Current Issues in Molecular Biology

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Open AccessReview

Stealth Strategies of Mycobacterium tuberculosis for Immune Evasion

by Muhammad Ahsan Naeem, Waqas Ahmad, Rohit Tyagi, Qaiser Akram, Muhammad Younus and Xilin Liu

Curr. Issues Mol. Biol. 2021, 41(1), 597-616; https://doi.org/10.21775/cimb.041.597 - 17 Oct 2020

Cited by 10 | Viewed by 1448

Tuberculosis is a devastating disease causing high mortality all over the world, especially in the developing countries. Mycobacterium tuberculosis (M. tb) is the causative agent of tuberculosis which replicates in the intracellular environment of host macrophages. Although the host immune system [...] Read more.

Tuberculosis is a devastating disease causing high mortality all over the world, especially in the developing countries. Mycobacterium tuberculosis (M. tb) is the causative agent of tuberculosis which replicates in the intracellular environment of host macrophages. Although the host immune system is capable of completely eliminating the pathogen, co-evolution of M. tb with humans has resulted in its ability to hijack the host innate and adaptive immune systems in numerous ways. Limited recent progress has been made in the understanding of M. tb immune escape mechanisms, hence exploration of survival strategies of M. tb has been critically reviewed with an insight into understanding its pathogenesis. We summarized the recent studies regarding the modulation of innate immune response, adaptive immune response, epigenetics and the role of miRNA. All of these advancements suggest that M. tb is well-familiarize with the host immune system and possess the ability to hijack it for intracellular survival. Full article

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Open AccessReview

The Cell Wall of Bacillus subtilis

by Danae Morales Angeles and Dirk-Jan Scheffers

Curr. Issues Mol. Biol. 2021, 41(1), 539-596; https://doi.org/10.21775/cimb.041.539 - 13 Oct 2020

Cited by 19 | Viewed by 1805

Abstract

The cell wall of Bacillus subtilis is a rigid structure on the outside of the cell that forms the first barrier between the bacterium and the environment, and at the same time maintains cell shape and withstands the pressure generated by the cell's [...] Read more.

The cell wall of Bacillus subtilis is a rigid structure on the outside of the cell that forms the first barrier between the bacterium and the environment, and at the same time maintains cell shape and withstands the pressure generated by the cell's turgor. In this review, the chemical composition of peptidoglycan, teichoic and teichuronic acids, the polymers that comprise the cell wall, and the biosynthetic pathways involved in their synthesis will be discussed, as well as the architecture of the cell wall. B. subtilis has been the first bacterium for which the role of an actin-like cytoskeleton in cell shape determination and peptidoglycan synthesis was identified and for which the entire set of peptidoglycan synthesizing enzymes has been localised. The role of the cytoskeleton in shape generation and maintenance will be discussed and results from other model organisms will be compared to what is known for B. subtilis. Finally, outstanding questions in the field of cell wall synthesis will be discussed. Full article

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Open AccessReview

Groundwater Microbial Communities in Times of Climate Change

by Alice Retter, Clemens Karwautz and Christian Griebler

Curr. Issues Mol. Biol. 2021, 41(1), 509-538; https://doi.org/10.21775/cimb.041.509 - 07 Oct 2020

Cited by 26 | Viewed by 1539

Abstract

Climate change has a massive impact on the global water cycle. Subsurface ecosystems, the earth largest reservoir of liquid freshwater, currently experience a significant increase in temperature and serious consequences from extreme hydrological events. Extended droughts as well as heavy rains and floods [...] Read more.

