Biology subjects

Calvo, M.

Publications and source records attributed to Calvo, M..

8 recordsLinked to original sources

bioRxiv2026

Single-cell atlas of transcript usage remodelling in antiviral immune responses across human populations

Humans exhibit substantial interindividual variation in their immune responses to infection, yet the contribution of transcript usage --the relative abundance of gene isoforms-- to this variation remains poorly understood. Here, we generate the first single-cell atlas of transcript usage variation during early responses to influenza A virus and SARS-CoV-2 across 160 individuals of African and European ancestry. We show that viral stimulation induces widespread remodelling of transcript usage across all major immune lineages, with changes that are largely lineage-restricted and frequently undetected at the gene expression level. We further find that ancestry-associated effects on transcript usage are predominantly cell type-specific and contribute to population differences in antiviral responses. In addition, the genetic regulation of transcript usage during stimulation differs between influenza A and SARS-CoV-2, pointing to virus-dependent regulatory architectures. Together, our findings establish transcript usage as a dynamic regulatory layer shaping responses to viral infection across immune cell types and human populations, providing new insights into the molecular basis of variation in human antiviral immunity.

immunology↗

bioRxiv2025

ATG4D loss leads to late-onset cardiomyopathy and stress-induced heart failure in mice, and its repression marks maladaptive cardiac remodeling in humans

In the last years, autophagy has emerged as an essential pathway for most cellular functions. Basal autophagy plays a protective role as a quality control mechanism by which damaged or noxious cellular components are degraded and cellular organelles are periodically renewed. Moreover, autophagic activity can be increased in situations of cellular stress, including nutrient or growth factor deprivation, hypoxia, reactive oxygen species, DNA damage, or the presence of intracellular pathogens. Normally, induction of autophagy is protective, although in some circumstances, such as conditions of hemodynamic stress, autophagosome accumulation upon autophagy induction can be a maladaptive process. The deficiency of the autophagic protease ATG4D in mice leads to the accumulation of cellular autophagosomes in most tissues, including the heart. Here, we show that the increased autophagosome content of atg4d-/- mice is linked to the development of late-onset cardiomyopathy and to increased susceptibility to heart failure induced by transverse aortic constriction. Furthermore, we report the existence of human ATG4D variants associated with cardiovascular pathologies and also that ATG4D expression is reduced in human obstructive hypertrophic cardiomyopathy and dilated cardiomyopathy, which highlights a conserved cardio-protective role of the ATG4D protease.

pathology↗

bioRxiv2025

High-throughput cultivation and isolation of environmental anaerobes using selectively permeable hydrogel capsules

Over the past two decades, metagenomics has greatly expanded our understanding of microbial phylogenetic and metabolic diversity. However, most microbial taxa remain uncultured, hindering research and biotechnological applications. Isolating environmental anaerobes using traditional methods is particularly cumbersome and low throughput. Here, we present a novel, high-throughput approach for the cultivation and isolation of anaerobes, which involves trapping and growing single microbes within selectively permeable hydrogel capsules followed by fluorescence-activated cell sorting to distribute compartmentalized isolates into liquid medium for further growth. We show that diverse anaerobes can grow within capsules and that slower-growing ones (e.g. methanogens) can be enriched with this platform. We also applied this approach to isolate anaerobes from soil, including strains of the sulfate-reducing bacteria Desulfovibrio desulfuricans and Nitratidesulfovibrio vulgaris. Overall, this work introduces a robust, high-throughput alternative to traditional techniques for isolating environmental anaerobes and expands the emerging set of microfluidics-based tools for the cultivation of novel taxa.

microbiology↗

bioRxiv2024

Coordinated variation in the immune systems and microbiomes of healthy humans is linked to tonic interferon states

Human immune systems are highly variable, with most variation attributable to non-genetic sources. The gut microbiome crucially shapes the immune system; however, its relationship with the baseline immune states of healthy humans remains incompletely understood. Therefore, we performed multi-omic profiling of 110 healthy participants through the ImmunoMicrobiome study. A factor-based integrative approach identified coordinated variation, revealing that the tonic interferon response was amongst the most variable immune features in healthy participants. Microbiome composition, pathways, and stool metabolites varied concomitantly with interferon response pathways. Distinct transcriptional programs involving inflammation and TGF-{beta} in SIGLEC-1high monocytes and CD69high activated MAIT and NK cells were representative of these programs. Our study provides extensive data to examine the relationship between the immune states and microbiomes of healthy individuals at steady state, which paves the way for delineating inter-individual differences relevant for disease susceptibility and responses to therapy.

immunology↗

bioRxiv2024

Longitudinal transcriptional changes reveal genes from the natural killer cell-mediated cytotoxicity pathway as critical players underlying COVID-19 progression

