Biology subjects

Graca, L.

Publications and source records attributed to Graca, L..

4 recordsLinked to original sources

bioRxiv2026

Age-dependent disease tolerance to SARS-CoV-2 infection

Disease tolerance limits infectious disease severity through tissue damage control mechanisms that do not target pathogens directly. Here we demonstrate that age-dependent decline in adipose tissue lipolysis compromises disease tolerance to SARS-CoV-2 infection. Young adult mice exhibited robust adipocyte lipolysis and 80% survival, whereas old mice showed impaired adipocyte lipolysis and only 20% survival. Genetic repression of adipocyte lipolysis eliminated this age-dependent survival advantage without affecting viral titers, revealing that adipocyte lipolysis is essential for disease tolerance to SARS-CoV-2 in young adults. Impaired adipocyte lipolysis in aged mice was associated with a plasma lipidomic signature that predicts COVID-19 severity and mortality in three independent human cohorts. Mechanistically, adipocyte lipolysis provides free fatty acids (FFA) to support bone marrow emergency myelopoiesis, through CD36- and CPT1-dependent FFA cellular uptake and mitochondrial import, respectively. Bone marrow derived monocytes migrate to the lung via CCL2/CCR2-dependent mechanism where they enforce an immune-metabolic communication network with parenchymal cells to sustain lung structure and function. This circuit is not required to confer protection against influenza infection, revealing pathogen-specific disease tolerance mechanisms. These findings reveal adipose tissue catabolism as a central age-dependent factor responsible for exacerbated COVID-19 mortality in aged populations. One-Sentence SummarySARS-CoV-2 infection induces adipose tissue lipolysis to release fatty acids that drive myelopoiesis and monocyte production for lung protection and COVID-19 disease tolerance, but this protective circuit declines with age, increasing disease severity in the elderly.

immunology↗

bioRxiv2025

Common origin for effector and regulatory Follicular and Tissue-Adapted CD4+ T cells in Non-Small Cell Lung Cancer

Tumor-invaded lymph nodes (LNs) serve as critical hubs for anti-tumor immunity, yet their role in orchestrating immune responses remains poorly understood. Using integrated single-cell RNA sequencing, T cell receptor sequencing, and chromatin accessibility profiling, we analyzed CD4+ T cells from matched blood, tumor-invaded LNs, and tumors of treatment-naive non-small cell lung cancer patients. We identified distinct immunological landscapes across these compartments. Compared to blood, tumor-invaded LNs and tumors were enriched for follicular regulatory T cells (Treg-Tfr), conventional T cell subsets with Tfh-like characteristics (Tconv-Tfh and Tconv-CXCL13), and tissue-resident memory Tregs (Treg-Trm). These populations share a BATF-dependent transcriptional program that governs T-cell activation and tissue adaptation, while simultaneously engaging distinct, subset-specific regulatory networks. Integrative TCR-RNA analysis revealed that tumor-reactive, neoantigen-specific T cell clones were enriched within these subsets and demonstrated extensive LN-tumor clonal sharing, indicating active recirculation between compartments. Through clonal coupling analysis and trajectory inference, we uncovered that Treg-Tfr cells function as multipotent progenitors that bifurcate into tissue-resident Treg-Trm or into ex-Tregs adopting a Tfh-like CXCL13+ ewector phenotype. Remarkably, follicular CD4+ T subsets from LNs and tumor were transcriptionally and epigenetically similar and localized to analogous germinal center niches. These findings establish tumor-invaded LNs as functional extensions of the tumor microenvironment that generate and maintain tumor-reactive CD4+ lineages. The identification of tissue-resident Treg-Tfr plasticity reveals a critical developmental checkpoint that could be therapeutically targeted to redirect immunosuppressive programs toward anti-tumor ewector responses.

immunology↗

bioRxiv2025

Transferrin Receptor 1-targeted polymersomes therapy for Colorectal Cancer

Colorectal cancer (CRC) is a major global health concern, ranking among the most common cancers and the second leading cause of cancer-related deaths. The high mortality associated with CRC is attributed mainly to difficulties in early detection and the lack of effective targeted therapies. The Transferrin receptor 1 (TfR1) is particularly attractive as a therapy target given its notable overexpression in tumor cells, particularly in CRC. This study explored the potential of a polymeric nanoparticle (POs)-based drug delivery system targeting TfR1 to improve the precision and efficacy of CRC treatment. For this study, we used three human colorectal cancer cell lines (SW480, HT-29, and HCT116), a healthy human intestinal epithelial cell line (hIECs), and a murine CRC cell line (MC38). We first engineered POs composed of poly (ethylene glycol) (PEG) and poly (lactic acid) (PLA), functionalized with the T7 peptide to enhance their specificity for TfR1-expressing cells. Targeting efficiency of these POs was assessed across all cell lines by evaluating the cellular uptake using flow cytometry. Upon establishing the optimal formulation for these NPs for TfR1-targeting, we encapsulated doxorubicin (DOX) to evaluate their therapeutic potential. Both in vitro and in vivo studies were performed to assess the efficacy of these DOX-loaded TfR1-targeted POs. In vitro studies demonstrated selective delivery of DOX to CRC cells, suggesting a marked reduction in off-target effects. In vivo studies in a murine model of CRC further supported these findings, showing that DOX-loaded TfR1-targeted POs significantly improved survival rates and reduced tumor growth compared to free DOX or PBS treatments. These results highlight the promise of TfR1-targeted POs as a precise strategy for CRC therapy, offering enhanced treatment efficacy while reducing systemic toxicity. This novel approach could lead to the development of more targeted and less harmful cancer treatments. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=76 SRC="FIGDIR/small/639871v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1714603org.highwire.dtl.DTLVardef@1ab7f15org.highwire.dtl.DTLVardef@245f6eorg.highwire.dtl.DTLVardef@1f56f75_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIT-7 peptide-functionalized polymersomes exhibit high binding affinity to CRC cell lines C_LIO_LIDoxorubicin-loaded T7-peptide polymersomes effectively suppress tumor growth and prolong survival in vivo C_LIO_LITargeted Doxorubicin delivery via T7-peptide polymersomes minimizes toxicity to healthy tissues C_LI

cancer biology↗

bioRxiv2022

Specialized Tfh cell subsets driving type-1 and type-2 humoral responses in lymphoid tissue

Effective antibody responses are essential to generate protective humoral immunity. Different inflammatory signals polarize T cells towards an appropriate effector phenotype during an infection or immunization. Th1 and Th2 cells have been associated with the polarization of humoral responses for several decades. However, it is now established that T follicular helper cells (Tfh) have a unique ability to access the B cell follicle and support the Germinal Centre (GCs) responses by providing help to B cells. We investigated the specialization of Tfh cells induced under type-1 and type-2 conditions. We first studied homogenous Tfh cell populations generated by adoptively transferred TCR-transgenic T cells in mice immunized with type-1 and type-2 adjuvants. Using a machine learning approach, we established a gene expression signature that discriminates Tfh cells polarized towards type-1 and type-2 response, defined as Tfh1 and Tfh2 cells. The Tfh1 and Tfh2 distinct signature was validated against datasets of Tfh cells induced following LCMV or helminth infection. Using single-cell transcriptomics, we also dissected the heterogeneity of Tfh cells from the two immunizing conditions. Our results show that Tfh cells acquire a specialized function under distinct types of immune responses, but with the coexistence of a small population of Tfh cells of the alternative type. Furthermore, the specific molecular hallmarks of Tfh1 and Tfh2 cells identified herein offer putative new targets for tuning humoral responses.

immunology↗