Peripheral Infection after Traumatic Brain Injury Augments Excitability in the Perilesional Cortex and Dentate Gyrus

Peripheral infections occur in up to 28% of patients with traumatic brain injury (TBI), which is a major etiology for structural epilepsies. We hypothesized that infection occurring after TBI acts as a “second hit” and facilitates post-traumatic epileptogenesis. Adult male Sprague–Dawley rats were subjected to lateral fluid-percussion injury or sham-operation. At 8 weeks post-injury, rats were treated with lipopolysaccharide (LPS, 5 mg/kg) to mimic Gram-negative peripheral infection. T2-weighted magnetic resonance imaging was used to detect the cortical lesion type (small focal inflammatory [TBIFI] vs. large cavity-forming [TBICF]). Spontaneous seizures were detected with video-electroencephalography, and seizure susceptibility was determined by the pentylenetetrazole (PTZ) test. Post-PTZ neuronal activation was assessed using c-Fos immunohistochemistry. LPS treatment increased the percentage of rats with PTZ-induced seizures among animals with TBIFI lesions (p < 0.05). It also increased the cumulative duration of PTZ-induced seizures (p < 0.01), particularly in the TBIFI group (p < 0.05). The number of c-Fos immunopositive cells was higher in the perilesional cortex of injured animals compared with sham-operated animals (p < 0.05), particularly in the TBI-LPS group (p < 0.05). LPS treatment increased the percentage of injured rats with bilateral c-Fos staining in the dentate gyrus (p < 0.05), particularly in the TBIFI group (p < 0.05). Our findings demonstrate that peripheral infection after TBI increases PTZ-induced seizure susceptibility and neuronal activation in the perilesional cortex and bilaterally in the dentate gyrus, particularly in animals with prolonged perilesional T2 enhancement. Our data suggest that treatment of infections and reduction of post-injury neuro-inflammation are important components of the treatment regimen aiming at preventing epileptogenesis after TBI.

Recent Advances on Possible Association Between the Periodontal Infection of Porphyromonas gingivalis and Central Nervous System Injury

Chronic periodontitis caused by Porphyromonas gingivalis (P. gingivalis) infection generally lasts for a lifetime. The long-term existence and development of P. gingivalis infection gradually aggravate the accumulation of inflammatory signals and toxic substances in the body. Recent evidence has revealed that P. gingivalis infection may be relevant to some central nervous system (CNS) diseases. The current work collects information and tries to explore the possible relationship between P. gingivalis infection and CNS diseases, including the interaction or pathways between peripheral infection and CNS injury, and the underlying neurotoxic mechanisms.

HIV Increases the Inhibitory Impact of Morphine and Antiretrovirals on Autophagy in Primary Human Macrophages: Contributions to Neuropathogenesis

HIV enters the CNS early after peripheral infection, establishing reservoirs in perivascular macrophages that contribute to development of HIV-associated neurocognitive disorders (HAND) in 15–40% of people with HIV (PWH) despite effective antiretroviral therapy (ART). Opioid use may contribute to dysregulated macrophage functions resulting in more severe neurocognitive symptoms in PWH taking opioids. Macroautophagy helps maintain quality control in long-lived cell types, such as macrophages, and has been shown to regulate, in part, some macrophage functions in the CNS that contribute to HAND. Using Western blotting and confocal immunofluorescence in primary human macrophages, we demonstrated that morphine and a commonly prescribed ART regimen induce bulk autophagy. Morphine and ART also inhibited completion of autophagy. HIV infection increased these inhibitory effects. We also examined two types of selective autophagy that degrade aggregated proteins (aggrephagy) and dysfunctional mitochondria (mitophagy). Morphine and ART inhibited selective autophagy mediated by p62 regardless of HIV infection, and morphine inhibited mitophagic flux in HIV-infected cells demonstrating potential mitotoxicity. These results indicate that inhibition of autophagy, both in bulk and selective, in CNS macrophages may mediate neurocognitive dysfunction in PWH using opioids. Increasing autophagic activity in the context of HIV may represent a novel therapeutic strategy for reducing HAND in these individuals.

Influenza causes alterations to oligodendrocyte-specific transcripts and the myelin lipidome in the adult mouse central nervous system.

The notion that myelin remains static during adulthood has been challenged in recent years. Myelin is not only crucial for proper cognitive function and behavior, but it is vulnerable to alterations from external factors outside the window of development. Here, in the adult mouse CNS, RNA analysis revealed global downregulation and subsequent recovery of oligodendrocyte-specific transcripts in response to peripheral influenza viral infection. Furthermore, shot-gun lipidomic analysis revealed that infection alters the lipid profile in the prefrontal cortex as well as in purified brain myelin. Finally, treatment with the colony stimulating factor receptor (CSFR)1 antagonist GW2580 during infection suppressed glial activation and partially restored oligodendrocyte-specific myelin transcripts to baseline levels. Together, these findings reveal a yet unforeseen consequence of peripheral infection on oligodendrocyte homeostasis in the adult mouse.

PATHOGENICITY OF TAIWAN FERRET BADGER RABIES VIRUS IN RODENTS

The outbreaks of Taiwan ferret badger rabies reported in 2013 terminated the “rabies-free” status of Taiwan. Subsequent phylogenetic and divergence analyses have demonstrated that Taiwan ferret badger rabies virus (RABV-TWFB) might have emerged 100 years previously; however, most rabies cases were restricted to the Formosan ferret badger. In this study, pathogenic characteristics of mouse intracranial median lethal dose (MICLD[Formula: see text], median tissue culture infectious dose (TCID[Formula: see text], mortality development patterns, and peripheral infection of RABV-TWFB were evaluated in experimental rodents. The results revealed that RABV-TWFB had low MICLD[Formula: see text] titers, whereas TCID[Formula: see text] titers could not be determined. Compared with the typical street rabies virus, the overall mortality development patterns were later onset and slower progression. RABV-TWFB was unable to produce peripheral infection in the experimental rodents. Taken together, RABV-TWFB was less virulent to experimental rodents than other more typical RABV strains. To provide more appropriate strategies for epidemics management, the pathogenic properties of RABV-TWFB should be further investigated using ferret badgers and sympatric animals as models.

Influenza infection triggers disease in a genetic model of experimental autoimmune encephalomyelitis

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system. Most MS patients experience periods of symptom exacerbation (relapses) followed by periods of partial recovery (remission). Interestingly, upper-respiratory viral infections increase the risk for relapse. Here, we used an autoimmune-prone T-cell receptor transgenic mouse (2D2) and a mouse-adapted human influenza virus to test the hypothesis that upper-respiratory viral infection can cause glial activation, promote immune cell trafficking to the CNS, and trigger disease. Specifically, we inoculated 2D2 mice with influenza A virus (Puerto Rico/8/34; PR8) and then monitored them for symptoms of inflammatory demyelination. Clinical and histological experimental autoimmune encephalomyelitis was observed in ∼29% of infected 2D2 mice. To further understand how peripheral infection could contribute to disease onset, we inoculated wild-type C57BL/6 mice and measured transcriptomic alterations occurring in the cerebellum and spinal cord and monitored immune cell surveillance of the CNS by flow cytometry. Infection caused temporal alterations in the transcriptome of both the cerebellum and spinal cord that was consistent with glial activation and increased T-cell, monocyte, and neutrophil trafficking to the brain at day 8 post infection. Finally,Cxcl5expression was up-regulated in the brains of influenza-infected mice and was elevated in cerebrospinal fluid of MS patients during relapse compared with specimens acquired during remission. Collectively, these data identify a mechanism by which peripheral infection may exacerbate MS as well as other neurological diseases.