Biology subjects

Borducchi, E.

Publications and source records attributed to Borducchi, E..

5 recordsLinked to original sources

bioRxiv2026

Displayed and Encoded Antigens on Adenovirus Vectors Optimize Humoral and Cellular Immune Responses in Rhesus Macaques

Adenovirus vector-based vaccines were deployed widely during the COVID-19 pandemic. In this study, we explored the potential of displaying an antigen on the surface of the adenovirus capsid as well as encoding an antigen as a transgene in the adenovirus vector to optimize both humoral and cellular immune responses. We show that displaying SARS-CoV-2 Spike receptor biding domain (RBD) on the Ad5 capsid while simultaneously encoding Spike as a transgene induced robust antibody and T cell responses in rhesus macaques. These data demonstrate that adenoviruses can be utilized simultaneously as both nanoparticle scaffolds and viral vectors.

immunology↗

bioRxiv2025

Origin and Correlates of Viral Rebound in SIV-Infected Rhesus Macaques Following ART Discontinuation

The vast majority of persons living with HIV-1 who discontinue antiretroviral therapy (ART) demonstrate viral rebound, but the tissue-level events that lead to rebound viremia are poorly understood. Here we report the origin, dynamics, and correlates of viral rebound in 16 rhesus macaques (RMs) infected with molecularly barcoded SIVmac239M, treated with ART for 70 weeks, and necropsied on day 12 after ART discontinuation. Barcode analysis of plasma following ART discontinuation identified 1 to 38 rebounding barcode-defined viral lineages per animal, with 1 to 4 rebounding lineages contributing to first measurable rebound viremia. Analysis of barcode viral RNA (vRNA) expression in necropsy tissues revealed presumptive anatomic origin sites for 56 of 175 total rebounding viral lineages, with significant enrichment in the gastrointestinal (GI) tract and GI-associated lymph nodes. Daily transcriptomic and proteomic profiling in peripheral blood following ART discontinuation showed upregulation of pathways related to T cell signaling, cytokine responses, and cellular metabolism prior to detectable rebound viremia. These data suggest that viral rebound following ART discontinuation is initiated by local tissue replication of a limited number of clonal lineages, followed by systemic expansion of the initial rebounding lineages and serial initiation of replication of multiple additional clonal lineages. These findings provide mechanistic insights into the processes that result in viral rebound following ART discontinuation and will contribute to next generation HIV-1 cure strategies.

microbiology↗

bioRxiv2024

Persistent Activation of Chronic Inflammatory Pathways in Long Covid

Long Covid, or Post-Acute Sequelae of COVID-19 (PASC), involves a spectrum of chronic symptoms following resolution of acute SARS-CoV-2 infection. Current hypotheses for the pathogenesis of Long Covid include persistent SARS-CoV-2, activation of other viruses, tissue damage, autoimmunity, endocrine insufficiency, immune dysfunction, and complement activation. We evaluated 142 participants, including uninfected controls (N=35), acutely infected individuals (N=54), convalescent controls (N=25), and Long Covid patients (N=28), by comprehensive immunologic, virologic, transcriptomic, and proteomic analyses. Long Covid was characterized by persistent inflammatory pathways compared with convalescent controls and uninfected controls, including upregulation of IL-6 and JAK-STAT pathways as well as activation of coagulation, complement, metabolism, and T cell exhaustion pathways. Moreover, robust activation of these pathways during acute COVID-19 infection correlated with the subsequent development of Long Covid. In an independent validation cohort (N=47), Long Covid patients had higher levels of plasma IL-6R compared with convalescent controls and uninfected controls. These data demonstrate that Long Covid is characterized by persistent activation of chronic inflammatory pathways, suggesting novel therapeutic targets and biomarkers of disease.

immunology↗

bioRxiv2022

Immunogenicity of the BA.5 Bivalent mRNA Vaccine Boosters

Waning immunity following mRNA vaccination and the emergence of SARS-CoV-2 variants has led to reduced mRNA vaccine efficacy against both symptomatic infection and severe disease. Bivalent mRNA boosters expressing the Omicron BA.5 and ancestral WA1/2020 Spike proteins have been developed and approved, because BA.5 is currently the dominant SARS-CoV-2 variant and substantially evades neutralizing antibodies (NAbs). Our data show that BA.5 NAb titers were comparable following monovalent and bivalent mRNA boosters.

immunology↗

bioRxiv2022

Rapid Loss of CD4 T Cells by Pyroptosis During Acute SIV Infection in Rhesus Macaques

The mechanisms underlying depletion of CD4 T cells during acute HIV-1 infection are not well understood. Here we show that caspase-1-induced pyroptosis, a highly inflammatory programmed cell death pathway, is the dominant mechanism responsible for the rapid depletion of CD4 T cells in gut-associated lymphatic tissue (GALT), spleen, and lymph nodes during acute simian immunodeficiency virus (SIV) infection in rhesus macaques. Upregulation of interferon-gamma inducible factor 16 (IFI16), a host DNA sensor that triggers pyroptosis, was also observed in tissue-resident CD4 T cells and correlated with viral loads and CD4 T cell loss. In contrast, caspase-3-mediated apoptosis and viral cytotoxicity only accounted for a small fraction of CD4 T cell death. Other programmed cell death mechanisms, including mitochondria-induced caspase-independent cell death, necroptosis, and autophagy, did not significantly contribute to CD4 T cell depletion. These data support a model in which caspase-1-mediated pyroptosis is the principal mechanism that results in CD4 T cell loss in the GALT and lymphoid organs and release of proinflammatory cytokines. These findings contribute to our understanding of the pathogenesis of acute SIV infection and have important implications for the development of therapeutic strategies. ImportanceDifferent mechanisms for CD4 T cell depletion during acute HIV-1 infection have been proposed. In this study, we should in SIV infected rhesus macaques that depletion of CD4 T cells is primarily due to pyroptosis. Other pathophysiologic mechanisms may also contribute in a minor way to CD4 T cell depletion.

microbiology↗