Interferons are cytokines that play a complex and central role in the resistance of mammalian hosts to pathogens. Type I interferon (IFN-alpha and IFN-beta) is secreted by virus-infected cells. Immune, type II, or gamma-interferon (IFN-gamma) is secreted by thymus-derived (T) cells under certain conditions of activation and by natural killer (NK) cells. Although originally defined as an agent with direct antiviral activity, the properties of IFN-gamma include regulation of several aspects of the immune response, stimulation of bactericidal activity of phagocytes, stimulation of antigen presentation through class I and class II major histocompatibility complex (MHC) molecules, orchestration of leukocyte-endothelium interactions, effects on cell proliferation and apoptosis, as well as the stimulation and repression of a variety of genes whose functional significance remains obscure. The implementation of such a variety of effects by a single cytokine is achieved by complex patterns of cell-specific gene regulation: Several IFN-gamma-regulated genes are themselves components of transcription factors. The IFN-gamma response is itself regulated by interaction with responses to other cytokines including IFN-alpha/beta, TNF-alpha, and IL-4. Over 200 genes are now known to be regulated by IFN-gamma and they are listed in a World Wide Web document that accompanies this review. However, much of the cellular response to IFN-gamma can be described in terms of a set of integrated molecular programs underlying well-defined physiological systems, for example the induction of efficient antigen processing for MHC-mediated antigen presentation, which play clearly defined roles in pathogen resistance. A promising approach to the complexity of the IFN-gamma response is to extend the analysis of the less understood IFN-gamma-regulated genes in terms of molecular programs functional in pathogen resistance.

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To contain the coronavirus disease 2019 (COVID-19) pandemic, a safe and effective vaccine against the new severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is urgently needed in quantities sufficient to immunise large populations. In this study, we report the design, preclinical development, immunogenicity and anti-viral protective effect in rhesus macaques of the BNT162b2 vaccine candidate. BNT162b2 contains an LNP-formulated nucleoside-modified mRNA that encodes the spike glycoprotein captured in its prefusion conformation. After expression of the BNT162b2 coding sequence in cells, approximately 20% of the spike molecules are in the one-RBD ‘up’, two-RBD ‘down’ state. Immunisation of mice with a single dose of BNT162b2 induced dose level-dependent increases in pseudovirus neutralisation titers. Prime-boost vaccination of rhesus macaques elicited authentic SARS-CoV-2 neutralising geometric mean titers 10.2 to 18.0 times that of a SARS-CoV-2 convalescent human serum panel. BNT162b2 generated strong TH1 type CD4+ and IFNγ+ CD8+ T-cell responses in mice and rhesus macaques. The BNT162b2 vaccine candidate fully protected the lungs of immunised rhesus macaques from infectious SARS-CoV-2 challenge. BNT162b2 is currently being evaluated in a global, pivotal Phase 2/3 trial (NCT04368728).

The assembly of individual mammalian proteasome subunits into catalytically active 20S proteasome is not well understood. Herein, we report the identification and characterization of human and mouse homologues of the yeast proteasome maturating factor Ump1p. We delineate the region of hUMP1 implicated in the specific interaction with proteasome precursors and show that hUMP1 protein is absent from the mature form of the 20S proteasome. We also show that the transcript level of mammalian UMP1 is increased after IFN-␥ treatment and that mammalian UMP1 is functionally related to but not interchangeable with its yeast homologue. The proteasome is one of the major nonlysosomal proteases present in the cytosol and nucleus of cells. Through its catabolic functions, it is implicated in many cellular processes including the progression of cell cycle, the removal of misfolded proteins, apoptosis, and the production of peptides for presentation by MHC class I molecules (1-3). The proteasome is composed of a 20S barrel-shaped core particle, capped on each side by a 19S protein complex. Whereas the 20S proteasome can degrade short peptides, its association with the 19S caps forms the 26S proteasome, which is able to degrade multiubiquitylated protein substrates (4).The basic three-dimensional architecture of the 20S proteasome has been maintained from archaebacteria to humans and is characterized by four heptameric rings (5). The two outer rings are identical and are composed of ␣-subunits. The two inner rings, within which the catalytic centers are located, are also identical and are composed of ␤-subunits. Whereas the ␣-and ␤-rings of the archaebacterial 20S proteasome are formed of 7 identical ␣-subunits and 7 identical ␤-subunits, the more complex eukaryotic proteasomes contain at least 14 subunits, 7 distinct ␣-subunits, and 7 distinct ␤-subunits (6). In mammals, the existence of three additional ␤-subunits, which are expressed and incorporated into the 20S proteasome after IFN-␥ treatment, further increases the complexity of the proteasome composition. Contrary to the archaebacterial proteasome, in which all seven ␤-subunits are catalytically active, only three of the seven different ␤-subunits (␤1, ␤2, and ␤5) of the eukaryotic standard proteasome possess catalytic properties. In cells exposed to IFN-␥, these three catalytic subunits are replaced by three distinct ones (␤1i͞LMP2, ␤2i͞MECL-1, and ␤5i͞LMP7) resulting in the formation of a 20S proteasome termed immunoproteasome. The different cleavage specificity of the immunoproteasome compared with the standard proteasome has been shown to modulate the production of certain antigenic peptides presented by MHC class I molecules (2, 7).A host of sequential reactions is required to reach the complex quaternary structure of eukaryotic proteasomes. The active ␤-subunits carry N-terminal propeptides, which have been shown to play an important role, not only in the assembly and maturation of the 20S proteasome (8), but also to protect the N-terminal catalytic Thr of the matur...