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The 1918 Influenza A Pandemic
Published in Patricia G. Melloy, Viruses and Society, 2023
Influenza virus is a classic example of a lytic virus as described in Chapter 1. This type of virus will invade host cells, use the host cell machinery to make copies of itself, and then get out. Influenza uses the host cell as if it owns the place. First, the virus binds to a host cellular receptor. Then the virus enters through the cellular trafficking network, sneaking into endosomes that normally bring in materials needed by the cell. Next, the viral genome is pushed into the cytoplasm of the cell, where it can be moved into the nucleus to make an RNA copy of the genome that can be recognized by the workings of the cell for genome replication. It is important to note that the influenza virus uses the cell’s own receptors, membranes, cytoskeleton, and ribosomes to complete its life cycle (Figure 3.1) (Lostroh 2019).
The Viruses
Published in Julius P. Kreier, Infection, Resistance, and Immunity, 2022
The neuraminidase enables influenza virus to penetrate mucous secretions by virtue of its enzymatic activity. Neuraminidase also promotes the release of the virions as they bud from the cell surface. The envelope hemagglutinin serves to attach the virus to cells by binding to cell receptors. The virus then enters the cell in an endosomal vesicle. As the pH of the vesicle becomes acidic, the hemagglutinin changes conformation and allows fusion of the viral envelope with the endosomal membrane, resulting in uncoating and release of the viral nucleocapsid into the cell cytoplasm. Influenza viruses, unlike most RNA viruses, replicate in the cell nucleus rather than in the cytoplasm. The influenza virus has a negative stranded RNA, which is not translated directly by the host cell. Initiation of replication is possible because the virus encodes and packages its own RNA-dependent RNA polymerase. The viral RNA consists of eight different single-stranded segments, each coding for at least one of the major viral proteins. If two strains of influenza A virus infect the same cell, an interchange of entire genomic segments can occur (reassortment). Unlike classical genetic recombination, splicing and rejoining of the nucleic acid is not required in this process. Related influenza A viruses also infect animals of a variety of species, including pigs and many types of birds. These viral strains represent potential pools of genetic material for pathogenic human influenza strains by reassortment of genomic segments between animal and human influenza strains that infect a common host.
The Emerging Role of Exosome Nanoparticles in Regenerative Medicine
Published in Harishkumar Madhyastha, Durgesh Nandini Chauhan, Nanopharmaceuticals in Regenerative Medicine, 2022
Zahra Sadat Hashemi, Mahlegha Ghavami, Saeed Khalili, Seyed Morteza Naghib
Biogenesis of exosomes is related to the endosome/lysosome pathway. In an endosome, budding from the perimeter membrane into the endosome lumen forms the membrane-bound intraluminal vesicles (ILVs). This late endosome is a multi-vesicular compartment also called multi-vesicular bodies (MVBs). Finally the MVB will be fused with the plasma membrane or the lysosomes. In the case of fusion with the plasma membrane, these ILVs will be released as exosomes (Johnsen et al. 2014; Raposo and Stoorvogel 2013; Yáñez-Mó et al. 2015). Consequently, the exosomes have endosome-derived membrane. This fusion is executed via a series of Rab GTPase proteins including RAB11, RAB27A, RAB27B, and RAB35 (Ostrowski et al. 2010). The micro-vesicles could directly bud from the plasma membrane and their size is larger than EVs (100–500 nm), so they have plasma-derived membrane. The third kind of EVs are apoptotic bodies that are 500–1000 nm in size and are released during the late phase of apoptosis (György et al. 2011).
The engineering challenges and opportunities when designing potent ionizable materials for the delivery of ribonucleic acids
Published in Expert Opinion on Drug Delivery, 2022
Yan Ming Anson Lau, Janice Pang, Grayson Tilstra, Julien Couture-Senécal, Omar F. Khan
The endosomal pathway exists to maintain cell homeostasis by sorting, processing, recycling, and degrading extracellular material that is internalized by a cell [102,103] (Figure 3). After being internalized by a cell, a nanoparticle will be transported into an early endosome. These early endosomes have a spherical vesicular body with outreaching tubules and act as a sorting station for endocytosed material. The material can be recycled back to the plasma membrane, transferred between organelles, or directed further down the endosomal pathway. Early endosomes then mature into late endosomes, which are large multivesicular structures without tubules. Late endosomes primarily route their cargo toward lysosomes for degradation though they can continue to recycle and transfer material to other organelles as well [84,104,105]. Throughout this process, the internal environment of proteins and lipids within the sub-compartments evolves [106], and the pH steadily drops from physiological 7.4, to 6.5 in the early endosome, ~6 in the late endosome, and ~5 in the lysosome [107].
Drugs repurposing for SARS-CoV-2: new insight of COVID-19 druggability
Published in Expert Review of Anti-infective Therapy, 2022
Sujit Kumar Debnath, Monalisha Debnath, Rohit Srivastava, Abdelwahab Omri
SID 26681509 and E64d are also CTSL inhibitors and are working on the cleavage of CTSL [40]. These drugs inhibited the pseudovirus infection in the Huh7 cell line infected with SARS-CoV-2. E64d exhibited lower toxicity than SID 26681509. Amantadine (previously approved for influenza and parkinsonism) downregulated the gene transcription of CTSL and showed an anti-pseudovirus effect in humanized mice [40]. An endosome is formed once the viral particles enter into cells. Afterward, M2 protein initiates the proton channel resulting in carrying protons into the interior of the virion. Due to the lipophilic nature, amantadine easily crosses the endosome membrane and interferes with the virion release into the cell [41]. An open-labeled, randomized clinical trial was conducted on 84 COVID-19 patients suffering from pneumonia where nafamostat mesylate was effective [42]. Developing a broad-spectrum protease inhibitor for SARS-CoV-2 is complex as proteases are expressed diversely into different tissues [43].
Regulation of cytochrome P450 enzyme activity and expression by nitric oxide in the context of inflammatory disease
Published in Drug Metabolism Reviews, 2020
Edward T. Morgan, Cene Skubic, Choon-myung Lee, Kaja Blagotinšek Cokan, Damjana Rozman
In general, proteasomal degradation regulates the turnover of short-lived proteins, while the ALP regulates degradation of organelles and long-lived proteins (Schmid and Munz 2007; Ohsumi 2014). Proteins are delivered to the lysosomes by three mechanisms. In microautophagy, the cytosol is imported into the lysosomes via invagination of the lysosomal membrane. In chaperone-mediated autophagy, targeted proteins carry signal peptide tags, and cytosolic and lysosomal HSC70 chaperones assist the LAMP-2a transporter to import the protein cargo (Schmid and Munz 2007). Macroautophagy is the most common autophagic pathway, involving the engulfment of cytosolic constituents by a double membrane vesicle, the autophagosome (Ohsumi 2014). This fuses with lysosomes or late endosomes for degradation.