Aerosol-induced brucellosis increases TLR-2 expression and increased complexity in the microanatomy of astroglia in rhesus macaques

Abstract

Brucella melitensis, a bacterial pathogen and agent of epizootic abortion causes multiple pathologies in humans as well as a number of agriculturally important animal species. Clinical human brucellosis manifests as a non-specific, chronic debilitating disease characterized by undulant fever, arthropathies, cardiomyopathies and neurological sequelae. These symptoms can occur acutely for a few weeks or persist for months to years. Within the brain, endothelial and glial cells can be infected leading to downstream activation events including matrix metalloprotease (MMP) and cytokine secretion and Toll-like receptor (TLR) signaling. These events are likely to lead to tissue remodeling, including morphologic changes in neuronal and glial cells, which are linked to neurological complications including depressive behavior, immune activation and memory loss. Our hypothesis was that B. melitensis infection and neurobrucellosis would lead to activation of astrocytes through upregulation of TLR2 and stimulate concurrent changes in the microanatomy. All six animals were infected via inhalation route. TLR2 expression was approximately doubled in white matter astrocytes of infected rhesus macaques. There was also a 50% increase in the number of astrocytes per unit area in subcortical white matter tracts suggesting increased innate immune activation. This coincided with dramatic increases in the length and complexity of the cell arbor of hypertrophic astrocytes in both cortical gray and white matter. Thus, aerosol-induced brucellosis results in dramatically increased innate immune activation of astrocytes in the absence of widespread neuroinflammation.

Neuropathogenesis of Chikungunya infection: astrogliosis and innate immune activation

“…We have previously shown increased levels of TLR2 on astrocytes following activation in bacterial, lentiviral or behavioral diseases [17,20,19]. As we anticipated infection of the CNS with Chikungunya [24,11,2,4], we attempted to determine cell types activated.…”

“…We performed an established protocol for astrocyte morphometric analyses [16,32,17,25,20,19]. All samples were coded and analyzed randomly by a researcher blinded to animal number and condition.…”

LAG3 Expression in Active Mycobacterium tuberculosis Infections

“…15 Animals with acute brucellosis were infected with Brucella melitensis via aerosol with between 8.5 Â 10 5 and 1.3 Â 10 6 CFUs, as previously described. 30 Animals infected with SIV alone were administered the virus i.v. with 100 animal infectious dose.…”

New advances on glial activation in health and disease

“…In the same way that neuronal dendrites are adaptable and respond to changes in CNS activity by altering their structure, astrocytic processes dynamically alter their morphology and interact with synapses in response to their environment [75] . Morphological changes in astrocytes have been documented in chronic stress [76] , traumatic brain injury [77] , neurodegenerative disease [78] , CNS viral and bacterial infections [79,80] , and behavioral and mood disorders [81,82] . Experimentally, changes in astrocyte morphology have been reported after ethanol administration [83] , dietary-induced obesity [84] , and physical exercise [85] .…”

“…Experimentally, astrocytes activated by heat-killed bacteria or lipoproteins react by secreting chemokines, proliferate, or enter apoptosis [140] . For instance, astrocyte infection by Brucella has been shown to induce MMPs, which are known to induce tissue remodeling [80,141] . In cultured astrocytes, viral mimic poly(I:C) induces the expression of several cytokines (TNF-α, IL-6, IFNβ, granulocytemacrophage colony-stimulating factor and transforming growth factor) and chemokines (CCL2, CCL5, CCL20, CXCL8 and CXCL10) [142] .…”