Publications by authors named "Richard Longnecker"

Article Synopsis
  • The study focuses on the structural characterization of Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), two members of the gammaherpesvirus subfamily known for their tumorigenicity, using advanced techniques like deep learning-enhanced cryogenic electron tomography (cryoET).
  • It reveals unique features of the viruses, such as their pleomorphic characteristics, the positioning of their nucleocapsids, and the composition of their envelopes, which differ significantly from alpha- and betaherpesviruses.
  • This research provides insights into the architecture of these viruses, which may influence their infection processes and cell tropism, enhancing our understanding of human herpesviruses and their roles in cancer.
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Article Synopsis
  • The study identifies two cases of herpes simplex virus 1 (HSV-1) encephalitis in children linked to rare genetic variants of the TMEFF1 gene, which plays a protective role in the brain.
  • TMEFF1 protein interacts with the HSV-1 receptor NECTIN-1, blocking the virus's ability to enter brain cells, but genetic deficiencies in TMEFF1 allow for easier viral entry and replication within neurons.
  • The research suggests that enhancing TMEFF1 levels or using type I interferon can restore resistance to HSV-1, indicating a potential therapeutic pathway for preventing HSV-1 encephalitis.
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Unlabelled: Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) are classified into the gammaherpesvirus subfamily of , which stands out from its alpha- and betaherpesvirus relatives due to the tumorigenicity of its members. Although structures of human alpha- and betaherpesviruses by cryogenic electron tomography (cryoET) have been reported, reconstructions of intact human gammaherpesvirus virions remain elusive. Here, we structurally characterize extracellular virions of EBV and KSHV by deep learning-enhanced cryoET, resolving both previously known monomorphic capsid structures and previously unknown pleomorphic features beyond the capsid.

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Neurotropic alphaherpesviruses, including herpes simplex virus type 1 and pseudorabies virus, establish a lifelong presence within the peripheral nervous system of their mammalian hosts. Upon entering cells, two conserved tegument proteins, pUL36 and pUL37, traffic DNA-containing capsids to nuclei. These proteins support long-distance retrograde axonal transport and invasion of the nervous system .

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Dopamine neurons are characterized by their response to unexpected rewards, but they also fire during movement and aversive stimuli. Dopamine neuron diversity has been observed based on molecular expression profiles; however, whether different functions map onto such genetic subtypes remains unclear. In this study, we established that three genetic dopamine neuron subtypes within the substantia nigra pars compacta, characterized by the expression of Slc17a6 (Vglut2), Calb1 and Anxa1, each have a unique set of responses to rewards, aversive stimuli and accelerations and decelerations, and these signaling patterns are highly correlated between somas and axons within subtypes.

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Article Synopsis
  • Viruses pose significant health challenges, leading to issues like respiratory infections, cancer, and neurological impairments, but virology research has developed vaccines and antivirals to mitigate these problems.
  • The COVID-19 pandemic has heightened public scrutiny of virology, especially regarding the safe conduct of research with human pathogens, leading to confusion and misinterpretation about the origins of SARS-CoV-2.
  • This article aims to clarify misconceptions by explaining gain-of-function research, the origins of SARS-CoV-2, and the regulatory frameworks in place, fostering informed discussions and emphasizing the need for balanced, evidence-based dialogue in virology.
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Article Synopsis
  • Viruses have historically caused serious health issues, including respiratory infections and cancer, leading to significant virology research that resulted in vaccines and antiviral treatments.
  • The COVID-19 pandemic highlighted the necessity for careful research on human pathogens, creating both concerns and confusion about the safety of virology work and the origins of SARS-CoV-2.
  • The article aims to clarify misunderstandings by explaining gain-of-function research, exploring the origins of SARS-CoV-2, and discussing regulatory oversight, while advocating for rational and evidence-based discussions to guide policy decisions in virology.
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Article Synopsis
  • Viruses pose significant health challenges, leading to various issues such as respiratory infections and cancer, prompting virology research to develop vaccines and antiviral treatments over the past 60+ years.
  • The COVID-19 pandemic has intensified focus on virology, bringing up safety concerns about research involving human pathogens and creating public confusion between safe research practices and the origins of SARS-CoV-2.
  • The article aims to clarify these issues by discussing gain-of-function research, the origins of SARS-CoV-2, and current regulatory frameworks, advocating for informed, balanced conversations to support necessary virology research.
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MYC translocations in association with Epstein-Barr virus (EBV) infection are often observed in B-cell lymphomas. A subset of Burkitt lymphoma (BL) expresses EBV latent membrane proteins 1 and 2A (LMP1 and LMP2A) in addition to the typical restricted EBV latent gene expression. EBV-associated diffuse large B-cell lymphoma (DLBCL) typically exhibits latency type II or III and expresses LMP1.

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Herpes simplex virus (HSV) infection of the neonatal brain causes severe encephalitis and permanent neurologic deficits. However, infants infected with HSV at the time of birth follow varied clinical courses, with approximately half of infants experiencing only external infection of the skin rather than invasive neurologic disease. Understanding the cause of these divergent outcomes is essential to developing neuroprotective strategies.

