Burkholderia pseudomallei Rapidly Infects the Brain Stem and Spinal Cord via the Trigeminal Nerve after Intranasal Inoculation

John, James St; Walkden, Heidi; Nazareth, Lynn; Beagley, Kenneth W.; Ulett, Glen C.; Batzloff, Michael R.; Beacham, Ifor R.; Ekberg, Jenny

doi:10.1128/iai.00361-16

Cited by 41 publications

(48 citation statements)

References 38 publications

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“…B. pseudomallei can enter the brain and spinal cord via nasal branches of the trigeminal or olfactory nerve. Two alternative routes by which bacteria can reach the brain are via epithelial cell invasion and crossing the blood-brain barrier (BBB) [47]. To our knowledge, our study is the first to show Burkholderia near-neighbor distribution in to the brain.…”

Section: Discussionmentioning

confidence: 72%

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A Mouse Model Of Binge Alcohol Consumption andBurkholderiaInfection

Jiménez

Moreno

Settles

et al. 2018

Preprint

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BackgroundBinge drinking, a common form of alcohol consumption, is associated with increased mortality and morbidity; yet, its effects on the immune system’s ability to defend against infectious agents are poorly understood. Burkholderia pseudomallei, the causative agent of melioidosis can occur in healthy humans, yet binge alcohol use is progressively being recognized as a major risk factor. Although our previous studies demonstrated that binge alcohol exposure results in reduced alveolar macrophage function and increased Burkholderia virulence in vitro, no experimental studies have investigated the outcomes of binge alcohol on Burkholderia spp. infection in vivo.Principal FindingsWe used the close genetic relatives of B. pseudomallei, B. thailandensis E264 and B. vietnamiensis, as useful BSL-2 model systems. Eight-week-old female C57BL/6 mice were administered alcohol comparable to human binge drinking episodes (4.4 g/kg) or PBS intraperitoneally 30 min before a non-lethal intranasal infection. In an initial B. thailandensis infection (3 x 105), bacteria accumulated in the lungs and disseminated to the spleen in alcohol administered mice only, compared with PBS treated mice at 24 h post-infection (PI). The greatest bacterial load occurred with B. vietnamiensis (1 x 106) in lungs, spleen, and brain tissue by 72 h PI. Pulmonary cytokine expression (TNF-α, GM-CSF) decreased, while splenic cytokine (IL-10) increased in binge drunk mice. Increased lung and brain permeability was observed as early as 2 h post alcohol administration in vivo. Trans-epithelial electrical resistance (TEER) was significantly decreased, while intracellular invasion of non-phagocytic cells increased with 0.2% v/v alcohol exposure in vitro.ConclusionsOur results indicate that a single binge alcohol dose suppressed innate immune functions and increased the ability of less virulent Burkholderia strains to disseminate through increased barrier permeability and intracellular invasion of non-phagocytic cells.Author SummaryBurkholderia pseudomallei causes the disease melioidosis, which occurs in most tropical regions across the globe. Exposure rarely evolves to significant disease in the absence of specific comorbidities, such as binge alcohol intoxication. In susceptible hosts, the disease is primarily manifested as pneumonic melioidosis and can be rapidly fatal if untreated. In this study, we utilized B. thailandensis, a genetically similar strain to B. pseudomallei, and opportunistic B. vietnamiensis, a known human pathogen that utilizes similar virulence strategies as B. pseudomallei in immunocompromised and cystic fibrosis patients. The study investigates the impact of a single binge alcohol episode on infectivity and immune response in vivo. We show that a single binge alcohol episode prior to inhaling Burkholderia species increases bacterial spread to the lungs and brain. We also identify alcohol-induced tissue permeability and epithelial cell invasion as modes of action for greater bacterial spread and survival inside the host. Our results support the public health responses being developed in melioidosis-endemic regions that emphasize the nature of binge drinking as a prime concern, especially around potential times of exposure to environmental B. pseudomallei.

