The coronavirus disease 2019 pandemic has made deployment of an effective vaccine a global health priority. We evaluated the protective activity of a chimpanzee adenovirus-vectored vaccine encoding a prefusion stabilized spike protein (ChAd-SARS-CoV-2-S) in challenge studies with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and mice expressing the human angiotensin-converting enzyme 2 receptor. Intramuscular dosing of ChAd-SARS-CoV-2-S induces robust systemic humoral and cell-mediated immune responses and protects against lung infection, inflammation, and pathology but does not confer sterilizing immunity, as evidenced by detection of viral RNA and induction of anti-nucleoprotein antibodies after SARS-CoV-2 challenge. In contrast, a single intranasal dose of ChAd-SARS-CoV-2-S induces high levels of neutralizing antibodies, promotes systemic and mucosal immunoglobulin A (IgA) and T cell responses, and almost entirely prevents SARS-CoV-2 infection in both the upper and lower respiratory tracts. Intranasal administration of ChAd-SARS-CoV-2-S is a candidate for preventing SARS-CoV-2 infection and transmission and curtailing pandemic spread.
Highlights d ZIKV preferentially infects glioblastoma stem cells (GSCs) rather than neural precursor cells d ZIKV kills SOX2 + cells from a diverse array of malignant brain tumors d SOX2 determines susceptibility to ZIKV infection with reduced antiviral responses d Integrin a v b 5 is a GSC marker and promotes Zika virus infection of GSCs
There are no licensed therapeutics or vaccines available against Zika virus (ZIKV) to counteract its potential for congenital disease. Antibody-based countermeasures targeting the ZIKV envelope protein have been hampered by concerns for cross-reactive responses that induce antibody-dependent enhancement (ADE) of heterologous flavivirus infection. Nonstructural protein 1 (NS1) is a membrane-associated and secreted glycoprotein that functions in flavivirus replication and immune evasion but is absent from the virion. Although some studies suggest that antibodies against ZIKV NS1 are protective, their activity during congenital infection is unknown. Here we develop mouse and human anti-NS1 monoclonal antibodies that protect against ZIKV in both non-pregnant and pregnant mice. Avidity of antibody binding to cell-surface NS1 along with Fc effector functions engagement correlate with protection in vivo. Protective mAbs map to exposed epitopes in the wing domain and loop face of the β-platform. Anti-NS1 antibodies provide an alternative strategy for protection against congenital ZIKV infection without causing ADE.
Receptor-induced NF-κB activation is controlled by NEMO, the NF-κB essential modulator. Hypomorphic NEMO mutations result in X-linked ectodermal dysplasia with anhidrosis and immunodeficiency, also referred to as NEMO syndrome. Here we describe a distinct group of patients with NEMO C-terminal deletion (ΔCT-NEMO) mutations. Individuals harboring these mutations develop inflammatory skin and intestinal disease in addition to ectodermal dysplasia with anhidrosis and immunodeficiency. Both primary cells from these patients, as well as reconstituted cell lines with this deletion, exhibited increased IκB kinase (IKK) activity and production of proinflammatory cytokines. Unlike previously described loss-of-function mutations, ΔCT-NEMO mutants promoted increased NF-κB activation in response to TNF and Toll-like receptor stimulation. Investigation of the underlying mechanisms revealed impaired interactions with A20, a negative regulator of NF-κB activation, leading to prolonged accumulation of K63-ubiquitinated RIP within the TNFR1 signaling complex. Recruitment of A20 to the C-terminal domain of NEMO represents a novel mechanism limiting NF-κB activation by NEMO, and its absence results in autoinflammatory disease.ctivation of the NF-κB family of transcription factors is required for normal development, innate and adaptive immunity, and the inflammatory response (1, 2). NF-κB-induced transcription of proinflammatory cytokines and chemokines amplifies immune-response programs and stimulates recruitment of inflammatory cells. Transcriptional activity of the classic NF-κB p65/p50 complex is regulated by the inhibitor of NF-κB kinase (IKK), consisting of the α-and β-catalytic subunits and the NEMO (NF-κB essential modulator, IKKγ) regulatory subunit. IKK activity leads to phosphorylation and K48-linked polyubiquitination of IκBα, the inhibitor of NF-κB. Ubiquitinated IκBα is then rapidly degraded, allowing nuclear translocation of NF-κB subunits and gene transactivation. NEMO functions as a scaffold within the IKK complex that is required for canonical IKK enzymatic activity and NF-κB activation (3).Activation of TNF, IL-1R, and Toll-like receptor (TLR) family receptors leads to K63 and linear (also termed M1) ubiquitination of cytosolic adapter proteins, such as receptor interacting protein 1 (RIP1). This in turn promotes recruitment of the IKK complex to the receptor signaling complex (4-8). A well-known negative regulator of NF-κB activation is A20 (encoded by the gene TNFAIP3). In the TNF-R1 complex, A20 removes K63-linked ubiquitin modifications on RIP1 through its deubiquitinase activity and converts these to K48-linked polyubiquitin chains through its E3 ligase activity (9). Editing of polyubiquitin linkages at the receptor complex in this manner results in rapid degradation of RIP1 and other signaling proteins, such as TRAF6, TRAF2, cIAP1, and cIAP2 (9, 10), promoting the termination of receptor-induced NF-κB activation. In addition, A20 directly inhibits IKK activity independently of its deubiquitinase activity in...
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