Medicine and Health Sciences Commons^™

Resistance To Ectromelia Virus Infection Requires Cgas In Bone Marrow-Derived Cells Which Can Be Bypassed With Cgamp Therapy., Eric B. Wong, Brian Montoya, Maria Ferez, Colby Stotesbury, Luis J. Sigal

Department of Microbiology and Immunology Faculty Papers

Cells sensing infection produce Type I interferons (IFN-I) to stimulate Interferon Stimulated Genes (ISGs) that confer resistance to viruses. During lympho-hematogenous spread of the mouse pathogen ectromelia virus (ECTV), the adaptor STING and the transcription factor IRF7 are required for IFN-I and ISG induction and resistance to ECTV. However, it is unknown which cells sense ECTV and which pathogen recognition receptor (PRR) upstream of STING is required for IFN-I and ISG induction. We found that cyclic-GMP-AMP (cGAMP) synthase (cGAS), a DNA-sensing PRR, is required in bone marrow-derived (BMD) but not in other cells for IFN-I and ISG induction and for …

Langerhans Cells Orchestrate The Protective Antiviral Innate Immune Response In The Lymph Node., Eric B. Wong, Brian Montoya, Colby Stotesbury, Maria Ferez, Ren-Huan Xu, Luis J. Sigal

Department of Microbiology and Immunology Faculty Papers

During disseminating viral infections, a swift innate immune response (IIR) in the draining lymph node (dLN) that restricts systemic viral spread is critical for optimal resistance to disease. However, it is unclear how this IIR is orchestrated. We show that after footpad infection of mice with ectromelia virus, dendritic cells (DCs) highly expressing major histocompatibility complex class II (MHC class II^hi DCs), including CD207⁺ epidermal Langerhans cells (LCs), CD103⁺CD207⁺ double-positive dermal DCs (DP-DCs), and CD103⁻CD207⁻ double-negative dermal DCs (DN-DCs) migrate to the dLN from the skin carrying virus. MHC class II^{hi …}

Incorporating B Cell Activating Factor (Baff) Into The Membrane Of Rabies Virus (Rabv) Particles Improves The Speed And Magnitude Of Vaccine-Induced Antibody Responses., Joseph R Plummer, James P Mcgettigan

Department of Microbiology and Immunology Faculty Papers

B cell activating factor (BAFF) is a member of the tumor necrosis factor (TNF) superfamily of cytokines that links innate with adaptive immunity. BAFF signals through receptors on B cells, making it an attractive molecule to potentiate vaccine-induced B cell responses. We hypothesized that a rabies virus (RABV)-based vaccine displaying both antigen and BAFF on the surface of the same virus particle would target antigen-specific B cells for activation and improve RABV-specific antibody responses. To test this hypothesis, we constructed a recombinant RABV-based vector expressing virus membrane-anchored murine BAFF (RABV-ED51-mBAFF). BAFF was incorporated into the RABV particle and determined to …

Inactivated Rabies Virus-Based Ebola Vaccine Preserved By Vaporization Is Heat-Stable And Immunogenic Against Ebola And Protects Against Rabies Challenge., Drishya Kurup, Christine R. Fisher, Todd G. Smith, Tiago Abreu-Mota, Yong Yang, Felix R. Jackson, Nadia Gallardo-Romero, Richard Franka, Victor Bronshtein, Matthias J. Schnell

Department of Microbiology and Immunology Faculty Papers

BACKGROUND: Ebola virus (EBOV) is a highly lethal member of the Filoviridae family associated with human hemorrhagic disease. Despite being a sporadic disease, it caused a large outbreak in 2014-2016 in West Africa and another outbreak recently in the Democratic Republic of Congo. Several vaccine candidates are currently in preclinical and clinical studies but none are stable without cold chain storage.

METHODS: We used preservation by vaporization (PBV), a novel processing technology to heat-stabilize FiloRab1 (inactivated rabies-based Ebola vaccine), a candidate Ebola vaccine, and stored the vials at temperatures ranging from 4°C to 50°C for 10 days to 12 months. …

Antibody Responses Against The Vaccine Antigens Ov-103 And Ov-Ral-2 Are Associated With Protective Immunity To Onchocerca Volvulus Infection In Both Mice And Humans., Parakkal Jovvian George, Jessica A. Hess, Sonia Jain, John B. Patton, Tingting Zhan, Nancy Tricoche, Bin Zhan, Maria Elena Bottazzi, Peter J. Hotez, David Abraham, Sara Lustigman

Department of Microbiology and Immunology Faculty Papers

BACKGROUND: The current strategy for the elimination of onchocerciasis is based on annual or bi-annual mass drug administration with ivermectin. However, due to several limiting factors there is a growing concern that elimination of onchocerciasis cannot be achieved solely through the current strategy. Additional tools are critically needed including a prophylactic vaccine. Presently Ov-103 and Ov-RAL-2 are the most promising vaccine candidates against an Onchocerca volvulus infection.

