Biology subjects

Cordeiro, B.

Publications and source records attributed to Cordeiro, B..

3 recordsLinked to original sources

bioRxiv2025

Cigarette smoke exposure sets up a pro-inflammatory circuit in the lung that induces the hyper-activation of myelin-specific T helper cells

Cigarette smoke (CS) exposure increases the risk of multiple sclerosis; however, the mechanisms are unclear. To investigate this, we exposed C57BL6/J mice to CS or ambient air (AA) for 8 weeks using a protocol modelling human chronic CS exposure and studied the impact of these exposures on the development of experimental autoimmune encephalomyelitis (EAE). We found that CS increased the incidence of neurological signs in 2D2 myelin oligodendrocyte glycoprotein (MOG) T cell receptor transgenic mice, whereas in active EAE induced by MOG peptide and Complete Freunds adjuvant, CS delayed the onset of disease. In both cases, the effects of CS tended to be greater in the males who also developed greater leukocyte infiltration and expression of IL-12p40 and other cytokines. To gain insights into the paradoxical effects of CS in these EAE models, we transferred congenically-marked pMOG-reactive T helper cells into AA- or CS-exposed mice and examined the phenotype of these cells in the lungs, spleen, and spinal cord. We found that CS-exposed lungs acted as a sink for the pMOG-reactive T cells, in that more of these T cells homed to the lungs instead of the spinal cord. However, these CS-educated pMOG Th cells exhibited a hyperactivated Th phenotype with greater expression of activation markers, IL-17, and GM-CSF, a cytokine that is essential for EAE development. Intranasal treatment with anti-IL-12p40 negated these effects of CS on the expression of pro-inflammatory cytokines by pMOG Th cells. These studies suggest that CS sets up a pro-inflammatory circuit in the lung that amplifies the encephalitogenic properties of myelin-specific T effector cells. HighlightsO_LICS exposure enhances the development of spontaneous neuroimmunity. C_LIO_LIMyelin-reactive T helper 1 responses are enhanced by CS exposure. C_LIO_LICS-exposed lung attracts myelin-specific T helper cells to this site. C_LIO_LICS enhances myelin-specific Th1/Th17 cytokine production and GM-CSF through lung IL-12p40 C_LI

immunology↗

bioRxiv2024

A rewiring of the earliest immune events leading to T-cell mediated disease following intestinal infection in a PINK1KO mouse model of Parkinsons disease

Parkinsons disease (PD) is characterized by a protracted period of non-motor symptoms, including gastrointestinal (GI) dysfunction, which can precede the development of the cardinal motor deficits by decades. This long prodrome of disease is highly suggestive of immune cell involvement in the initiation of disease, but currently the field lacks robust model systems to study such mechanisms. It has been hypothesized that pathology may be first initiated in the periphery due to environmental triggers, such as pathogens that enter the GI tract. We further speculate that the impact of such pathogens on the immune system could be exacerbated in genetically predisposed individuals. Our group has developed a GI-targeted pathogen-induced PD mouse model system in PINK1 KO mice with Gram-negative bacterial infections and found that T cells are a major player in driving PD-like motor symptoms at late stages following infection. Herein, we now map the initiating immune events at the site of infection at the earliest stages with the goal of shedding light on the earliest mechanisms triggering immune-mediated pathological processes relevant to PD. Using unbiased single cell sequencing, we demonstrate that myeloid cells are the earliest dysregulated immune cell type in PINK1 KO infected mice at 1-week post-infection, followed by a dysregulated T cell response shortly after, at 2 weeks post-infection. We find that these myeloid cells have an enhanced proinflammatory profile, are more mature, and develop enhanced capacity for antigen presentation. Using unbiased prediction analysis, our data suggest that cytotoxic T cells and myeloid cells are particularly poised for interacting with each other, and we identify possible direct cell-cell interaction pathways that might be implicated. Taken together, deciphering the earliest immune mechanisms in the periphery underpinning PD autoimmunity will be instrumental in the development of effective therapeutic targeting strategies before irrevocable neuronal damage ensues.

immunology↗

bioRxiv2021

{-}{-} Histone H2B.V demarcates strategic regions in the Trypanosoma cruzi genome, associates with a bromodomain factor and affects parasite differentiation and host cell invasion

Histone variants play a crucial role in chromatin structure organization and gene expression. Trypanosomatids have an unusual H2B variant (H2B.V) that is known to dimerize with the variant H2A.Z generating unstable nucleosomes. Previously, we found that H2B.V protein is enriched in nonreplicative life forms of Trypanosoma cruzi, suggesting that this variant may contribute to the differences in chromatin structure and global transcription rates observed among parasite life forms. Here, we performed the first genome-wide profiling of histone localization in T. cruzi using replicative and nonreplicative life forms, and we found that H2B.V was preferentially located at the edges of divergent switch regions, which encompass putative transcriptional start regions; at some tDNA loci; and between the conserved and disrupted genome compartments, mainly at trans-sialidase, mucin and MASP genes. Remarkably, the chromatin of nonreplicative forms was depleted of H2B.V-enriched peaks in comparison to replicative forms. Interactome assays indicated that H2B.V associated specifically with H2A.Z, bromodomain factor 2, nucleolar proteins and a histone chaperone, among others. Parasites expressing reduced H2B.V levels were associated with higher rates of parasite differentiation and mammalian cell infectivity. Taken together, H2B.V demarcates critical genomic regions and associates with regulatory chromatin proteins, suggesting a scenario wherein local chromatin structures associated with parasite differentiation and invasion are regulated during the parasite life cycle. Author SummaryTrypanosomatids have to adapt to different environmental conditions, changing their morphology, gene expression and metabolism. These organisms have many unique features in terms of gene expression regulation. The genomic organization includes polycistronic regions with the absence of well-defined transcription start sites. In T. brucei, histone variants mark the start and ending sites of transcription; however, little is known about whether these proteins change their genome location, expression levels and interactors along life forms and what the impact is of these changes on parasite differentiation and infection. In T. cruzi, the causative agent of Chagas disease, we previously found that the histone variant of H2B is enriched in nonreplicative and infective forms, suggesting that this variant may contribute to the differences in chromatin structure and global transcription rates observed among these life forms. Here, we aimed to go one step further and performed the first histone ChIP-seq analysis in T. cruzi, in which we found that H2B.V was enriched at divergent strand switch regions, some tDNA loci and other critical genomic regions associated with T. cruzi genome compartments. We found that H2B.V interacts with a bromodomain factor, suggesting an intricate network involving chromatin acetylation around H2B.V enriched sites. Moreover, parasites expressing reduced H2B.V levels were associated with higher rates of differentiation and mammalian cell infectivity.

microbiology↗