Biology subjects

Correia-Neves, M.

Publications and source records attributed to Correia-Neves, M..

6 recordsLinked to original sources

bioRxiv2026

PIM6 Induces Tolerance and Confers Protection against Mycobacterium tuberculosis in Primary Macrophages

Glycolipids are major components of the mycobacterial cell envelope and play critical roles in host-pathogen interactions. Here we investigate the capacity of the mycobacterial glycolipid phosphatidyl-myo-inositol hexamannosides (PIM6) to modulate innate responsiveness in naive primary human monocytes and monocyte-derived macrophages (MDMs). Monocytes and MDMs prestimulated with PIM6, followed by 5 days of rest, secreted attenuated levels of tumor necrosis factor alpha (TNF-), interleukin 6 (IL-6), and interleukin 10 (IL-10) following LPS challenge. PIM6 pretreatment significantly altered pattern recognition receptor expression through the experimental time course and programmed a tolerized phenotype in myeloid cells independent of TLR2 activity. In an infection challenge with H37Rv Mycobacterium tuberculosis (M.tb), MDMs pretreated with PIM6 secreted decreased levels of TNF- and IL-10 and exhibited early increased bacterial control. Together, these data reveal PIM6 as a complex immunomodulator that tolerizes myeloid cells to subsequent stimuli and exerts direct effects on the control of M.tb infection.

immunology↗

bioRxiv2024

IMMUNOPHENOTYPING AND FUNCTIONAL ANALYSIS OF NK CELL SUBSETS IN Mycobacterium tuberculosis-INFECTED INDIVIDUALS

Infection with Mycobacterium tuberculosis remains a global health challenge, with diverse clinical outcomes ranging from latent TB (LTB) infection to active TB disease (ATB). We conducted a comprehensive analysis of NK cell subsets and function in individuals with LTB, ATB, and healthy controls to elucidate their potential association with TB pathogenesis. Peripheral blood mononuclear cells (PBMCs) were isolated from Mtb-infected individuals and analyzed by mass cytometry and flow cytometry. We identified distinct NK cell subsets and evaluated their functional responses to stimulation. Our findings revealed comparable frequencies of total and NK cell subsets across LTB, ATB, and controls. Functional assays demonstrated similar degranulation, cytokine production, and proliferation capabilities among NK cell subsets across the three groups. This study provides insights into the heterogeneity of NK cell responses in TB and highlights the need for standardized methodologies with well-characterized cohorts controlling for donor background. Further investigations are warranted to delineate the specific roles of NK cells in TB immunity and pathogenesis.

immunology↗

bioRxiv2023

Distinct disease-modifying therapies are associated with different blood immune cell profiles in people with relapsing-remitting multiple sclerosis

Disease modifying therapies (DMTs) used for treating people with relapsing-remitting multiple sclerosis (pwRRMS) target the immune system by different mechanisms of action. However, there is a lack of a comprehensive comparison of their effects on the immune system. Herein, we evaluated the numbers of circulating B cells, CD4+ and CD8+ T cells, regulatory T cells (Tregs), natural killer (NK) cells and NKT cells, and their subsets, in pwRRMS who were treatment-naive or treated with different DMTs. Compared to treatment-naive pwRRMS, common and divergent effects on immune system cells were observed on pwRRMS treated with different DMTs, with no consistent pattern across all therapies in any of the cell populations analysed. PwRRMS treated with fingolimod, dimethyl fumarate (DMF), or alemtuzumab have reduced numbers of CD4+ and CD8+ T cells, as well as Treg subsets, with fingolimod causing the most pronounced decrease in T cell subsets. In contrast, teriflunomide and interferon (IFN) {beta} have minimal impact on T cells, and natalizumab marginally increases the number of memory T cells in the blood. The effect of DMTs on the B cell, NKT and NK cell subsets is highly variable with alemtuzumab inducing a strong increase in the number of the most immature NK cells and its subsets. This study highlights the absence of a consistent pattern of the impact of various DMTs on immune system cells, with variations in both direction and magnitude of effect thus reenforcing the notion that distinct immune cell subsets are potential players in MS pathophysiology and/or DMT efficacy.

immunology↗

bioRxiv2022

Low memory T cells blood counts and high naive regulatory T cells percentage at relapsing remitting multiple sclerosis diagnosis

