Biology subjects

Sandoval, T. A.

Publications and source records attributed to Sandoval, T. A..

3 recordsLinked to original sources

bioRxiv2024

High-grade serous ovarian cancer development and anti-PD-1 resistance is driven by IRE1α activity in neutrophils

High-grade serous ovarian cancer (HGSOC) is an aggressive malignancy that remains refractory to current immunotherapies. While advanced stage disease has been extensively studied, the cellular and molecular mechanisms that promote early immune escape in HGSOC remain largely unexplored. Here we report that primary HGSO tumors program neutrophils to inhibit T cell anti-tumor function by activating the endoplasmic reticulum (ER) stress sensor IRE1. We found that intratumoral neutrophils exhibited overactivation of ER stress response markers compared with their counterparts at non-tumor sites. Selective deletion of IRE1 in neutrophils delayed primary ovarian tumor growth and extended the survival of mice with HGSOC by enabling early T cell-mediated tumor control. Notably, loss of IRE1 in neutrophils sensitized tumor-bearing mice to PD-1 blockade, inducing HGSOC regression and long-term survival in [~]50% of treated hosts. Hence, neutrophil-intrinsic IRE1 facilitates early adaptive immune escape in HGSOC and targeting this ER stress sensor might be used to unleash endogenous and immunotherapy-elicited immunity that controls metastatic disease.

immunology↗

bioRxiv2022

Inflammatory ER Stress Responses Dictate the Immunopathogenic Progression of Systemic Candidiasis

Recognition of pathogen-associated molecular patterns can trigger the IRE1 arm of the endoplasmic reticulum (ER) stress response in immune cells. IRE1 activation has been shown to maintain ER homeostasis while simultaneously coordinating diverse immunomodulatory programs in the setting of bacterial and viral infections. However, the role of IRE1 signaling in innate immune responses to fungal pathogens is unknown. Here we report that systemic infection with the fungus Candida albicans causes severe renal immunopathology by triggering inflammatory IRE1 hyperactivation in host myeloid cells. Mechanistically, sensing of fungal {beta}-glucans by the C-type lectin receptor Dectin-1 induced Src-Syk-NOX-dependent accumulation of intracellular reactive oxygen species and the ensuing generation of lipid peroxidation byproducts that sustained IRE1 activation. Selective deletion of IRE1 in leukocytes, or treatment with an IRE1 pharmacological inhibitor, reduced detrimental inflammatory responses in the kidney and extended survival in mice systemically infected with C. albicans. Hence, controlling IRE1 overactivation may be useful to impede the fatal immunopathogenic progression of disseminated candidiasis. One sentence summaryInnate IRE1 signaling in disseminated candidiasis

immunology↗

bioRxiv2019

The microbiomes of seven lichen genera reveal host specificity, a reduced core community and potential as source of antimicrobials

The High Andean Paramo ecosystem is a unique neotropical mountain biome considered a diversity and evolutionary hotspot. Lichens, which are complex symbiotic structures that contain diverse commensal microbial communities, are prevalent in Paramos. There they play vital roles in soil formation and mineral fixation. In this study we analyzed the microbiomes of seven lichen genera in two Colombian Paramos using 16S rRNA gene analyses and provide the first description of the bacterial communities associated with Cora and Hypotrachyna lichens. Paramo lichen microbiomes were diverse, and in some cases were distinguished based on the identity of the lichen host. The majority of the lichen-associated microorganisms were not present in all lichens sampled and could be considered transient or specialists. We also uncovered sixteen shared taxa that suggest a core lichen microbiome among this diverse group of lichens, broadening our concept of these symbiotic structures. Additionally, we identified strains producing compounds active against clinically relevant pathogens. These results indicate that lichen microbiomes from the Paramo ecosystem are diverse and host-specific but share a taxonomic core and can be a source of new bacterial taxa and antimicrobials.

microbiology↗