Apoptosis during ZIKA Virus Infection: Too Soon or Too Late?

Cell death by apoptosis is a major cellular response in the control of tissue homeostasis and as a defense mechanism in the case of cellular aggression such as an infection. Cell self-destruction is part of antiviral responses, aimed at limiting the spread of a virus. Although it may contribute to the deleterious effects in infectious pathology, apoptosis remains a key mechanism for viral clearance and the resolution of infection. The control mechanisms of cell death processes by viruses have been extensively studied. Apoptosis can be triggered by different viral determinants through different pathways as a result of virally induced cell stresses and innate immune responses. Zika virus (ZIKV) induces Zika disease in humans, which has caused severe neurological forms, birth defects, and microcephaly in newborns during the last epidemics. ZIKV also surprised by revealing an ability to persist in the genital tract and in semen, thus being sexually transmitted. Mechanisms of diverting antiviral responses such as the interferon response, the role of cytopathic effects and apoptosis in the etiology of the disease have been widely studied and debated. In this review, we examined the interplay between ZIKV infection of different cell types and apoptosis and how the virus deals with this cellular response. We illustrate a duality in the effects of ZIKV-controlled apoptosis, depending on whether it occurs too early or too late, respectively, in neuropathogenesis, or in long-term viral persistence. We further discuss a prospective role for apoptosis in ZIKV-related therapies, and the use of ZIKV as an oncolytic agent.

Host-virus interaction and viral evasion.

With each infectious pandemic or outbreak, the medical community feels the need to revisit basic concepts of immunology to understand and overcome the difficult times brought about by these infections. Regarding viruses, they have historically been responsible for many deaths, and such a peculiarity occurs because they are known to be obligate intracellular parasites that depend upon the host's cell machinery for their replication. Successful infection with the production of essential viral components requires constant viral evolution as a strategy to manipulate the cellular environment, including host internal factors, the host's nonspecific and adaptive immune responses to viruses, the metabolic and energetic state of the infected cell, and changes in the intracellular redox environment during the viral infection cycle. Based on this knowledge, it is fundamental to develop new therapeutic strategies for controlling viral dissemination, by means of antiviral therapies, vaccines, or antioxidants, or by targeting the inhibition or activation of cell signaling pathways or metabolic pathways that are altered during infection. The rapid recovery of altered cellular homeostasis during viral infection is still a major challenge. Here, we review the strategies by which viruses evade the host's immune response and potential tools used to develop more specific antiviral therapies to cure, control, or prevent viral diseases.

PANoptosis in microbial infection.

The immune system has evolved multiple mechanisms to restrict microbial infections and regulate inflammatory responses. Without appropriate regulation, infection-induced inflammatory pathology can be deadly. The innate immune system recognizes the microbial molecules conserved in many pathogens and engages a rapid response by producing inflammatory mediators and activating programmed cell death pathways, including pyroptosis, apoptosis, and necroptosis. Activation of pattern recognition receptors, in combination with inflammatory cytokine-induced signaling through death domain-containing receptors, initiates a highly interconnected cell death process called PANoptosis (pyroptosis, apoptosis, necroptosis). Broadly speaking, PANoptosis is critical for restricting a wide range of pathogens (including bacteria, viruses, fungi, and parasites), which we describe in this review. We propose that re-examining the role of cell death and inflammatory cytokines through the lens of PANoptosis will advance our understanding of host-pathogen evolution and may reveal new treatment strategies for controlling a wide range of infectious diseases.

Tick-virus interactions: Current understanding and future perspectives.

Ticks are the primary vector of arboviruses in temperate climates worldwide. They are both the vector of these pathogens to humans and an integral component of the viral sylvatic cycle. Understanding the tick-pathogen interaction provides information about the natural maintenance of these pathogens and informs the development of countermeasures against human infection. In this review, we discuss currently available information on tick-viral interactions within the broader scope of general tick immunology. While the tick immune response to several pathogens has been studied extensively, minimal work centres on responses to viral infection. This is largely due to the high pathogenicity of tick-borne viruses; this necessitates high-containment laboratories or low-pathogenicity substitute viruses. This has biased most research towards tick-borne flaviviruses. More work is required to fully understand the role of tick-virus interaction in sylvatic cycling and transmission of diverse tick-borne viruses.

Coronavirus disease 2019-Historical context, virology, pathogenesis, immunotherapy, and vaccine development.