ObjectiveTo assess the peripheral immune system of newly diagnosed relapsing remitting multiple sclerosis (RRMS) patients and compare it to healthy controls (HC). MethodsCross-sectional study with 30 treatment-naive newly diagnosed RRMS patients, and 33 sex and age-matched HC. Their peripheral blood mononuclear cells were analysed regarding: i) thymic function surrogates [T cell receptor excision circles (TRECs) and recent thymic emigrants (RTEs)]; ii) naive and memory CD4+ and CD8+ T cells subsets; iii) T helper (Th) phenotype and chemokine receptors expression on T cells subsets; iv) regulatory T cell (Tregs) phenotype; and vi) expression of activating/inhibitory receptors by natural killer (NK) and NKT cells. Analyses were controlled for age, sex, and human cytomegalovirus (HCMV) IgG seroprevalence. ResultsNewly diagnosed RRMS patients and HC have equivalent thymic function as determined by similar numbers of RTEs, and levels of sjTRECs, DJ{beta}TRECs and sj/DJ{beta}TREC ratio. In the CD8+ T cells compartment RRMS patients have a higher naive/memory ratio and lower memory cell counts in blood, specifically of effector memory and TemRA CD8+ T cells. Among CD4+ T cells lower blood counts of effector memory cells are found in patients upon controlling for sex, age and HCMV IgG seroprevalence. RRMS patients have higher percentage of naive Tregs comparing to HC. Percentages of immature CD56bright NK cells expressing the inhibitory receptor KLRG1, and of mature CD56dimCD57+ NK cells expressing NKp30 are higher in patients. No major alterations are observed on NKT cells. MS severity and time from relapse correlate with immune cells alterations. ConclusionCharacterization of the peripheral immune system of treatment-naive newly diagnosed RRMS patients unveiled immune features present at clinical onset including lower memory T cells blood counts, particularly among CD8+ T cells, higher percentage of naive Tregs and altered percentages of NK cells subsets expressing inhibitory or activating receptors. These findings might set the basis to better understand disease pathogenesis.

immunology↗

bioRxiv2021

Stimulation with mycobacterial glycolipids and PPD reveals different innate immune response profiles in active and latent TB

Upon infection with Mycobacterium tuberculosis (Mtb) the host immune response might clear the bacteria, control its growth leading to latent tuberculosis (LTB), or fail to control its growth resulting in active TB (ATB). There is however no clear understanding of the features underlying a more or less effective response. Mtb glycolipids are abundant in the bacterial cell envelope and modulate the immune response to Mtb, but the patterns of response to glycolipids are still underexplored. To identify the CD45+ leukocyte activation landscape induced by Mtb glycolipids in peripheral blood of ATB and LTB, we performed a detailed assessment of the immune response of PBMCs to the Mtb glycolipids lipoarabinomannan (LAM) and its biosynthetic precursor phosphatidyl-inositol mannoside (PIM), and PPD. At 24 h and 5 days of stimulation, cell profiling and secretome analysis was done using mass cytometry and high-multiplex immunoassay. PIM mainly affected antigen-presenting cells to produce both proinflammatory (IL-2, IL-6, IL-17A, TNF- and GM-CSF), and IL-4 and IL-10 cytokines, but not IFN-{gamma}. LAM triggered a similar, albeit weaker, response. By contrast, PPD induced an increase in IFN-{gamma}-producing cells. Moreover, PPD also led to increased numbers of IL-2, IL-6, IL-10, IL-17A, TNF- and GrzB-producing cells. Treatment with an anti-TLR2 antibody led to partial inhibition of PIM-induced IL-6 production in myeloid cells, suggesting that PIM induces IL-6 production through TLR2. Expansion of monocyte subsets in response to PIM or LAM was reduced in both ATB and LTB as compared to healthy controls, suggesting a hyporesponsive/tolerance pattern in Mtb-infected individuals.

immunology↗

bioRxiv2021

IFNγ and iNOS-mediated alterations in the bone marrow and thymus and its impact on Mycobacterium avium-induced thymic atrophy

Disseminated infection with the high virulence strain of Mycobacterium avium 25291 lead to progressive thymic atrophy. We previously uncovered that M. avium-induced thymic atrophy is due to increased levels of glucocorticoids synergizing with nitric oxide (NO) produced by interferon gamma (IFN{gamma}) activated macrophages. Where and how these mediators are playing, was yet to be understood. We hypothesized that IFN{gamma} and NO might be affecting bone marrow (BM) T cell precursors and/or T cell differentiation in the thymus. We show that M. avium infection causes a reduction on the percentage of lymphoid-primed multipotent progenitors (LMPP) and common lymphoid progenitors (CLP). Additionally, BM precursors from infected mice are unable to reconstitute thymi of RAGKO mice in an IFN{gamma}-dependent way. Thymi from infected mice presents a NO-dependent inflammation. When transplanted under the kidney capsule of non-infected mice, thymic stroma from infected mice is unable to sustain T cell differentiation. Finally, we observed increased thymocyte death via apoptosis after infection, independent of both IFN{gamma} and iNOS, and a decrease on activated caspase-3 positive thymocytes, that was not observed in the absence of iNOS expression. Together our data suggests that M. avium-induced thymic atrophy results from a combination of impairments, mediated by IFN{gamma} and NO, affecting different steps of T cell differentiation from T cell precursor cells in the BM to the thymic stroma and thymocytes.

immunology↗