Climate change has a massive impact on the global water cycle. Subsurface ecosystems, the earth largest reservoir of liquid freshwater, currently experience a significant increase in temperature and serious consequences from extreme hydrological events. Extended droughts as well as heavy rains and floods have measurable impacts on groundwater quality and availability. In addition, the growing water demand puts increasing pressure on the already vulnerable groundwater ecosystems. Global change induces undesired dynamics in the typically nutrient and energy poor aquifers that are home to a diverse and specialized microbiome and fauna. Current and future changes in subsurface environmental conditions, without doubt, alter the composition of communities, as well as important ecosystem functions, for instance the cycling of elements such as carbon and nitrogen. A key role is played by the microbes. Understanding the interplay of biotic and abiotic drivers in subterranean ecosystems is required to anticipate future effects of climate change on groundwater resources and habitats. This review summarizes potential threats to groundwater ecosystems with emphasis on climate change and the microbial world down below our feet in the water saturated subsurface. Full article

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Open AccessReview

Alphaherpesvirus Vaccines

by Clare Burn Aschner and Betsy C. Herold

Curr. Issues Mol. Biol. 2021, 41(1), 469-508; https://doi.org/10.21775/cimb.041.469 - 23 Sep 2020

Cited by 17 | Viewed by 786

Abstract

Prophylactic and therapeutic vaccines for the alphaherpesviruses including varicella zoster virus (VZV) and herpes simplex virus types 1 and 2 have been the focus of enormous preclinical and clinical research. A live viral vaccine for prevention of chickenpox and a subunit therapeutic vaccine [...] Read more.

Prophylactic and therapeutic vaccines for the alphaherpesviruses including varicella zoster virus (VZV) and herpes simplex virus types 1 and 2 have been the focus of enormous preclinical and clinical research. A live viral vaccine for prevention of chickenpox and a subunit therapeutic vaccine to prevent zoster are highly successful. In contrast, progress towards the development of effective prophylactic or therapeutic vaccines against HSV-1 and HSV-2 has met with limited success. This review provides an overview of the successes and failures, the different types of immune responses elicited by various vaccine modalities, and the need to reconsider the preclinical models and immune correlates of protection against HSV. Full article

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Open AccessReview

Oncolytic HSV Vectors and Anti-Tumor Immunity

by Joseph C. Glorioso, Justus B. Cohen, William F. Goins, Bonnie Hall, Joseph W. Jackson, Gary Kohanbash, Nduka Amankulor, Balveen Kaur, Michael A. Caligiuri, E. Antonio Chiocca, Eric C. Holland and Christophe Quéva

Curr. Issues Mol. Biol. 2021, 41(1), 381-468; https://doi.org/10.21775/cimb.041.381 - 17 Sep 2020

Cited by 7 | Viewed by 1506

Abstract

The therapeutic promise of oncolytic viruses (OVs) rests on their ability to both selectively kill tumor cells and induce anti-tumor immunity. The potential of tumors to be recognized and eliminated by an effective anti-tumor immune response has been spurred on by the discovery [...] Read more.

The therapeutic promise of oncolytic viruses (OVs) rests on their ability to both selectively kill tumor cells and induce anti-tumor immunity. The potential of tumors to be recognized and eliminated by an effective anti-tumor immune response has been spurred on by the discovery that immune checkpoint inhibition can overcome tumor-specific cytotoxic T cell (CTL) exhaustion and provide durable responses in multiple tumor indications. OV-mediated tumor destruction is now recognized as a powerful means to assist in the development of anti-tumor immunity for two important reasons: (i) OVs, through the elicitation of an anti-viral response and the production of type I interferon, are potent stimulators of inflammation and can be armed with transgenes to further enhance anti-tumor immune responses; and (ii) lytic activity can promote the release of tumor-associated antigens (TAAs) and tumor neoantigens that function as in situ tumor-specific vaccines to elicit adaptive immunity. Oncolytic herpes simplex viruses (oHSVs) are among the most widely studied OVs for the treatment of solid malignancies, and Amgen's oHSV Imlygic^® for the treatment of melanoma is the only OV approved in major markets. Here we describe important biological features of HSV that make it an attractive OV, clinical experience with HSV-based vectors, and strategies to increase applicability to cancer treatment. Full article

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Open AccessReview

Aquatic Viruses and Climate Change

by Rui Zhang, Markus G. Weinbauer and Peter Peduzzi

Curr. Issues Mol. Biol. 2021, 41(1), 357-380; https://doi.org/10.21775/cimb.041.357 - 13 Sep 2020

Cited by 12 | Viewed by 1407

Abstract

The viral component in aquatic systems clearly needs to be incorporated into future ocean and inland water climate models. Viruses have the potential to influence carbon and nutrient cycling in aquatic ecosystems significantly. Changing climate likely has both direct and indirect influence on [...] Read more.

