient in caspase-1 and apoptosis-associated speck-like protein containing a CARD failed to induce HBMEC activation. Consistently, treatment of CS with neutralizing anti–IL-1β inhibited HBMEC activation. Both absent in melanoma 2 and Nod-like receptor containing a pyrin domain 3 are partially required for caspase-1 activation and IL-1β secretion, suggesting that multiple apoptosis-associated speck-like protein containing CARD–dependent inflammasomes contribute to IL-1β–induced activation of the brain microvasculature. Inflammasome-mediated IL-1β secretion in glial cells depends on TLR2 and MyD88 adapter-like/TIRAP. Finally, neutrophil and monocyte migration across HBMEC monolayers was increased by CS from Brucella-infected glial cells in an IL-1β–dependent fashion, and the infiltration of neutrophils into the brain parenchyma upon intracranial injection of B. abortus was diminished in the absence of Nod-like receptor containing a pyrin domain 3 and absent in melanoma 2. Our results indicate that innate immunity of the CNS set in motion by B. abortus contributes to the activation of the blood–brain barrier in neurobrucellosis and IL-1β mediates this phenomenon.

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confidence: 99%

Glial Cell–Elicited Activation of Brain Microvasculature in Response to Brucella abortus Infection Requires ASC Inflammasome–Dependent IL-1β Production

Miraglia

Franco

Rodrı́guez

et al. 2016

The Journal of Immunology

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Brucella abortus‐activated microglia induce neuronal death through primary phagocytosis

Rodrı́guez

Delpino

Miraglia

et al. 2017

Glia

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Inflammation has long been implicated as a contributor to pathogenesis in neurobrucellosis. Many of the associated neurocognitive symptoms of neurobrucellosis may be the result of neuronal dysfunction resulting from the inflammatory response induced by Brucella abortus infection in the central nervous system. In this manuscript, we describe an immune mechanism for inflammatory activation of microglia that leads to neuronal death upon B. abortus infection. B. abortus was unable to infect or harm primary cultures of mouse neurons. However, when neurons were co-cultured with microglia and infected with B. abortus significant neuronal loss occurred. This phenomenon was dependent on TLR2 activation by Brucella lipoproteins. Neuronal death was not due to apoptosis, but it was dependent on the microglial release of nitric oxide (NO). B. abortus infection stimulated microglial proliferation, phagocytic activity and engulfment of neurons. NO secreted by B. abortus-activated microglia induced neuronal exposure of the "eat-me" signal phosphatidylserine (PS). Blocking of PS-binding to protein milk fat globule epidermal growth factor-8 (MFG-E8) or microglial vitronectin receptor-MFG-E8 interaction was sufficient to prevent neuronal loss by inhibiting microglial phagocytosis without affecting their activation. Taken together, our results indicate that B. abortus is not directly toxic to neurons; rather, these cells become distressed and are killed by phagocytosis in the inflammatory surroundings generated by infected microglia. Neuronal loss induced by B. abortus-activated microglia may explain, in part, the neurological deficits observed during neurobrucellosis.

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