Biology subjects

Teixeira, A. L.

Publications and source records attributed to Teixeira, A. L..

4 recordsLinked to original sources

bioRxiv2024

PI3Kγ pathway contributes to neuroinflammation and neuronal death induced by Zika virus infection

Zika virus (ZIKV) is an emerging arbovirus belonging to the Flaviviridae family and Orthoflavivirus genus, with a pronounced tropism for the central nervous system (CNS), where it induces neuroinflammation and neuronal death. ZIKV is known to exploit host cellular mechanisms, including the activation of survival pathways such as the PI3K/AKT signaling cascade, to evade apoptosis and enhance its replication. The phosphatidylinositol 3-kinase {gamma} (PI3K{gamma}) pathway regulates critical cellular processes, including differentiation, recruitment, and survival, and is abundantly expressed in both brain tissue and leukocytes. This study aimed to investigate the role of the PI3K{gamma} pathway during ZIKV infection. Primary neuronal cultures from PI3K{gamma}-deficient mice (PI3K{gamma}kd/kd) and human neuroblastoma SH-SY5Y cells treated with the PI3K{gamma} inhibitor AS605240 were infected with ZIKV to assess the impact of PI3K{gamma} signaling on viral replication and neuronal survival. Additionally, interferon /{beta} receptor knockout (A129) mice were treated with AS605240 either before or after ZIKV infection to evaluate the pathways role in neuroinflammation. In vitro, both genetic ablation and pharmacological inhibition of PI3K{gamma} suppressed ZIKV replication and prevented neuronal death. In vivo, mice treated with the PI3K{gamma} inhibitor exhibited enhanced protection against ZIKV infection, characterized by reduced viral load, and diminished brain and optic nerve damage. This neuroprotective effect correlated with altered astrocyte and microglia activation, marked by reduced TNF production in microglia. Furthermore, inhibition of PI3K{gamma} curtailed the recruitment and activation of CD8+ T cells and decreased the production of pro-inflammatory mediators, including IFN-{gamma} and IL-17, in the brains of ZIKV-infected mice. These findings suggest that PI3K{gamma} activation facilitates ZIKV infection and exacerbates neuroinflammation. Pharmacological inhibition of the PI3K{gamma} pathway may offer therapeutic benefits by limiting viral replication and alleviating neuroinflammatory responses during ZIKV infection.

immunology↗

bioRxiv2024

Neuropsychiatric sequelae in an experimental model of post-COVID syndrome in mice

The global impact of the COVID-19 pandemic has been unprecedented, and presently, the world is facing a new challenge known as Post-COVID syndrome (PCS). Current estimates suggest that more than 65 million people are grappling with PCS, encompassing several manifestations, including pulmonary, musculoskeletal, metabolic, and neuropsychiatric sequelae (cognitive and behavioral). The mechanisms underlying PCS remain unclear. The present study aimed to: (i) comprehensively characterize the acute effects of pulmonary inoculation of the betacoronavirus MHV-A59 in immunocompetent mice at clinical, cellular, and molecular levels; (ii) examine potential acute and long-term pulmonary, musculoskeletal, and neuropsychiatric sequelae induced by the betacoronavirus MHV-A59; and to (iii) assess sex-specific differences. Male and female C57Bl/6 mice were initially inoculated with varying viral titers (3x103 to 3x105 PFU/30 L) of the betacoronavirus MHV-A59 via the intranasal route to define the highest inoculum capable of inducing disease without causing mortality. Further experiments were conducted with the 3x104 PFU inoculum. Mice exhibited an altered neutrophil/lymphocyte ratio in the blood in the 2nd and 5th day post-infection (dpi). Marked lung lesions were characterized by hyperplasia of the alveolar walls, infiltration of polymorphonuclear leukocytes (PMN) and mononuclear leukocytes, hemorrhage, increased concentrations of CCL2, CCL3, CCL5, and CXCL1 chemokines, as well as high viral titers until the 5th dpi. While these lung inflammatory signs resolved, other manifestations were observed up to the 60 dpi, including mild brain lesions with gliosis and hyperemic blood vessels, neuromuscular dysfunctions, anhedonic-like behavior, deficits in spatial working memory, and short-term aversive memory. These musculoskeletal and neuropsychiatric complications were exclusive to female mice and were prevented after ovariectomy. In summary, our study describes for the first time a novel sex-dependent model of PCS focused on neuropsychiatric and musculoskeletal disorders. This model provides a unique platform for future investigations regarding the effects of acute therapeutic interventions on the long-term sequelae unleashed by betacoronavirus infection.

neuroscience↗

bioRxiv2022

MicroRNA-mRNA networks are dysregulated in opioid use disorder postmortem brain: further evidence for opioid-induced neurovascular alterations