The viral component in aquatic systems clearly needs to be incorporated into future ocean and inland water climate models. Viruses have the potential to influence carbon and nutrient cycling in aquatic ecosystems significantly. Changing climate likely has both direct and indirect influence on virus-mediated processes, among them an impact on food webs, biogeochemical cycles and on the overall metabolic performance of whole ecosystems. Here we synthesise current knowledge on potential climate-related consequences for viral assemblages, virus-host interactions and virus functions, and in turn, viral processes contributing to climate change. There is a need to increase the accuracy of predictions of climate change impacts on virus- driven processes, particularly of those linked to biological production and biogeochemical cycles. Comprehension of the relationships between microbial/viral processes and global phenomena is essential to predict the influence on as well as the response of the biosphere to global change. Full article

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Open AccessReview

Alphaherpesvirus Latency and Reactivation with a Focus on Herpes Simplex Virus

by Nancy M. Sawtell and Richard L. Thompson

Curr. Issues Mol. Biol. 2021, 41(1), 267-356; https://doi.org/10.21775/cimb.041.267 - 04 Sep 2020

Cited by 11 | Viewed by 1124

Abstract

We are at an interesting time in the understanding of alpha herpesvirus latency and reactivation and their implications to human disease. Conceptual advances have come from both animal and neuronal culture models. This review focuses on the concept that the tegument protein and [...] Read more.

We are at an interesting time in the understanding of alpha herpesvirus latency and reactivation and their implications to human disease. Conceptual advances have come from both animal and neuronal culture models. This review focuses on the concept that the tegument protein and viral transactivator VP16 plays a major role in the transition from latency to the lytic cycle. During acute infection, regulation of VP16 transactivation balances spread in the nervous system, establishment of latent infections and virulence. Reactivation is dependent on this transactivator to drive entry into the lytic cycle. In vivo de novo expression of VP16 protein is mediated by sequences conferring pre-immediate early transcription embedded in the normally leaky late promoter. In vitro, alternate mechanisms regulating VP16 expression in the context of latency have come from the SCG neuron culture model and include the concepts that (i) generalized transcriptional derepression of the viral genome and sequestration of VP16 in the cytoplasm for ~48 hours (Phase I) precedes and is required for VP16-dependent reactivation (Phase II); and (ii) a histone methyl/phospho switch during Phase I is required for Phase II reactivation. The challenge to the field is reconciling these data into a unified model of virus reactivation. The greatest enemy of knowledge is not ignorance, it is the illusion of knowledge.---Daniel J. Boorstin. The task of compiling this review was uncomfortably humbling, as if cataloging the stars in the universe. While not completely dark, our night sky is missing a multitude of studies which are among the many points of light contributing to our field. This article is a focused review in which we discuss from the vantage point of our expertise, just a handful of concepts that have or are emerging. A lookback at some of the pioneering work that grounds our field is also included. Full article

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Open AccessReview

The Fate of Incoming HSV-1 Genomes Entering the Nucleus

by Oren Kobiler and Amichay Afriat

Curr. Issues Mol. Biol. 2021, 41(1), 221-266; https://doi.org/10.21775/cimb.041.221 - 03 Sep 2020

Cited by 7 | Viewed by 992

Abstract

Herpesvirus genomes enter the eukaryotic nucleus as large linear double stranded DNA molecules that are free of any proteins (naked DNA). Once inside the nucleus, the HSV-1 genomes immediately associate with proteins that will be instrumental in the organization and regulation of these [...] Read more.