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The viral fusion protein glycoprotein B (gB) is conserved in all herpesviruses and is essential for virus entry. During entry, gB fuses viral and host cell membranes by refolding from a prefusion to a postfusion form. We previously introduced three structure-based mutations (gB-I671A/H681A/F683A) into the domain V arm of the gB ectodomain that resulted in reduced cell-cell fusion.

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Herpes simplex virus encephalitis (HSE) is the most common cause of sporadic viral encephalitis, and despite targeted antiviral therapy, outcomes remain poor. Although the innate immune system is critical for restricting herpes simplex virus type I (HSV-1) in the brain, there is evidence that prolonged neuroinflammation contributes to HSE pathogenesis. In this study, we investigated the contribution of inflammasomes to disease pathogenesis in a murine model of HSE.

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Herpesviruses are ubiquitous, double-stranded DNA, enveloped viruses that establish lifelong infections and cause a range of diseases. Entry into host cells requires binding of the virus to specific receptors, followed by the coordinated action of multiple viral entry glycoproteins to trigger membrane fusion. Although the core fusion machinery is conserved for all herpesviruses, each species uses distinct receptors and receptor-binding glycoproteins.

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Epstein-Barr virus (EBV) infects human B cells and reprograms them to allow virus replication and persistence. One key viral factor in this process is latent membrane protein 2A (LMP2A), which has been described as a B cell receptor (BCR) mimic promoting malignant transformation. However, how LMP2A signaling contributes to tumorigenesis remains elusive.

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Both Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) are human gammaherpesviruses and are important in a variety of malignancies. Eph family receptor tyrosine kinase A2 (EphA2) is a cellular receptor for KSHV and EBV. Previous studies identified five conserved residues (ELEFN) in the N-terminal domain of KSHV gH that are critical for Eph binding and KSHV infection.

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Newborns are particularly susceptible to severe forms of herpes simplex virus 1 (HSV-1) infection, including encephalitis and multisystemic disseminated disease. The underlying age-dependent differences in the immune response that explain this increased susceptibility relative to the adult population remain largely understudied. Using a murine model of HSV-1 infection, we found that newborn mice are largely susceptible to intracranial and intraperitoneal challenge while adult mice are highly resistant.

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Ocular herpes simplex virus 1 (HSV-1) infection leads to an immunopathogenic disease called herpes stromal keratitis (HSK), in which CD4 T cell-driven inflammation contributes to irreversible damage to the cornea. Herpesvirus entry mediator (HVEM) is an immune modulator that activates stimulatory and inhibitory cosignals by interacting with its binding partners, LIGHT (TNFSF14), BTLA (B and T lymphocyte attenuator), and CD160. We have previously shown that HVEM exacerbates HSK pathogenesis, but the involvement of its binding partners and its connection to the pathogenic T cell response have not been elucidated.

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Epstein-Barr Virus (EBV) is etiologically associated with multiple human malignancies including Burkitt lymphoma and Hodgkin disease as well as nasopharyngeal and gastric carcinoma. Entry of EBV into target cells is essential for virus to cause disease and is mediated by multiple viral envelope glycoproteins and cell surface associated receptors. The target cells of EBV include B cells and epithelial cells.

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Article Synopsis
  • Epstein-Barr virus (EBV) and Kaposi Sarcoma-associated herpesvirus (KSHV) are two human γ-herpesviruses linked to various cancers and share common features like latency and fusion machinery for infection.
  • EBV has developed specific adaptations for cell entry involving B- and epithelial cells and has extensively studied entry proteins and their receptors, while KSHV's receptor-binding mechanisms remain less clear.
  • This review focuses on the key molecular players involved in the entry processes of both viruses and discusses how different cell types are infected.
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Epstein-Barr virus (EBV) latent membrane protein 2A (LMP2A), expressed in EBV latency, contributes to Burkitt lymphoma (BL) development in a murine model by acting as a constitutively active B cell receptor (BCR) mimic. Mice expressing both LMP2A and transgenes (LMP2A/λ-) develop tumors significantly faster than mice only expressing (λ-). Previously, we demonstrated the cell cycle inhibitor p27 is present at significantly lower levels in LMP2A/λ- mice due to increased posttranslational degradation.

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Sex differences related to immune response and inflammation play a role in the susceptibility and pathogenesis of a variety of viral infections and disease (S. L. Klein, Bioessays 34:1050-1059, 2012, https://doi.

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Kaposi's sarcoma-associated herpesvirus (KSHV) is a human gammaherpesvirus associated with the development of Kaposi's sarcoma (KS). KSHV target cells include endothelial cells, B cells, monocytes, epithelial cells, dendritic cells, macrophages, and fibroblasts. KSHV entry into target cells is a complex multistep process and is initiated by the binding and interaction of viral envelope glycoproteins with the cellular receptors.

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