Biology subjects

Brito, I.

Publications and source records attributed to Brito, I..

4 recordsLinked to original sources

bioRxiv2020

Organoid Polymer Functionality and Mode of Klebsiella Pneumoniae Membrane Antigen Presentation Regulates Ex Vivo Germinal Center Epigenetics in Young and Aged B Cells

Antibiotic-resistant bacteria are a major global health threat that continues to rise due to a lack of effective vaccines. Of concern are Klebsiella pneumoniae that fail to induce in vivo germinal center B cell responses, which facilitate antibody production to fight infection. Immunotherapies using antibodies targeting antibiotic-resistant bacteria are emerging as promising alternatives, however, cannot be efficiently derived ex vivo, necessitating the need for immune technologies to develop therapeutics. Here, four-arm PEG-organoids were developed to elucidate the effects of polymer end-point chemistry, integrin ligands, and mode of K. pneumoniae antigen presentation on germinal center-like B cell epigenetics, to better define the cell-microenvironment factors regulating ex vivo germinal center dynamics. Notably, PEG vinyl sulfone or acrylate failed to sustain primary immune cells, but functionalization with maleimide (PEG-4MAL) led to B cell expansion and germinal center-like induction. RNA sequencing analysis of lymph node stromal and germinal center B cells showed niche associated heterogeneity of integrin-related genes. Incorporation of niche-mimicking bioadhesive peptides revealed that collagen 1 mimicking peptides promoted germinal center-like dynamics and epigenetics. PEG-4MAL organoids elucidated the impact of K. pneumoniae membrane embedded protein antigen versus soluble antigen presentation on germinal center-like activation and preserved the response across young and aged mice.

immunology↗

bioRxiv2019

Host-microbiome protein-protein interactions capture mechanisms in human disease

Host-microbe interactions are crucial for normal physiological and immune system development and are implicated in a wide variety of diseases, including inflammatory bowel disease (IBD), colorectal cancer (CRC), obesity, and type 2 diabetes (T2D). Despite large-scale case-control studies aimed at identifying microbial taxa or specific genes involved in pathogeneses, the mechanisms linking them to disease have thus far remained elusive. To identify potential mechanisms through which human-associated bacteria impact host health, we leveraged publicly-available interspecies protein-protein interaction (PPI) data to find clusters of microbiome-derived proteins with high sequence identity to known human protein interactors. We observe differential targeting of putative human-interacting bacterial genes in metagenomic case-control microbiome studies. In nine independent case studies, we find evidence that the microbiome broadly targets human proteins involved in immune, oncogenic, apoptotic, and endocrine signaling pathways in relation to IBD, CRC, obesity and T2D diagnoses. This host-centric analysis strategy provides a mechanistic hypothesis-generating platform for any metagenomics cohort study and extensively adds human functional annotation to commensal bacterial proteins. One-sentence summaryMicrobiome-derived proteins are linked to disease-associated human pathways by metagenomic and protein-protein interaction analyses.

microbiology↗

bioRxiv2019

24-hour multi-omics analysis of residential sewage reflects human activity and informs public health

High-throughput molecular analysis of sewage is a promising tool for precision public health. Here, we combine sewer network and demographic data to identify a residential catchment for sampling, and explore the potential of applying untargeted genomics and metabolomics to sewage to collect actionable public health data. We find that wastewater sampled upstream in a residential catchment is representative of the human microbiome and metabolome, and we are able to identify glucuronidated compounds indicative of direct human excretion, which are typically degraded too quickly to be detected at treatment plants. We show that diurnal variations during 24-hour sampling can be leveraged to discriminate between biomarkers in sewage that are associated with human activity from those related to the environmental background. Finally, we putatively annotate a suite of human-associated metabolites, including pharmaceuticals, food metabolites, and biomarkers of human health and activity, suggesting that mining untargeted data derived from residential sewage can expand currently-used biomarkers with direct public health or policy relevance.

genomics↗

bioRxiv2019

Highly Multiplexed Spatial Mapping of Microbial Communities

Mapping the complex biogeography of microbial communities in situ with high taxonomic and spatial resolution poses a major challenge because of the high density and rich diversity of species in environmental microbiomes and the limitations of optical imaging technology. Here, we introduce High Phylogenetic Resolution microbiome mapping by Fluorescence In-Situ Hybridization (HiPR-FISH), a versatile and cost-effective technology that uses binary encoding and spectral imaging and machine learning based decoding to create micron-scale maps of the locations and identities of hundreds of microbial species in complex communities. We demonstrate the ability of 10-bit HiPR-FISH to distinguish 1023 E. coli strains, each fluorescently labeled with a unique binary barcode. HiPR-FISH, in conjunction with custom algorithms for automated probe design and segmentation of single-cells in the native context of tissues, reveals the intricate spatial architectures formed by bacteria in the human oral plaque microbiome and disruption of spatial networks in the mouse gut microbiome in response to antibiotic treatment. HiPR-FISH provides a framework for analyzing the spatial organization of microbial communities in tissues and the environment at single cell resolution.

microbiology↗