To understand mechanisms and identify potential targets for intervention in the current crisis of opioid use disorder (OUD), postmortem brains represent an under-utilized resource. To refine previously reported gene signatures of neurobiological alterations in OUD from the dorsolateral prefrontal cortex (Brodmann Area 9, BA9), we explored the role of microRNAs (miRNA) as powerful epigenetic regulators of gene function. Building on the growing appreciation that miRNAs can cross the blood-brain barrier, we carried out miRNA profiling in same-subject postmortem samples from BA9 and blood tissues. miRNA-mRNA network analysis showed that even though miRNAs identified in BA9 and blood were fairly distinct, their target genes and corresponding enriched pathways were highly overlapping, with tube development and morphogenesis, and pathways related to endothelial cell function and vascular organization, among the dominant enriched biological processes. These findings point to robust, redundant, and systemic opioid-induced miRNA dysregulation with potential functional impact on transcriptomic changes. Further, using correlation network analysis we identified cell-type specific miRNA targets, specifically in astrocytes, neurons, and endothelial cells, associated with OUD transcriptomic dysregulation. Our refined miRNA-mRNA networks enabled identification of novel pharmaco-chemical interventions for OUD, particularly targeting the TGF beta-p38MAPK signaling pathway. Finally, leveraging a collection of control brain transcriptomes from the Genotype-Tissue Expression (GTEx) project, we identified correlation of OUD miRNA targets with TGF beta, hypoxia, angiogenesis, coagulation, immune system and inflammatory pathways. These findings support previous reports of neurovascular and immune system alterations as a consequence of opioid abuse.

bioinformatics↗

bioRxiv2018

Oral microbial dysbiosis linked to worsened periodontal condition in rheumatoid arthritis patients

Rheumatoid arthritis (RA) is an autoimmune disorder associated with increased periodontal destruction. It is thought that RA increases the risk of periodontal disease; it is not known how it influences the oral microbiota. Our aim was to analyze the impact of RA on subgingival microbiota and its association with periodontal inflammation and RA activity. Forty-two patients with RA were compared to 47 control subjects without RA. Patients were screened for probing depth, clinical attachment level, bleeding on probing and classified as with or without periodontitis. Subgingival plaque was examined by Illumina MiSeq Sequencing of 16S rRNA gene V4 region and inflammatory cytokines were measured in saliva. RA was associated to severe periodontal disease. In addition, the severity of RA, reflected by the number of tender and swollen joints, was significantly correlated with the presence of pathogenic oral bacteria (i.e. Fusobacterium nucleatum and Treponema socransky). Non-periodontitis RA patients compared to healthy controls had increased microbial diversity and bacterial load, higher levels of pathogenic species (Prevotella, Selenomonas, Anaeroglobus geminatus, Parvimonas micra, Aggregatibacter actinomycetemcomitans) and reduction of health-related species (Streptococcus, Rothia aeria, Kingela oralis). Genes involved with bacterial virulence (i.e. lipopolysaccharide biosynthesis, peptidases) were more prevalent in the subgingival metagenome of subjects with RA. In addition, the degree of oral inflammation reflected by IL-2, IL-6, TNF-, IFN-{gamma} salivary levels was increased in non-periodontitis RA patients in comparison with controls. Our findings support the hypothesis that RA triggers dysbiosis of subgingival microbiota, which may contribute to worsening periodontal status.\n\nAuthor SummaryRheumatoid arthritis (RA) is an autoimmune disease characterized by joints inflammation, swelling, pain and stiffness. Exactly what starts this disease is still unclear. Some recent studies have suggested mucosal surfaces in the body, like those in the gums, could affect the disease process. It has been observed that people with RA have higher risk of periodontitis (a bacterial inflammatory disease of the gums), compared with the general population, and this may be the start of the autoimmune process. Also, periodontitis increases the severity of RA while interventions by treating periodontitis can improve the symptoms of RA. One of the possible mechanisms that link the higher prevalence of periodontitis in RA patients is the dysbiosis of the oral microbiota triggered by the chronic inflammation in RA. Increased levels of molecules of inflammation may affect the oral environment and change the type of bacteria that live there. Here, we examined RA patients and healthy subjects, screening their oral health and inflammatory markers. We collected their saliva and the dental plaque from the space between the teeth and the gum. We found that RA patients exhibited severe periodontitis, increased levels of inflammatory mediators on their saliva and distinct bacterial communities, with higher proportions of bacteria species linked to periodontal disease, even in patients without periodontitis. We also found that the presence of these bacteria species was linked to worse RA conditions. Our study provides new insights to understand the bi-directional mechanisms linking periodontal disease to the development of RA, showing that we need to pay attention to the oral cavity in patients with RA and refer people for dental evaluation. This practice might have a positive impact in the course of RA.

microbiology↗