Biology subjects

Guarnieri, J. W.

Publications and source records attributed to Guarnieri, J. W..

7 recordsLinked to original sources

bioRxiv2026

A mitochondrial-immune axis drives the transcriptomic transition from brain aging to Alzheimer's disease

Aging is the primary risk factor for Alzheimers disease (AD), yet the molecular transitions linking normal brain aging to neurodegeneration remain poorly defined. Here, we performed integrative bulk transcriptomic analyses across a multi-region mouse aging atlas, a human aging-to-AD cohort, and an independent human AD validation dataset. Aging is associated with a progressive, region-specific increase in transcriptional perturbation, with the entorhinal cortex and choroid plexus showing the most pronounced age-associated remodeling. Females develop more extensive late-stage remodeling than males, characterized by stronger immune activation and greater suppression of mitochondrial metabolic pathways. Across cohorts, aging drives a coordinated shift toward immune activation and suppression of oxidative phosphorylation and respiratory-chain programs that is amplified in AD. Aged brains occupy an intermediate molecular state between young and AD conditions, supporting a continuum model. Together, our findings define a sex-modulated mitochondrial-immune axis linking normal aging to AD and highlight early immune-metabolic changes as potential intervention targets.

bioinformatics↗

bioRxiv2024

ZNFX1 is a Novel Master Regulator in Epigenetically-induced Pathogen Mimicry and Inflammasome Signaling in Cancer

DNA methyltransferase and poly(ADP-ribose) polymerase inhibitors (DNMTis, PARPis) induce a stimulator of interferon (IFN) genes (STING)-dependent pathogen mimicry response (PMR) in ovarian (OC) and other cancers. We now show that combining DNMTis and PARPis upregulates expression of a little-studied nucleic-acid sensor, NFX1-type zinc finger-containing 1 protein (ZNFX1). We demonstrate that ZNFX1 is a novel master regulator for PMR induction in mitochondria, serving as a gateway for STING-dependent PMR. In patient OC databases, high ZNFX1 expression levels correlate with advanced stage disease. ZNFX1 expression alone significantly correlates with an increase in overall survival in a phase 3 trial for therapy-resistant OC patients receiving bevacizumab in combination with chemotherapy. In correlative RNA-seq data, inflammasome signaling through ZNFX1 correlates with abnormal vasculogenesis. ZNFX1 controls PMR signaling through the mitochondria and may serve as a biomarker to facilitate offering personalized therapy in OC patients, highlighting the strong translational significance of our findings. Significance statementDNA methyltransferase and poly(ADP-ribose) polymerase inhibitors upregulate expression of a novel nucleic-acid sensor, ZNFX1 that serves as a mitochondrial gateway to STING-dependent interferon/inflammasome signaling with tumor suppressor properties in ovarian cancer.

cancer biology↗

bioRxiv2024

Mitochondrial Hyperactivity and Reactive Oxygen Species Drive Innate Immunity to the Yellow Fever Virus-17D Live-Attenuated Vaccine

The yellow fever virus 17D (YFV-17D) live attenuated vaccine is considered one of the successful vaccines ever generated associated with high antiviral immunity, yet the signaling mechanisms that drive the response in infected cells are not understood. Here, we provide a molecular understanding of how metabolic stress and innate immune responses are linked to drive type I IFN expression in response to YFV-17D infection. Comparison of YFV-17D replication with its parental virus, YFV-Asibi, and a related dengue virus revealed that IFN expression requires RIG-I-like Receptor signaling through MAVS, as expected. However, YFV-17D uniquely induces mitochondrial respiration and major metabolic perturbations, including hyperactivation of electron transport to fuel ATP synthase. Mitochondrial hyperactivity generates reactive oxygen species (mROS) and peroxynitrite, blocking of which abrogated IFN expression in non-immune cells without reducing YFV-17D replication. Scavenging ROS in YFV-17D-infected human dendritic cells increased cell viability yet globally prevented expression of IFN signaling pathways. Thus, adaptation of YFV-17D for high growth uniquely imparts mitochondrial hyperactivity generating mROS and peroxynitrite as the critical messengers that convert a blunted IFN response into maximal activation of innate immunity essential for vaccine effectiveness.

