Biology subjects

Duran, V.

Publications and source records attributed to Duran, V..

5 recordsLinked to original sources

bioRxiv2023

Systems immunology of transcriptional responses to viral infection identifies conserved antiviral pathways across macaques and humans

Viral pandemics and epidemics pose a significant global threat, with emerging and re-emerging viruses responsible for four pandemics in the 21st century alone. While macaques have been utilized as a model for understanding viral disease in a controlled setting, it remains unclear how conserved the antiviral responses to diverse viruses are between macaques and humans. To address this critical knowledge gap, we conducted a comprehensive cross-species analysis of transcriptomic data from over 6000 blood samples from macaques and humans infected with one of 31 viruses, including Lassa, Ebola, Marburg, Zika, and dengue. Our findings demonstrate that irrespective of primate or viral species, there are conserved antiviral responses which are consistent regardless of infection phase (acute, chronic, or latent) and viral genome type (DNA or RNA viruses). Moreover, by leveraging longitudinal data from experimental challenges, we identified virus-specific response dynamics such as host responses to Coronaviridae and Orthomyxoviridae infections peaking 1-3 days earlier than responses to Filoviridae and Arenaviridae viral infections. Additionally, through comparative analysis of immune responses across viruses, we identified a unique enrichment of lymphoid cellular response modules in macaque Flaviviridae infection that persists in human responses to dengue. Our results underscore macaque studies as a powerful tool for gaining new insights into viral pathogenesis and immune responses that translate to humans, which can inform viral therapeutic development and enable pandemic preparedness. One sentence summaryUsing longitudinal macaque viral challenge studies, we identified shared and virus-specific responses to infection that replicate in human viral disease - thereby demonstrating the utility of macaque models of viral infection to understand antiviral biology and for pandemic preparedness.

immunology↗

bioRxiv2023

Single B cell transcriptomics identifies multiple isotypes of broadly neutralizing antibodies against flaviviruses

Sequential dengue virus (DENV) infections often generate neutralizing antibodies against all four DENV serotypes and sometimes, Zika virus. Characterizing cross-flavivirus broadly neutralizing antibody (bnAb) responses can inform countermeasure strategies that avoid infection enhancement associated with non-neutralizing antibodies. Here, we used single cell transcriptomics to mine the bnAb repertoire following secondary DENV infection. We identified several new bnAbs with comparable or superior breadth and potency to known bnAbs, and with distinct recognition determinants. Unlike all known flavivirus bnAbs, which are IgG1, one newly identified cross-flavivirus bnAb (F25.S02) was derived from IgA1. Both IgG1 and IgA1 versions of F25.S02 and known bnAbs displayed neutralizing activity, but only IgG1 enhanced infection in monocytes expressing IgG and IgA Fc receptors. Moreover, IgG-mediated enhancement of infection was inhibited by IgA1 versions of bnAbs. We demonstrate a role for IgA in flavivirus infection and immunity with implications for vaccine and therapeutic strategies.

microbiology↗

bioRxiv2022

Global and cell type-specific immunological hallmarks of severe dengue progression

Severe dengue (SD) is a major cause of morbidity and mortality impacting approximately 5 million of the 400 million people infected with dengue virus (DENV) annually. To define DENV target cells and immunological hallmarks of SD progression in childrens blood, we integrated virus-inclusive single cell RNA-Seq 2 (viscRNA-Seq 2) with functional assays. Beyond myeloid cells, in natural infection, B cells harbor replicating DENV capable of infecting permissive cells. Alterations in cell type abundance, gene and protein expression and secretion, and cell-cell communications point towards increased migration and inflammation in SD progressors (SDp). Concurrently, antigen presenting cells from SDp demonstrate intact uptake, yet impaired interferon responses and antigen presentation, in part DENV-modulated. Increased activation, regulation, and exhaustion of effector responses and expansion of HLA-DR-expressing, possibly compensatory, adaptive-like NK cells also characterize SDp. These findings reveal DENV target cells in the human blood and provide insight into SD pathogenesis beyond antibody-mediated enhancement.

immunology↗

bioRxiv2022

Magnitude and kinetics of the human immune cell response associated with severe dengue progression by single-cell proteomics

Approximately five million dengue virus-infected patients, particularly children, progress to a potentially life-threatening severe dengue (SD) infection annually. To identify the immune features and temporal dynamics underlying SD progression, we performed deep immune profiling by mass cytometry of PBMCs collected longitudinally from SD progressors (SDp) and uncomplicated dengue (D) patients. While D is characterized by early activation of innate immune responses, in SDp there is rapid expansion and activation of IgG-secreting plasma cells and memory and regulatory T cells. Concurrently, SDp, particularly children, demonstrate increased proinflammatory NK cells, inadequate expansion of CD16+ monocytes, and high expression of the Fc{gamma}R, CD64 on myeloid cells, yet diminished antigen presentation. Syndrome-specific determinants include suppressed dendritic cell abundance in shock/hemorrhage vs. enriched plasma cell expansion in organ impairment. This study reveals uncoordinated immune responses in SDp and provides insights into SD pathogenesis in humans with potential implications for prediction and treatment.

immunology↗

bioRxiv2020

Sequential MAVS- and MyD88/TRIF-signaling triggers anti-viral responses of tick-borne encephalitis virus-infected murine astrocytes

Tick-borne encephalitis virus (TBEV), a member of the Flaviviridae family, is typically transmitted upon tick bite and can cause meningitis and encephalitis in humans. In TBEV infected mice, mitochondrial antiviral signaling protein (MAVS), the downstream adaptor of retinoic acid inducible gene I-like receptor (RLR)-signaling, is needed to induce early type I interferon (IFN) responses and to confer protection. To identify the brain resident cell subset that produces protective IFN-β in TBEV infected mice, we isolated neurons, astrocytes and microglia and exposed these cells to TBEV in vitro. Under such conditions, neurons showed the highest percentage of infected cells, whereas astrocytes and microglia were infected to a lesser extent. In the supernatant (SN) of infected neurons, IFN-β was not detectable, while infected astrocytes showed very high and microglia low IFN-β production. Transcriptome analyses of astrocytes implied that MAVS-signaling was needed early after TBEV infection. Accordingly, MAVS-deficient astrocytes showed enhanced TBEV infection and significantly reduced early IFN-β responses. At later time points, moderate amounts of IFN-β were detected in the SN of infected MAVS-deficient astrocytes. Transcriptome analyses indicated that MAVS-deficiency negatively affected the induction of early anti-viral responses, which resulted in significantly increased TBEV replication. Treatment with MyD88 and TRIF inhibiting peptides reduced late IFN-β responses of TBEV infected WT astrocytes and entirely blocked IFN-β responses of infected MAVS-deficient astrocytes. Thus, upon TBEV exposure of brain-resident cells, astrocytes are important IFN-β producers that show biphasic IFN-β induction that initially depends on MAVS- and later on MyD88/TRIF-signaling.Competing Interest StatementThe authors have declared no competing interest.View Full Text

immunology↗