Advances in Virus Research

Rabies infects all mammals; however, transmission cycles are only maintained in certain bat and carnivore species. The high incidence of rabies in Greater Kudu (Tragelaphus strepsiceros) observed in Namibia for over 40 years has led to postulation that independent virus transmission is occurring within this antelope population. We have analysed extensive experimental, epidemiological, phylogeographic and deep sequence data, which collectively refute maintenance of an independent rabies cycle in kudu. As rabies in kudu continues to have a negative impact on the Namibian agricultural sector, measures to protect kudu have been investigated, including the use of a third-generation oral rabies vaccine...

Reverse genetics is the prospective analysis of how genotype determines phenotype. In a typical experiment, a researcher alters a viral genome, then observes the phenotypic outcome. Among RNA viruses, this approach was first applied to positive-strand RNA viruses in the mid-1970s and over nearly 50 years has become a powerful and widely used approach for dissecting the mechanisms of viral replication and pathogenesis. During this time the global health importance of two virus groups, flaviviruses (genus Flavivirus, family Flaviviridae) and betacoronaviruses (genus Betacoronavirus, subfamily Orthocoronavirinae, family Coronaviridae), have dramatically increased, yet these viruses have genomes that are technically challenging to manipulate...

Phages are viruses that specifically infect bacteria, and their biodiversity contributes to historical and current development of phage therapy to treat myriad bacterial infections. Phage therapy holds promise as an alternative to failing chemical antibiotics, but there are benefits and costs of this technology. Here, we review the rich history of phage therapy, highlighting reasons (often political) why it was widely rejected by Western medicine until recently. One longstanding idea involves mixing different phages together in cocktails, to increase the probability of killing target pathogenic bacteria without pre-screening for phage susceptibility...

The evolution of human-virus associations is usually reconstructed from contemporary patterns of genomic diversity. An intriguing, though still rarely implemented, alternative is to search for the genetic material of viruses in archeological and medical archive specimens to document evolution as it happened. In this chapter, we present lessons from ancient DNA research and incorporate insights from virology to explore the potential range of applications and likely limitations of archeovirological approaches...

Alphaviruses are positive-strand RNA viruses, typically transmitted by mosquitoes between vertebrate hosts. They encode four essential replication proteins, the non-structural proteins nsP1-4, which possess the enzymatic activities of RNA capping, RNA helicase, site-specific protease, ADP-ribosyl removal and RNA polymerase. Alphaviruses have been key models in the study of membrane-associated RNA replication, which is a conserved feature among the positive-strand RNA viruses of animals and plants. We review new structural and functional information on the nsPs and their interaction with host proteins and membranes, as well as with viral RNA sequences...

Parainfluenza viruses, members of the enveloped, negative-sense, single stranded RNA Paramyxoviridae family, impact global child health as the cause of significant lower respiratory tract infections. Parainfluenza viruses enter cells by fusing directly at the cell surface membrane. How this fusion occurs via the coordinated efforts of the two molecules that comprise the viral surface fusion complex, and how these efforts may be blocked, are the subjects of this chapter. The receptor binding protein of parainfluenza forms a complex with the fusion protein of the virus, remaining stably associated until a receptor is reached...

Within only one year after the first detection of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), nearly 100 million infections were reported in the human population globally, with more than two million fatal cases. While SARS-CoV-2 most likely originated from a natural wildlife reservoir, neither the immediate viral precursor nor the reservoir or intermediate hosts have been identified conclusively. Due to its zoonotic origin, SARS-CoV-2 may also be relevant to animals. Thus, to evaluate the host range of the virus and to assess the risk to act as potential animal reservoir, a large number of different animal species were experimentally infected with SARS-CoV-2 or monitored in the field in the last months...

Herpes simplex viruses (HSV) cause chronic infection in humans that are characterized by periodic episodes of mucosal shedding and ulcerative disease. HSV causes millions of infections world-wide, with lifelong bouts of viral reactivation from latency in neuronal ganglia. Infected individuals experience different levels of disease severity and frequency of reactivation. There are two distantly related HSV species, with HSV-1 infections historically found most often in the oral niche and HSV-2 infections in the genital niche...

Over the last two decades, the viromes of our closest relatives, the African great apes (AGA), have been intensively studied. Comparative approaches have unveiled diverse evolutionary patterns, highlighting both stable host-virus associations over extended evolutionary timescales and much more recent viral emergence events. In this chapter, we summarize these findings and outline how they have shed a new light on the origins and evolution of many human-infecting viruses. We also show how this knowledge can be used to better understand the evolution of human health in relation to viral infections...