Herpesvirus genomes enter the eukaryotic nucleus as large linear double stranded DNA molecules that are free of any proteins (naked DNA). Once inside the nucleus, the HSV-1 genomes immediately associate with proteins that will be instrumental in the organization and regulation of these genomes. These initial interactions are thought to determine the fate of the infecting genomes. In general, the host cell has evolved several mechanisms to suppress viral genomes and induce latent or abortive infections. On the other hand, the virus has evolved to use viral and cellular factors to promote lytic infection. Recent findings suggest that not all viral genomes in the infected nucleus will develop progeny and that not all genetically identical cells will support successful virus propagation. Thus, the decision between different fates of infection is determined at both single-cell and single-genome levels. Here we summarize current knowledge on the conditions and interactions that lead to each outcome and discuss the unknown determinants. Full article

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Open AccessReview

Navigating the Cytoplasm: Delivery of the Alphaherpesvirus Genome to the Nucleus

by Gregory A. Smith

Curr. Issues Mol. Biol. 2021, 41(1), 171-220; https://doi.org/10.21775/cimb.041.171 - 18 Aug 2020

Cited by 8 | Viewed by 743

Abstract

Herpesviruses virions are large and complex structures that deliver their genetic content to nuclei upon entering cells. This property is not unusual as many other viruses including the adenoviruses, orthomyxoviruses, papillomaviruses, polyomaviruses, and retroviruses, do likewise. However, the means by which viruses in [...] Read more.

Herpesviruses virions are large and complex structures that deliver their genetic content to nuclei upon entering cells. This property is not unusual as many other viruses including the adenoviruses, orthomyxoviruses, papillomaviruses, polyomaviruses, and retroviruses, do likewise. However, the means by which viruses in the alphaherpesvirinae subfamily accomplish this fundamental stage of the infectious cycle is tied to their defining ability to efficiently invade the nervous system. Fusion of the viral envelope with a cell membrane results in the deposition of the capsid, along with an assortment of tegument proteins, into the cytosol. Establishment of infection requires that the capsid traverse the cytosol, dock at a nuclear pore, and inject its genome into the nucleoplasm. Accumulating evidence indicates that the capsid is not the effector of this delivery process, but is instead shepherded by tegument proteins that remain capsid bound. At the same time, tegument proteins that are released from the capsid upon entry act to increase the susceptibility of the cell to the ensuing infection. Mucosal epithelial cells and neurons are both susceptible to alphaherpesvirus infection and, together, provide the niche to which these viruses have adapted. Although much has been revealed about the functions of de novo expressed tegument proteins during the late stages of assembly and egress, this review will specifically address the roles of tegument proteins brought into the cell with the incoming virion, and our current understanding of alphaherpesvirus genome delivery to nuclei. Full article

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Open AccessReview

Nuclear Egress

by Elizabeth B. Draganova, Michael K. Thorsen and Ekaterina E. Heldwein

Curr. Issues Mol. Biol. 2021, 41(1), 125-170; https://doi.org/10.21775/cimb.041.125 - 07 Aug 2020

Cited by 26 | Viewed by 803

Abstract

During viral replication, herpesviruses utilize a unique strategy, termed nuclear egress, to translocate capsids from the nucleus into the cytoplasm. This initial budding step transfers a newly formed capsid from within the nucleus, too large to fit through nuclear pores, through the inner [...] Read more.

During viral replication, herpesviruses utilize a unique strategy, termed nuclear egress, to translocate capsids from the nucleus into the cytoplasm. This initial budding step transfers a newly formed capsid from within the nucleus, too large to fit through nuclear pores, through the inner nuclear membrane to the perinuclear space. The perinuclear enveloped virion must then fuse with the outer nuclear membrane to be released into the cytoplasm for further maturation, undergoing budding once again at the trans-Golgi network or early endosomes, and ultimately exit the cell non-lytically to spread infection. This first budding process is mediated by two conserved viral proteins, UL31 and UL34, that form a heterodimer called the nuclear egress complex (NEC). This review focuses on what we know about how the NEC mediates capsid transport to the perinuclear space, including steps prior to and after this budding event. Additionally, we discuss the involvement of other viral proteins in this process and how NEC-mediated budding may be regulated during infection. Full article