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Section: Discussionmentioning

confidence: 72%

“…To our knowledge, our study is the first to show Burkholderia near-neighbor distribution in to the brain. Our data suggest a singular binge alcohol episode could modulate nasal mucosa and related upper respiratory defenses that lead to greater pulmonary and neurological infections [47].…”

Section: Discussionmentioning

confidence: 99%

A Mouse Model Of Binge Alcohol Consumption andBurkholderiaInfection

Jiménez

Moreno

Settles

et al. 2018

Preprint

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“…We have previously used these two antibodies to characterize expression of GFAP and S100β in astrocytes in both tissue sections and cells (Chehrehasa et al, ; Windus et al, ). (3) Rabbit anti‐ B. pseudomallei antibodies raised against the sarkosyl‐insoluble fraction enriched for outer membrane proteins (RRID: AB_2736920) (Boddey et al, ), which was made in‐house, and we have previously used this antibody extensively to label B. pseudomallei in tissue sections (St John et al, ) and cells (Horton et al, ). (4) Goat anti‐OMP which labels primary olfactory neurons (RRID: AB664696).…”

Section: Methodsmentioning

confidence: 99%

“…(3) Rabbit anti-B. pseudomallei antibodies raised against the sarkosyl-insoluble fraction enriched for outer membrane proteins (RRID:AB_2736920) (Boddey et al, 2007), which was made in-house, and we have previously used this antibody extensively to label B. pseudomallei in tissue sections (St John et al, 2016) and cells (Horton et al, 2013). (4) Goat anti-OMP which labels primary olfactory neurons (RRID:AB664696).…”

Section: Antibody Characterization and Immunohistochemistrymentioning

confidence: 99%

Novel insights into the glia limitans of the olfactory nervous system

Nazareth

Chen

Shelper

et al. 2019

J of Comparative Neurology

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Olfactory ensheathing cells (OECs) are often described as being present in both the peripheral and the central nervous systems (PNS and CNS). Furthermore, the olfactory nervous system glia limitans (the glial layer defining the PNS–CNS border) is considered unique as it consists of intermingling OECs and astrocytes. In contrast, the glia limitans of the rest of the nervous system consists solely of astrocytes which create a distinct barrier to Schwann cells (peripheral glia). The ability of OECs to interact with astrocytes is one reason why OECs are believed to be superior to Schwann cells for transplantation therapies to treat CNS injuries. We have used transgenic reporter mice in which glial cells express DsRed fluorescent protein to study the cellular constituents of the glia limitans. We found that the glia limitans layer of the olfactory nervous system is morphologically similar to elsewhere in the nervous system, with a similar low degree of intermingling between peripheral glia and astrocytes. We found that the astrocytic layer of the olfactory bulb is a distinct barrier to bacterial infection, suggesting that this layer constitutes the PNS–CNS immunological barrier. We also found that OECs interact with astrocytes in a similar fashion as Schwann cells in vitro. When cultured in three dimensions, however, there were subtle differences between OECs and Schwann cells in their interactions with astrocytes. We therefore suggest that glial fibrillary acidic protein–reactive astrocyte layer of the olfactory bulb constitutes the glia limitans of the olfactory nervous system and that OECs are primarily “PNS glia.”

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“…5 In contrast, in an outbred Quackenbush murine model, intranasal inoculation of Burkholderia pseudomallei led to rapid infection of branches of the trigeminal nerve after which the bacteria progressed directly to the brainstem and spinal cord within 48 hours after inoculation. 6 In these nerve infection routes, the bacterial infection resulted in the death of axons which created hollow nerve bundles through which the bacteria could travel.…”

mentioning

confidence: 99%

Burkholderia pseudomallei Rapidly Infects the Brain Stem and Spinal Cord via the Trigeminal Nerve after Intranasal Inoculation

Cited by 41 publications

References 38 publications

A Mouse Model Of Binge Alcohol Consumption andBurkholderiaInfection

A Mouse Model Of Binge Alcohol Consumption andBurkholderiaInfection

Novel insights into the glia limitans of the olfactory nervous system

Trojan horse L-selectin monocytes: A portal of Burkholderia pseudomallei entry into the brain

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