Patients present a wide range of clinical severities in response SARS-CoV-2 infection, but the underlying molecular and cellular reasons why clinical outcomes vary so greatly within the population remains unknown. Here, we report that negative clinical outcomes in severely ill patients were associated with divergent RNA transcriptome profiles in peripheral immune cells compared with mild cases during the first weeks after disease onset. Protein-protein interaction analysis indicated that early-responding cytotoxic NK cells were associated with an effective clearance of the virus and a less severe outcome. This innate immune response was associated with the activation of select cytokine-cytokine receptor pathways and robust Th1/Th2 cell differentiation profiles. In contrast, severely ill patients exhibited a dysregulation between innate and adaptive responses affiliated with divergent Th1/Th2 profiles and negative outcomes. This knowledge forms the basis of clinical triage that may be used to preemptively detect high-risk patients before life-threatening outcomes ensue. Highlights- Mild COVID-19 patients displayed an early transcriptional commitment with NK cell function, whereas severe patients do so with neutrophil function. - The identified co-expressed genes give insights into a coordinated transcriptional program of NK cell cytotoxic activity being associated with mild patients. - Key checkpoints of NK cell cytotoxicity that were enriched in mild patients include: KLRD1, CD247, and IFNG. - The early innate immune response related to NK cells connects with the Th1/Th2 adaptive immune responses, supporting their relevance in COVID-19 progression.

immunology↗

bioRxiv2022

A fast non-parametric test of association for multiple traits

The increasing availability of multidimensional phenotypic data in large cohorts of genotyped individuals requires efficient methods to identify genetic effects on multiple traits. Permutational multivariate analysis of variance (PERMANOVA) offers a powerful non-parametric approach. However, it relies on permutations to assess significance, which hinders the analysis of large datasets. Here, we derive the limiting null distribution of the PERMANOVA test statistic, providing a framework for the fast computation of asymptotic p values. We show that the asymptotic test presents controlled type I error and high power, comparable to or higher than parametric approaches. We illustrate the applicability of our method in a number of use-cases. Using the GTEx cohort, we perform the first population-biased splicing QTL mapping study across multiple tissues. We identify thousands of genetic variants that affect alternative splicing differently depending on ethnicity, including potential disease markers. Using the UK Biobank cohort, we perform the largest GWAS to date of MRI-derived volumes of hippocampal subfields. Most of the identified loci have not been previously related to the hippocampus, but many are associated to cognition or brain disorders, thus contributing to understand the intermediate traits through which genetic variants impact complex organismal phenotypes.

bioinformatics↗

bioRxiv2021

Humoral immune responses against seasonal coronaviruses predict efficiency of SARS-CoV-2 spike targeting, FcγR activation, and corresponding COVID-19 disease severity

Despite SARS-CoV-2 being a "novel" coronavirus, several studies suggest that detection of anti-spike IgG early in infection may be attributable to the amplification of humoral memory responses against seasonal hCoVs in severe COVID-19 patients. In this study, we examined this concept by characterizing anti-spike IgG from a cohort of non-hospitalized convalescent individuals with a spectrum of COVID-19 severity. We observed that anti-spike IgG levels positively correlated with disease severity, higher IgG cross-reactivity against betacoronaviruses (SARS-CoV-1 and OC43), and higher levels of proinflammatory Fc gamma receptor 2a and 3a (Fc{gamma}R2a & Fc{gamma}R3a) activation. In examining the levels of IgG targeting betacoronavirus conserved and immunodominant epitopes versus disease severity, we observed a positive correlation with the levels of IgG targeting the conserved S2FP region, and an inverse correlation with two conserved epitopes around the heptad repeat (HR) 2 region. In comparing the levels of IgG targeting non-conserved epitopes, we observed that only one of three non-conserved immunodominant epitopes correlated with disease severity. Notably, the levels of IgG targeting the receptor binding domain (RBD) were inversely correlated with severity. Importantly, targeting of the RBD and HR2 regions have both been shown to mediate SARS-CoV-2 neutralization. These findings show that, aside from antibody (Ab) targeting of the RBD region, humoral memory responses against seasonal betacoronaviruses are potentially an important factor in dictating COVID-19 severity, with anti-HR2-dominant Ab profiles representing protective memory responses, while an anti-S2FP dominant Ab profiles indicate deleterious recall responses. Though these profiles are masked in whole antigen profiling, these analyses suggest that distinct Ab memory responses are detectable with epitope targeting analysis. These findings have important implications for predicting severity of SARS-CoV-2 infections (primary and reinfections), and may predict vaccine efficacy in subpopulations with different dominant antibody epitope profiles.

microbiology↗

bioRxiv2020

Identification and analysis of splicing quantitative trait loci across multiple tissues in the human genome

We have developed an efficient and reproducible pipeline for the discovery of genetic variants affecting splicing (sQTLs), based on an approach that captures the intrinsically multivariate nature of this phenomenon. We employed it to analyze the multi-tissue transcriptome GTEx dataset, generating a comprehensive catalogue of sQTLs in the human genome. A core set of these sQTLs is shared across multiple tissues. Downstream analyses of this catalogue contribute to the understanding of the mechanisms underlying splicing regulation. We found that sQTLs often target the global splicing pattern of genes, rather than individual splicing events. Many of them also affect gene expression, but not always of the same gene, potentially uncovering regulatory loci that act on different genes through different mechanisms. sQTLs tend to be preferentially located in introns that are post-transcriptionally spliced, which would act as hotspots for splicing regulation. While many variants affect splicing patterns by directly altering the sequence of splice sites, many more modify the binding of RNA-binding proteins (RBPs) to target sequences within the transcripts. Genetic variants affecting splicing can have a phenotypic impact comparable or even stronger than variants affecting expression, with those that alter RBP binding playing a prominent role in disease.

genomics↗