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1.
Viruses ; 14(1)2021 12 22.
Article in English | MEDLINE | ID: covidwho-1636836

ABSTRACT

Human adenoviruses (HAdV) cause a variety of infections in human hosts, from self-limited upper respiratory tract infections in otherwise healthy people to fulminant pneumonia and death in immunocompromised patients. Many HAdV enter polarized epithelial cells by using the primary receptor, the Coxsackievirus and adenovirus receptor (CAR). Recently published data demonstrate that a potent neutrophil (PMN) chemoattractant, interleukin-8 (IL-8), stimulates airway epithelial cells to increase expression of the apical isoform of CAR (CAREx8), which results in increased epithelial HAdV type 5 (HAdV5) infection. However, the mechanism for PMN-enhanced epithelial HAdV5 transduction remains unclear. In this manuscript, the molecular mechanisms behind PMN mediated enhancement of epithelial HAdV5 transduction are characterized using an MDCK cell line that stably expresses human CAREx8 under a doxycycline inducible promoter (MDCK-CAREx8 cells). Contrary to our hypothesis, PMN exposure does not enhance HAdV5 entry by increasing CAREx8 expression nor through activation of non-specific epithelial endocytic pathways. Instead, PMN serine proteases are responsible for PMN-mediated enhancement of HAdV5 transduction in MDCK-CAREx8 cells. This is evidenced by reduced transduction upon inhibition of PMN serine proteases and increased transduction upon exposure to exogenous human neutrophil elastase (HNE). Furthermore, HNE exposure activates epithelial autophagic flux, which, even when triggered through other mechanisms, results in a similar enhancement of epithelial HAdV5 transduction. Inhibition of F-actin with cytochalasin D partially attenuates PMN mediated enhancement of HAdV transduction. Taken together, these findings suggest that HAdV5 can leverage innate immune responses to establish infections.


Subject(s)
Adenoviruses, Human/pathogenicity , Epithelial Cells/virology , Leukocyte Elastase/metabolism , Neutrophils/immunology , Virus Internalization , Adenoviruses, Human/immunology , Adenoviruses, Human/physiology , Animals , Autophagy , Coxsackie and Adenovirus Receptor-Like Membrane Protein/metabolism , Cytochalasin B/pharmacology , Dogs , Endocytosis , Humans , Immunity, Innate , Macrolides/pharmacology , Madin Darby Canine Kidney Cells , Receptors, Virus/metabolism
2.
Front Immunol ; 12: 729837, 2021.
Article in English | MEDLINE | ID: covidwho-1450810

ABSTRACT

We have developed a dual-antigen COVID-19 vaccine incorporating genes for a modified SARS-CoV-2 spike protein (S-Fusion) and the viral nucleocapsid (N) protein with an Enhanced T-cell Stimulation Domain (N-ETSD) to increase the potential for MHC class II responses. The vaccine antigens are delivered by a human adenovirus serotype 5 platform, hAd5 [E1-, E2b-, E3-], previously demonstrated to be effective in the presence of Ad immunity. Vaccination of rhesus macaques with the hAd5 S-Fusion + N-ETSD vaccine by subcutaneous prime injection followed by two oral boosts elicited neutralizing anti-S IgG and T helper cell 1-biased T-cell responses to both S and N that protected the upper and lower respiratory tracts from high titer (1 x 106 TCID50) SARS-CoV-2 challenge. Notably, viral replication was inhibited within 24 hours of challenge in both lung and nasal passages, becoming undetectable within 7 days post-challenge.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/prevention & control , Coronavirus Nucleocapsid Proteins/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Adenoviruses, Human/genetics , Adenoviruses, Human/immunology , Adenoviruses, Human/metabolism , Administration, Oral , Animals , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19 Vaccines/administration & dosage , Cytokines/blood , Immunization, Secondary/methods , Immunoglobulin G/blood , Lung/virology , Macaca mulatta , Nose/virology , Phosphoproteins/immunology , Protein Domains/immunology , T-Lymphocytes, Helper-Inducer/immunology , Vaccination , Virus Replication/immunology
3.
Viruses ; 13(7)2021 06 24.
Article in English | MEDLINE | ID: covidwho-1389547

ABSTRACT

Adenovirus vector-based genetic vaccines have emerged as a powerful strategy against the SARS-CoV-2 health crisis. This success is not unexpected because adenoviruses combine many desirable features of a genetic vaccine. They are highly immunogenic and have a low and well characterized pathogenic profile paired with technological approachability. Ongoing efforts to improve adenovirus-vaccine vectors include the use of rare serotypes and non-human adenoviruses. In this review, we focus on the viral capsid and how the choice of genotypes influences the uptake and subsequent subcellular sorting. We describe how understanding capsid properties, such as stability during the entry process, can change the fate of the entering particles and how this translates into differences in immunity outcomes. We discuss in detail how mutating the membrane lytic capsid protein VI affects species C viruses' post-entry sorting and briefly discuss if such approaches could have a wider implication in vaccine and/or vector development.


Subject(s)
Adenoviruses, Human/immunology , Adenoviruses, Human/physiology , Capsid/metabolism , Genetic Vectors , Viral Vaccines/immunology , Virus Internalization , Adaptive Immunity , Adenoviruses, Human/genetics , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , Capsid/immunology , Capsid Proteins/genetics , Capsid Proteins/immunology , Capsid Proteins/metabolism , Clinical Trials as Topic , Humans , Immunity, Innate , Mice , SARS-CoV-2/immunology
4.
Viruses ; 12(12)2020 11 26.
Article in English | MEDLINE | ID: covidwho-951267

ABSTRACT

The aim of this review is to highlight how, in a syngeneic system, human mononuclear phagocytes respond to environments containing human adenovirus (HAdV) and soluble extracellular proteins that influence their innate immune response. Soluble extracellular proteins, including immunoglobulins, blood clotting factors, proteins of the complement system, and/or antimicrobial peptides (AMPs) can exert direct effects by binding to a virus capsid that modifies interactions with pattern recognition receptors and downstream signaling. In addition, the presence, generation, or secretion of extracellular proteins can indirectly influence the response to HAdVs via the activation and recruitment of cells at the site of infection.


Subject(s)
Adenovirus Infections, Human/immunology , Adenovirus Infections, Human/virology , Adenoviruses, Human/immunology , Host-Pathogen Interactions/immunology , Immunity, Innate , Phagocytes/immunology , Phagocytes/metabolism , Animals , Antibodies, Viral/immunology , Cellular Microenvironment , Complement System Proteins/immunology , Dendritic Cells , Extracellular Space/metabolism , Humans , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/metabolism , Lymphocytes/immunology , Lymphocytes/metabolism
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