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Open AccessReview

Entry of Alphaherpesviruses

by Tina M. Cairns and Sarah A. Connolly

Curr. Issues Mol. Biol. 2021, 41(1), 63-124; https://doi.org/10.21775/cimb.041.063 - 07 Aug 2020

Cited by 11 | Viewed by 740

Abstract

Alphaherpesviruses are enveloped viruses that enter cells by fusing the viral membrane with a host cell membrane, either within an endocytic vesicle or at the plasma membrane. This entry event is mediated by a set of essential entry glycoproteins, including glycoprotein D (gD), [...] Read more.

Alphaherpesviruses are enveloped viruses that enter cells by fusing the viral membrane with a host cell membrane, either within an endocytic vesicle or at the plasma membrane. This entry event is mediated by a set of essential entry glycoproteins, including glycoprotein D (gD), gHgL, and gB. gHgL and gB are conserved among herpesviruses, but gD is unique to the alphaherpesviruses and is not encoded by all alphaherpesviruses. gD is a receptor-binding protein, the heterodimer gHgL serves as a fusion regulator, and gB is a class III viral fusion protein. Sequential interactions among these glycoproteins are thought to trigger the virus to fuse at the right place and time. Structural studies of these glycoproteins from multiple alphaherpesviruses has enabled the design and interpretation of functional studies. The structures of gD in a receptor- bound and in an unliganded form reveal a conformational change in the C terminus of the gD ectodomain upon receptor binding that may serve as a signal for fusion. By mapping neutralizing antibodies to the gHgL structures and constructing interspecies chimeric forms of gHgL, interaction sites for both gD and gB on gHgL have been proposed. A comparison of the post fusion structure of gB and an alternative conformation of gB visualized using cryo- electron tomography suggests that gB undergoes substantial refolding to execute membrane fusion. Although these structures have provided excellent insights into the entry mechanism, many questions remain about how these viruses coordinate the interactions and conformational changes required for entry. Full article

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Open AccessReview

Invasion of the Nervous System

by Orkide O. Koyuncu, Lynn W. Enquist and Esteban A. Engel

Curr. Issues Mol. Biol. 2021, 41(1), 1-62; https://doi.org/10.21775/cimb.041.001 - 29 Jul 2020

Cited by 6 | Viewed by 799

Abstract

In vertebrates, the nervous system (NS) is composed of a peripheral collection of neurons (the peripheral nervous system, PNS), a central set found in the brain and spinal cord (the central nervous system, CNS). The NS is protected by rather complicated multi-layer barriers [...] Read more.

In vertebrates, the nervous system (NS) is composed of a peripheral collection of neurons (the peripheral nervous system, PNS), a central set found in the brain and spinal cord (the central nervous system, CNS). The NS is protected by rather complicated multi-layer barriers that allow access to nutrients and facilitate contact with the peripheral tissues, but block entry of pathogens and toxins. Virus infections usually begin in peripheral tissues and if these barriers are weakened, they can spread into the PNS and more rarely into the CNS. Most viral infections of the NS are opportunistic or accidental pathogens that gain access via the bloodstream (e.g., HIV and various arboviruses). But a few have evolved to enter the NS efficiently by invading neurons directly and by exploiting neuronal cell biology (e.g., rhabdoviruses and alphaherpesviruses). Most NS infections are devastating and difficult to manage. Remarkably, the alphaherpesviruses (α-HVs) establish life-long quiescent infections in the PNS, with rare but often serious CNS pathology. In this review, we will focus on how α-HVs gain access to and spread in the NS, with particular emphasis on bidirectional transport and spread within and between neurons and neural circuits, which is regulated by complex viral-host protein interactions. Finally, we will describe the wide use of α-HVs as tools to study nerve connectivity and function in animal models. Full article

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Curr. Issues Mol. Biol., Volume 41, Issue 1 (February 2021) – 12 articles

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