Biology subjects

Hong, S.-H.

Publications and source records attributed to Hong, S.-H..

4 recordsLinked to original sources

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↗

bioRxiv2024

Inhibition of nitric oxide synthase transforms carotid occlusion-mediated benign oligemia into de novo large cerebral infarction

It remains unclear why unilateral proximal carotid artery occlusion (UCAO) causes benign oligemia, without progressing to cerebral infarction, in mice, yet leads to a wide variety of outcomes (ranging from asymptomatic to death) in humans. We hypothesized that inhibition of NOS both transforms UCAO-mediated oligemia into full infarction and expands pre-existing infarction. In support, intraperitoneal administration of N{omega}-nitro-L-arginine methyl ester (L-NAME) followed by UCAO induced large-arterial infarction in mice, unlike UCAO alone. Six-hour laser-speckle-contrast imaging detected spreading ischemia in mice with infarction as assessed at 24h. In agreement with vasoconstriction/microthrombus formation shown by intravital microscopy, the NO-donor, molsidomine and the endothelial-NOS- activating antiplatelet, cilostazol, attenuated or prevented progression to infarction. Moreover, UCAO without L-NAME caused infarction in mice with hyperglycemia and hyperlipidemia, which, in turn, were associated with greater symmetric dimethylarginine (SDMA) levels. Further, increased levels of glucose and cholesterol associated with significantly larger infarct volumes in 438 consecutive patients with UCAO-mediated infarction. Lastly, Mendelian randomization identified a causative role of NOS inhibition, particularly in elevated SDMA concentration, in ischemic stroke risk. Therefore, NOS activity is a key factor determining the fate of hypoperfused brain following acute carotid occlusion, where SDMA could be a potential risk predictor.

neuroscience↗

bioRxiv2024

A Genome-Wide Arrayed CRISPR Screen Reveals PLSCR1 as an Intrinsic Barrier to SARS-CoV-2 Entry

Interferons (IFNs) play a crucial role in the regulation and evolution of host-virus interactions. Here, we conducted a genome-wide arrayed CRISPR knockout screen in the presence and absence of IFN to identify human genes that influence SARS-CoV-2 infection. We then performed an integrated analysis of genes interacting with SARS-CoV-2, drawing from a selection of 67 large-scale studies, including our own. We identified 28 genes of high relevance in both human genetic studies of COVID-19 patients and functional genetic screens in cell culture, with many related to the IFN pathway. Among these was the IFN-stimulated gene PLSCR1. PLSCR1 did not require IFN induction to restrict SARS-CoV-2 and did not contribute to IFN signaling. Instead, PLSCR1 specifically restricted spike-mediated SARS-CoV-2 entry. The PLSCR1-mediated restriction was alleviated by TMPRSS2 over-expression, suggesting that PLSCR1 primarily restricts the endocytic entry route. In addition, recent SARS-CoV-2 variants have adapted to circumvent the PLSCR1 barrier via currently undetermined mechanisms. Finally, we investigate the functional effects of PLSCR1 variants present in humans and discuss an association between PLSCR1 and severe COVID-19 reported recently.

immunology↗

bioRxiv2023

Periodontitis promotes bacterial extracellular vesicle-induced neuroinflammation in the brain and trigeminal ganglion

Gram-negative bacteria derived extracellular vesicles (EVs), also known as outer membrane vesicles, have attracted significant attention due to their pathogenic roles in various inflammatory diseases. We recently demonstrated that EVs secreted by the periodontopathogen Aggregatibacter actinomycetemcomitans (Aa) can cross the blood-brain barrier (BBB) and that their extracellular RNA cargo can promote the secretion of proinflammatory cytokines, such as IL-6 and TNF-, in the brain. To gain more insight into the relationship between periodontal disease (PD) and neuroinflammatory diseases, we investigated the effect of Aa EVs in a mouse model of ligature-induced PD. When EVs were administered through intragingival injection or EV-soaked gel, proinflammatory cytokines were strongly induced in the brains of PD mice. The use of TLR (Toll-like receptor)-reporter cell lines and MyD88 knockout mice confirmed that the increased release of cytokines was triggered by Aa EVs via TLR4 and TLR8 signaling pathways and their downstream MyD88 pathway. Furthermore, the injection of EVs through the epidermis and gingiva resulted in the direct retrograde transfer of Aa EVs from axon terminals to the cell bodies of trigeminal ganglion (TG) neurons and the subsequent activation of TG neurons. We also found that the Aa EVs changed the action potential of TG neurons. These findings suggest that EVs derived from periodontopathogens such as Aa might be involved in pathogenic pathways for neuroinflammatory diseases, neuropathic pain, and other systemic inflammatory symptoms as a comorbidity of periodontitis. Author summaryExtracellular vesicles (EVs) secreted from bacterial cells play a key role in microbe-host cell communication. Bacterial EVs (bEVs) may be closely linked to the pathogenesis underlying neuroinflammatory diseases. In the current experiments, bEVs caused the brain to release proinflammatory cytokines by activating the host TLR signaling pathway. This induction of neuroinflammation was significantly more prominent in the periodontitis disease model, implying a substantial link between periodontal and neuroinflammatory diseases through bEVs. We also show that bEVs are translocated to the neuronal cell body via retrograde axonal transport, where they directly activate neuronal proinflammatory signals (Fig 8). Our findings reveal that bEVs are a pathogenic pathway for neurological conditions potentially linked to periodontitis, such as Alzheimers disease and trigeminal neuropathic pain. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=159 SRC="FIGDIR/small/548287v1_fig8.gif" ALT="Figure 8"> View larger version (32K): org.highwire.dtl.DTLVardef@ff2928org.highwire.dtl.DTLVardef@1e72688org.highwire.dtl.DTLVardef@92e002org.highwire.dtl.DTLVardef@b0e125_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFig 8.C_FLOATNO Graphic summary. Model of bacterial EV (bEVs) function in the brain and trigeminal neuron. bEVs have the ability to enter host brain cells through the bloodstream and to enter the trigeminal ganglion neuronal cell body through retrograde axonal transport, where they directly trigger proinflammatory neuronal signals. Through the TLR4/TLR8-MyD88 and NF-{kappa}B signaling pathways, bEVs and their RNA cargo can stimulate the production of TNF- and IL-6 in the host cells. The production of neuroinflammation is noticeably more pronounced in the periodontitis disease model, suggesting a strong association between periodontal and neuroinflammatory diseases via bEVs. C_FIG

pathology↗