immunology↗

bioRxiv2023

LETHAL COVID-19 ASSOCIATES WITH RAAS-INDUCED INFLAMMATION FOR MULTIPLE ORGAN DAMAGE INCLUDING MEDIASTINAL LYMPH NODES

Lethal COVID-19 outcomes are most often attributed to classic cytokine storm and attendant excessive immune signaling. We re-visit this question using RNA sequencing in nasopharyngeal and 40 autopsy samples from COVID-19-positive and negative individuals. In nasal swabs, the top 100 genes which significantly correlated with COVID-19 viral load, include many canonical innate immune genes. However, 22 much less studied "non-canonical" genes are found and despite the absence of viral transcripts, subsets of these are upregulated in heart, lung, kidney, and liver, but not mediastinal lymph nodes. An important regulatory potential emerges for the non-canonical genes for over-activating the renin-angiotensin-activation-system (RAAS) pathway, resembling this phenomenon in hereditary angioedema (HAE) and its overlapping multiple features with lethal COVID-19 infections. Specifically, RAAS overactivation links increased fibrin deposition, leaky vessels, thrombotic tendency, and initiating the PANoptosis death pathway, as suggested in heart, lung, and especially mediastinal lymph nodes, with a tightly associated mitochondrial dysfunction linked to immune responses. For mediastinal lymph nodes, immunohistochemistry studies validate the transcriptomic findings showing abnormal architecture, excess fibrin and collagen deposition, and pathogenic fibroblasts. Further, our findings overlap findings in SARS-CoV-2 infected hamsters, C57BL/6 and BALB/c mouse models, and importantly peripheral blood mononuclear cell (PBMC) and whole blood samples from COVID-19 patients infected with early variants and later SARS-CoV-2 strains. We thus present cytokine storm in lethal COVID-19 disease as an interplay between upstream immune gene signaling producing downstream RAAS overactivation with resultant severe organ damage, especially compromising mediastinal lymph node function.

immunology↗

bioRxiv2022

Targeted Down Regulation Of Core Mitochondrial Genes During SARS-CoV-2 Infection

Defects in mitochondrial oxidative phosphorylation (OXPHOS) have been reported in COVID-19 patients, but the timing and organs affected vary among reports. Here, we reveal the dynamics of COVID-19 through transcription profiles in nasopharyngeal and autopsy samples from patients and infected rodent models. While mitochondrial bioenergetics is repressed in the viral nasopharyngeal portal of entry, it is up regulated in autopsy lung tissues from deceased patients. In most disease stages and organs, discrete OXPHOS functions are blocked by the virus, and this is countered by the host broadly up regulating unblocked OXPHOS functions. No such rebound is seen in autopsy heart, results in severe repression of genes across all OXPHOS modules. Hence, targeted enhancement of mitochondrial gene expression may mitigate the pathogenesis of COVID-19. One-Sentence SummaryCovid-19 is associated with targeted inhibition of mitochondrial gene transcription.

molecular biology↗

bioRxiv2022

SARS-CoV-2 Viroporins Activate The NLRP3-Inflammasome Via The Mitochondrial Permeability Transition Pore

Cytokine storm precipitated by activation of the host innate immune defenses is a major cause of COVID19 death. To elucidate how SARS-CoV-2 initiates this inflammatory process, we studied viroporin proteins E and Orf3a (2-E+2-3a). Expression of 2-E+2-3a in human 293T cells resulted in increased cytosolic Ca++ and then elevated mitochondrial Ca++, taken up through the MUCi11-sensitive mitochondrial calcium uniporter (MCU). Increased mitochondrial Ca++ resulted in stimulation of mitochondrial reactive oxygen species (mROS) production, which was blocked by mitochondrially-targeted catalase or MnTBAP. To determined how mROS activates the inflammasome, we transformed 293T cells with NLRP3, ASC, pro-caspase-1 and pro-IL-1{beta} plus used THP1 derived macrophages to monitor the secretion of mature IL-1{beta}. This revealed that mROS activates a factor that is released via the NIM811-sensitive mitochondrial permeability pore (mtPTP) to activate the inflammasome. Hence, interventions targeting mROS and the mtPTP may mitigate the severity of COVID19 cytokine storms.

immunology↗

bioRxiv2021

The Great Deceiver: miR-2392's Hidden Role in Driving SARS-CoV-2 Infection

MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene regulation that have a major impact on many diseases and provides an exciting avenue towards antiviral therapeutics. From patient transcriptomic data, we have discovered a circulating miRNA, miR-2392, that is directly involved with SARS-CoV-2 machinery during host infection. Specifically, we show that miR-2392 is key in driving downstream suppression of mitochondrial gene expression, increasing inflammation, glycolysis, and hypoxia as well as promoting many symptoms associated with COVID-19 infection. We demonstrate miR-2392 is present in the blood and urine of COVID-19 positive patients, but not detected in COVID-19 negative patients. These findings indicate the potential for developing a novel, minimally invasive, COVID-19 detection method. Lastly, using in vitro human and in vivo hamster models, we have developed a novel miRNA-based antiviral therapeutic that targets miR-2392, significantly reduces SARS-CoV-2 viability in hamsters and may potentially inhibit a COVID-19 disease state in humans.

systems biology↗