Biology subjects

Kurland, A. P.

Publications and source records attributed to Kurland, A. P..

4 recordsLinked to original sources

bioRxiv2026

Powassan Virus NS5 Antagonizes TYK2-Mediated Immune Signaling Pathways

Powassan virus (POWV) is an emerging neurotropic tick-borne flavivirus, yet the mechanisms by which POWV evades host antiviral immunity remain poorly defined. Here, we identify multiple mechanisms of POWV innate immune antagonism with the viral polymerase NS5 protein as a central inhibitor of cytokine signaling. Both POWV lineages potently inhibited type I interferon (IFN) signaling, and NS5 expression suppressed signaling and downstream interferon-stimulated gene expression. Affinity purification-mass spectrometry identified the host kinase TYK2 as a conserved NS5 interactor. POWV NS5 binds the TYK2 kinase domain through a discrete interface within the RNA-dependent RNA polymerase (RdRp) region between catalytic motifs B and C and inhibits TYK2 phosphorylation. Disruption of this interface abrogated TYK2 binding and reduced NS5-mediated IFN antagonism, while revealing additional TYK2-independent mechanisms of immune suppression. POWV NS5 also inhibited TYK2-dependent IFN-{lambda} and IL-12 signaling, demonstrating that its immune antagonism extends beyond type I IFN. Together, these findings identify TYK2 as a central target of POWV immune evasion and implicate the variable RdRp B-C region as an interface for flavivirus-host interactions. More broadly, our results reveal how POWV can coordinately suppress multiple antiviral cytokine pathways and provide insight into mechanisms that may shape tick-borne flavivirus host adaptation and pathogenesis.

microbiology↗

bioRxiv2024

The EZH2 inhibitor tazemetostat mitigates HIV immune evasion, reduces reservoir formation, and promotes durable CD8+ T-cell revitalization

Persistent HIV reservoirs in CD4 T-cells pose a barrier to curing HIV infection. We identified overexpression of enhancer of zeste homolog 2 (EZH2) in HIV-infected CD4 T- cells that survive cytotoxic T lymphocyte (CTL) exposure, suggesting a mechanism of CTL resistance. Inhibition of EZH2 with the FDA-approved drug tazemetostat increased surface expression of major histocompatibility complex class I (MHC-I) on CD4 T-cells, counterbalancing HIV Nef-mediated MHC-I downregulation. This improved CTL-mediated elimination of HIV-infected cells and suppressed viral replication in vitro. In a participant-derived xenograft mouse model, tazemetostat elevated MHC-I and the pro-apoptotic protein BIM in CD4 T-cells, facilitating CD8 T-cell-mediated reductions of HIV reservoir seeding. Additionally, tazemetostat promoted sustained skewing of CD8 T-cells toward less differentiated and exhausted phenotypes. Our findings reveal EZH2 overexpression as a novel mechanism of CTL resistance and support the clinical evaluation of tazemetostat to enhance clearance of HIV reservoirs and improve CD8+ T-cell function.

immunology↗

bioRxiv2024

Broad-spectrum RNA antiviral inspired by ISG15-/- deficiency

Type I interferons (IFN-I) are cytokines with potent antiviral and inflammatory capacities. IFN-I signaling drives the expression of hundreds of IFN-I stimulated genes (ISGs), whose aggregate function results in the control of viral infection. A few of these ISGs are tasked with negatively regulating the IFN-I response to prevent overt inflammation. ISG15 is a negative regulator whose absence leads to persistent, low-grade elevation of ISG expression and concurrent, self-resolving mild autoinflammation. The limited breadth and low-grade persistence of ISGs expressed in ISG15 deficiency are sufficient to confer broad-spectrum antiviral resistance. Inspired by ISG15 deficiency, we have identified a nominal collection of 10 ISGs that recapitulate the broad antiviral potential of the IFN-I system. The expression of the 10 ISG collection in an IFN-I non-responsive cell line increased cellular resistance to Zika, Vesicular Stomatitis, Influenza A (IAV), and SARS-CoV-2 viruses. A deliverable prophylactic formulation of this syndicate of 10 ISGs significantly inhibited IAV PR8 replication in vivo in mice and protected hamsters against a lethal SARS-CoV-2 challenge, suggesting its potential as a broad-spectrum antiviral against many current and future emerging viral pathogens. One-Sentence SummaryHuman inborn error of immunity-guided discovery and development of a broad-spectrum RNA antiviral therapy

immunology↗

bioRxiv2022

Immunological landscape of human lymph nodes during ex vivo measles virus infection

In humans, lymph nodes are the primary site of measles virus (MeV) replication. To understand the immunological events that occur at this site, we infected human lymphoid tissue explants using a pathogenic strain of MeV that expresses GFP. We found that MeV infected between 5-15% of cells across donors. Using single cell RNA-Seq (scRNA-Seq) and flow cytometry, we found that while most of the 29 cell populations identified in the lymphoid culture were susceptible to MeV, there was a broad preferential infection of B cells and reduced infection of T cells. Further subsetting of T cells revealed that this reduction may be driven by the decreased infection of naive T cells. Transcriptional changes in infected B cells were dominated by an interferon stimulated gene (ISG) signature. To determine which of these ISGs were most substantial, we evaluated the proteome of MeV-infected Raji cells by mass spectrometry. We found that IFIT1, IFIT2, IFIT3, ISG15, CXCL10, MX2, and XAF1 proteins were the most highly induced, and positively correlated with their expression in the transcriptome. These data provide insight into the immunological events that occur in lymph nodes during infection and may lead to the development of therapeutic interventions.

immunology↗