METHODOLOGY/PRINCIPAL FINDINGS: Protection induced by immunization of mice with the alum-adjuvanted Ov-103 or Ov-RAL-2 vaccines appeared to be antibody dependent since AID-/- mice that could not mount antigen-specific IgG antibody responses were not …

Cytoplasmic Daxx Drives Sqstm1/P62 Phase Condensation To Activate Nrf2-Mediated Stress Response., Yi Yang, Thea L. Willis, Robert W. Button, Conor J. Strang, Yuhua Fu, Xue Wen, Portia R.C. Grayson, Tracey Evans, Rebecca J. Sipthorpe, Sheridan L. Roberts, Bing Hu, Jianke Zhang, Boxun Lu, Shouqing Luo

Department of Microbiology and Immunology Faculty Papers

Autophagy cargo recognition and clearance are essential for intracellular protein quality control. SQSTM1/p62 sequesters intracellular aberrant proteins and mediates cargo delivery for their selective autophagic degradation. The formation of p62 non-membrane-bound liquid compartments is critical for its function as a cargo receptor. The regulation of p62 phase separation/condensation has yet been poorly characterised. Using an unbiased yeast two-hybrid screening and complementary approaches, we found that DAXX physically interacts with p62. Cytoplasmic DAXX promotes p62 puncta formation. We further elucidate that DAXX drives p62 liquid phase condensation by inducing p62 oligomerisation. This effect promotes p62 recruitment of Keap1 and subsequent Nrf2-mediated …

From Vaccine Vector To Oncomodulation: Understanding The Complex Interplay Between Cmv And Cancer., Nicole A. Wilski, Christopher M. Snyder

Department of Microbiology and Immunology Faculty Papers

Cytomegalovirus (CMV) is a herpesvirus that establishes a persistent, but generally asymptomatic, infection in most people in the world. However, CMV drives and sustains extremely large numbers of antigen-specific T cells and is, therefore, emerging as an exciting platform for vaccines against infectious diseases and cancer. Indeed, pre-clinical data strongly suggest that CMV-based vaccines can sustain protective CD8+ T cell and antibody responses. In the context of vaccines for infectious diseases, substantial pre-clinical studies have elucidated the effcacy and protective mechanisms of CMV-based vaccines, including in non-human primate models of various infections. In the context of cancer vaccines, however, much …

Rabies-Based Vaccine Induces Potent Immune Responses Against Nipah Virus., Rohan Keshwara, Thomas Shiels, Elena Postnikova, Drishya Kurup, Christoph Wirblich, Reed F. Johnson, Matthias J. Schnell

Department of Microbiology and Immunology Faculty Papers

Nipah Virus (NiV) is a re-emerging zoonotic pathogen in the genus Henipavirus of the Paramyxoviridae family of viruses. NiV is endemic to Bangladesh and Malaysia and is highly fatal to both livestock and humans (human case fatality rate = 74.5%). Currently, there is no approved vaccine against NiV on the market. The goal of this study was to use a recombinant RABV vector expressing NiV glycoprotein (NiV G) to develop a bivalent candidate vaccine against NiV disease and rabies virus (RABV) disease, which is also a significant health burden in the regions where NiV is endemic. The rabies vector is …

Ripk1 Can Mediate Apoptosis In Addition To Necroptosis During Embryonic Development., Xuhua Zhang, John P. Dowling, Jianke Zhang

Department of Microbiology and Immunology Faculty Papers

RIPK1 has emerged as a key effector in programmed necrosis or necroptosis. This function of RIPK1 is mediated by its protein serine/threonine kinase activity and through the downstream kinase RIPK3. Deletion of RIPK1 prevents embryonic lethality in mice lacking FADD, a signaling adaptor protein required for activation of Caspase 8 in extrinsic apoptotic pathways. This indicates that FADD-mediated apoptosis inhibits RIPK1-dependent necroptosis to ensure successful embryogenesis. However, the molecular mechanism for this critical regulation remains unclear. In the current study, a novel mouse model has been generated, by disrupting a potential caspase cleavage site at aspartic residue (D)324 in RIPK1. …

Tradd Regulates Perinatal Development And Adulthood Survival In Mice Lacking Ripk1 And Ripk3., John P. Dowling, Mohamed Alsabbagh, Christina Del Casale, Zheng-Gang Liu, Jianke Zhang

Department of Microbiology and Immunology Faculty Papers

TRADD is an adaptor for TNFR1-induced apoptosis and NFκB activation. However, TRADD-deficient mice undergo normal development and contain normal lymphoid populations, which contrasts with an embryonic defect in mice lacking FADD, the shared adaptor mediating apoptosis. Recent studies indicate FADD suppresses embryonic necroptosis mediated by RIPK1. TRADD was suggested to also mediate necroptosis. Here we report that targeting TRADD fails to rescue Fadd ^−/− embryos from necroptosis, and ablation of TRADD rescues Ripk1 ^−/− mice from perinatal lethality when RIPK3-mediated necroptosis is disabled. The resulting Ripk1 ^−/− Ripk3 ^−/− Tradd ^−/− mice survive until early adulthood, but die thereafter. A …