Publications by authors named "Kristen Valentine"

The continuing evolution of SARS-CoV-2 variants challenges the durability of existing spike (S)-based COVID-19 vaccines. We hypothesized that vaccines composed of both S and nucleocapsid (N) antigens would increase the durability of protection by strengthening and broadening cellular immunity compared with S-based vaccines. To test this, we examined the immunogenicity and efficacy of wild-type SARS-CoV-2 S- and N-based DNA vaccines administered individually or together to K18-hACE2 mice.

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Article Synopsis
  • Mouse models with humanized ACE2 and TMPRSS2 genes were created to study how Th1 and Th2 immune responses affect SARS-CoV-2 infection.
  • Mice infected with the Delta variant required ACE2 for lung infection, while Omicron didn't, with Omicron causing more severe disease in specific mouse models.
  • The study suggests that the genetic background of the host influences the immune response and severity of SARS-CoV-2 infections, highlighting the need for more research on this variability.
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  • Some healthy individuals who haven’t been exposed to SARS-CoV-2 have T cells that react to it, likely due to previous infections with the common cold coronavirus OC43.
  • A study using genetically modified mice shows that infection with OC43 can produce T cells that also respond to SARS-CoV-2, helping to lessen severity of subsequent SARS-CoV-2 infections.
  • The role of CD4 T cells is significant; their depletion increases the viral load in the lungs after SARS-CoV-2 infection, highlighting their importance for cross-protection and informing future vaccine development against similar coronaviruses.
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Therapeutic antibodies are an important tool in the arsenal against coronavirus infection. However, most antibodies developed early in the pandemic have lost most or all efficacy against newly emergent strains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), particularly those of the Omicron lineage. Here, we report the identification of a panel of vaccinee-derived antibodies that have broad-spectrum neutralization activity.

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Although severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) initially infects the respiratory tract, it also directly or indirectly affects other organs, including the brain. However, little is known about the relative neurotropism of SARS-CoV-2 variants of concern (VOCs), including Omicron (B.1.

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Monoclonal antibodies (mAbs) are emerging as safe and effective therapeutics against SARS-CoV-2. However, variant strains of SARS-CoV-2 have evolved, with early studies showing that some mAbs may not sustain their efficacy in the face of escape mutants. Also, from the onset of the COVID-19 pandemic, concern has been raised about the potential for Fcγ receptor-mediated antibody-dependent enhancement (ADE) of infection.

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Follicular CXCR5+ PD-1+ CD8 T cells (CD8 Tfc) arise in multiple models of systemic autoimmunity yet their functional contribution to disease remains in debate. Here we define the follicular localization and functional interactions of CD8 Tfc with B cells during autoimmune disease. The absence of functional T regulatory cells in autoimmunity allows for CD8 Tfc development that then expands with lymphoproliferation.

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IL-2Rα, in part, comprises the high affinity receptor for IL-2, a cytokine important in immune proliferation, activation, and regulation. IL-2Rα deficient mice (IL-2Rα-KO) develop systemic autoimmune disease and die from severe anemia between 18 and 80 days of age. These mice develop kinetically distinct autoimmune progression, with approximately a quarter dying by 21 days of age and half dying after 30 days.

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Pre-existing immunity to dengue virus (DENV) can either protect against or exacerbate, a phenomenon known as antibody dependent enhancement (ADE), a secondary DENV infection. DENV, as an escalating health problem worldwide, has increased the urgency to understand the precise parameters shaping the anti-DENV antibody (Ab) and T cell responses, thereby tipping the balance towards protection versus pathogenesis. Herein, we present the current state of knowledge of about the interplay between the Ab and T cell responses that dictate the outcome of DENV infection and discuss how this newfound knowledge is reshaping strategies for developing safe and effective DENV vaccines.

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The underlying mechanisms by which prior immunity to dengue virus (DENV) affords cross-protection against the related flavivirus Zika virus (ZIKV) are poorly understood. Here, we examine the ability of DENV/ZIKV-cross-reactive CD4 T cells to protect against versus exacerbate ZIKV infection by using a histocompatibility leukocyte antigen (HLA)-DRB10101 transgenic, interferon α/β receptor-deficient mouse model that supports robust DENV and ZIKV replication. By mapping the HLA-DRB10101-restricted T cell response, we identify DENV/ZIKV-cross-reactive CD4 T cell epitopes that stimulate interferon gamma (IFNγ) and/or tumor necrosis factor (TNF) production.

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CD8 T cells are infrequently considered part of germinal center reactions. Yet, a distinct CXCR5+ CD8 T cell subset identified within the B cell follicle and germinal center in situations of chronic antigen has recently been defined. CXCR5+ CD8 T cells maintain transcriptional and phenotypic features consistent with the CD8 T cell nomenclature of a non-exhausted, effector memory population.

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T cell exhaustion is a state of hyporesponsiveness that develops during many chronic infections and cancer. Neutralization of inhibitory receptors, or "checkpoint blockade," can reverse T cell exhaustion and lead to beneficial prognoses in experimental and clinical settings. Whether checkpoint blockade can resolve lethal acute infections is less understood but may be beneficial in vaccination protocols that fail to elicit sterilizing immunity.

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CD8 T cells can play both a protective and pathogenic role in inflammation and autoimmune development. Recent studies have highlighted the ability of CD8 T cells to function as T follicular helper (Tfh) cells in the germinal center in the context of infection. However, whether this phenomenon occurs in autoimmunity and contributes to autoimmune pathogenesis is largely unexplored.

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