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Cellular compartmentalization of proteins and protein complex formation allow cells to tightly control biological processes. Therefore, understanding the subcellular localization and interactions of a specific protein is crucial to uncover its biological function. The advent of proximity labeling (PL) has reshaped cellular proteomics in infection biology. PL utilizes a genetically modified enzyme that generates a "labeling cloud" by covalently labeling proteins in close proximity to the enzyme. Fusion of a PL enzyme to a specific antibody or a "bait" protein of interest in combination with affinity enrichment mass spectrometry (AE-MS) enables the isolation and identification of the cellular proximity proteome, or proxisome...

Mass spectrometry imaging (MSI) is a label-free molecular imaging technique allowing an untargeted detection of a broad range of biomolecules and xenobiotics. MSI enables imaging of the spatial distribution of proteins, peptides, lipids and metabolites from a wide range of samples. To date, this technique is commonly applied to tissue sections in cancer diagnostics and biomarker development, but also molecular histology in general. Advances in the methodology and bioinformatics improved the resolution of MS images below the single cell level and increased the flexibility of the workflow...

The DNA viruses, Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV), are members of the gammaherpesvirus subfamily, a group of viruses whose infection is associated with multiple malignancies, including cancer. The primary host for these viruses is humans and, like all herpesviruses, infection with these pathogens is lifelong. Due to the persistence of gammaherpesvirus infection and the potential for cancer formation in infected individuals, there is a driving need to understand not only the biology of these viruses and how they remain undetected in host cells but also the mechanism(s) by which tumorigenesis occurs...

The vertebrate innate immune system confers host cells with mechanisms to protect against both evolutionarily ancient pathogens and newly emerging pathogenic strains. Innate immunity relies on the host cell's ability to distinguish between self and pathogen-derived molecules. To achieve this, the innate immune system uses germline encoded receptors called pattern recognition receptors (PRRs), which recognize various molecular signatures, including nucleic acids, proteins, lipids, glycans and glycolipids. Among these molecules, the recognition of pathogenic, mislocalized, or damaged DNA by cellular protein receptors, commonly called DNA sensors, represents a major surveillance pathway for initiating immune signaling...

Proteases precisely and irreversibly catalyze the hydrolysis of peptide bonds, regulating the fate, localization, and activity of many proteins. Consequently, proteolytic activity plays an important role in fundamental cellular processes such as differentiation and migration, immunological and inflammatory reactions, apoptosis and survival. During virus infection, host proteases are involved in several processes, from cell entry to initiation, progression and resolution of inflammation. On the other hand, many viruses encode their own highly specific proteases, responsible for the proteolytic processing of viral proteins, but, at the same time, to cleave host proteins to corrupt antiviral host responses and adjust protein activity to favor viral replication...

The cellular surfaceome and its residing extracellularly exposed proteins are involved in a multitude of molecular signaling processes across the viral infection cycle. Successful viral propagation, including viral entry, immune evasion, virion release and viral spread rely on dynamic molecular interactions with the surfaceome. Decoding of these viral-host surfaceome interactions using advanced technologies enabled the discovery of fundamental new functional insights into cellular and viral biology. In this review, we highlight recently developed experimental strategies, with a focus on spatial proteotyping technologies, aiding in the rational design of theranostic strategies to combat viral infections...

The host cell proteome undergoes a variety of dynamic changes during viral infection, elicited by the virus itself or host cell defense mechanisms. Studying these changes on a global scale by integrating functional and physical interactions within protein networks during infection is an important tool to understand pathology. Indeed, proteomics studies dissecting protein signaling cascades and interaction networks upon infection showed how global information can significantly improve understanding of disease mechanisms of diverse viral infections...

A critical step in the life cycle of a virus is spread to a new target cell, which generally involves the release of new viral particles from the infected cell which can then initiate infection in the next target cell. While cell-free viral particles released into the extracellular environment are necessary for long distance spread, there are disadvantages to this mechanism. These include the presence of immune system components, the low success rate of infection by single particles, and the relative fragility of viral particles in the environment...

The human betaherpesviruses, human cytomegalovirus (HCMV; species Human betaherpesvirus 5) and human herpesviruses 6A, 6B, and 7 (HHV-6A, -6B, and -7; species Human betaherpesviruses 6A, 6B, and 7) are highly prevalent and can cause severe disease in immune-compromised and immune-naive populations in well- and under-developed communities. Herpesvirus virion assembly is an intricate process that requires viral orchestration of host systems. In this review, we describe recent advances in some of the many cellular events relevant to assembly and egress of betaherpesvirus virions...

The flavivirus genus encompasses more than 75 unique viruses, including dengue virus which accounts for almost 390 million global infections annually. Flavivirus infection can result in a myriad of symptoms ranging from mild rash and flu-like symptoms, to severe encephalitis and even hemorrhagic fever. Efforts to combat the impact of these viruses have been hindered due to limited antiviral drug and vaccine development. However, the advancement of knowledge in the structural biology of flaviviruses over the last 25 years has produced unique perspectives for the identification of potential therapeutic targets...