The current Coronavirus Disease 2019 (COVID-19) pandemic is causing great alarm around the world. The pathogen for COVID-19 - severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) - is the seventh known coronavirus to cause pneumonia in humans. While much remains unknown about SARS-CoV-2, physicians and researchers have begun to publish relevant findings, and much evidence is available on coronaviruses previously circulating in human and animal populations. In this review, we situate COVID-19 in its context as a transboundary viral disease, and provide a comprehensive discussion focused on the discovery, spread, virology, pathogenesis, and clinical features of this disease, its causative coronaviral pathogen, and approaches to combating the disease through immunotherapies and other treatments and vaccine development. An epidemiological survey revealed a potentially large number of asymptomatic SARS-CoV-2 carriers within the population, which may hamper efforts against COVID-19. Finally, we emphasize that vaccines against SARS-CoV-2, which may be developed by 2021, will be essential for prevention of COVID-19.

Hijacking the Supplies: Metabolism as a Novel Facet of Virus-Host Interaction.

Viral replication is a process that involves an extremely high turnover of cellular molecules. Since viruses depend on the host cell to obtain the macromolecules needed for their proper replication, they have evolved numerous strategies to shape cellular metabolism and the biosynthesis machinery of the host according to their specific needs. Technologies for the rigorous analysis of metabolic alterations in cells have recently become widely available and have greatly expanded our knowledge of these crucial host-pathogen interactions. We have learned that most viruses enhance specific anabolic pathways and are highly dependent on these alterations. Since uninfected cells are far more plastic in their metabolism, targeting of the virus-induced metabolic alterations is a promising strategy for specific antiviral therapy and has gained great interest recently. In this review, we summarize the current advances in our understanding of metabolic adaptations during viral infections, with a particular focus on the utilization of this information for therapeutic application.

Infection against infection: parasite antagonism against parasites, viruses and bacteria.

BACKGROUND: Infectious diseases encompass a large spectrum of diseases that threaten human health, and coinfection is of particular importance because pathogen species can interact within the host. Currently, the antagonistic relationship between different pathogens during concurrent coinfections is defined as one in which one pathogen either manages to inhibit the invasion, development and reproduction of the other pathogen or biologically modulates the vector density. In this review, we provide an overview of the phenomenon and mechanisms of antagonism of coinfecting pathogens involving parasites. MAIN BODY: This review summarizes the antagonistic interaction between parasites and parasites, parasites and viruses, and parasites and bacteria. At present, relatively clear mechanisms explaining polyparasitism include apparent competition, exploitation competition, interference competition, biological control of intermediate hosts or vectors and suppressive effect on transmission. In particular, immunomodulation, including the suppression of dendritic cell (DC) responses, activation of basophils and mononuclear macrophages and adjuvant effects of the complement system, is described in detail. CONCLUSIONS: In this review, we summarize antagonistic concurrent infections involving parasites and provide a functional framework for in-depth studies of the underlying mechanisms of coinfection with different microorganisms, which will hasten the development of promising antimicrobial alternatives, such as novel antibacterial vaccines or biological methods of controlling infectious diseases, thus relieving the overwhelming burden of ever-increasing antimicrobial resistance.

Breaking Bad: How Viruses Subvert the Cell Cycle.

Interactions between the host and viruses during the course of their co-evolution have not only shaped cellular function and the immune system, but also the counter measures employed by viruses. Relatively small genomes and high replication rates allow viruses to accumulate mutations and continuously present the host with new challenges. It is therefore, no surprise that they either escape detection or modulate host physiology, often by redirecting normal cellular pathways to their own advantage. Viruses utilize a diverse array of strategies and molecular targets to subvert host cellular processes, while evading detection. These include cell-cycle regulation, major histocompatibility complex-restricted antigen presentation, intracellular protein transport, apoptosis, cytokine-mediated signaling, and humoral immune responses. Moreover, viruses routinely manipulate the host cell cycle to create a favorable environment for replication, largely by deregulating cell cycle checkpoints. This review focuses on our current understanding of the molecular aspects of cell cycle regulation that are often targeted by viruses. Further study of their interactions should provide fundamental insights into cell cycle regulation and improve our ability to exploit these viruses.

Human monoclonal antibodies as candidate therapeutics against emerging viruses.

The emergence of new pathogens, such as severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and Ebola virus, poses serious challenges to global public health and highlights the urgent need for novel antiviral approaches. Monoclonal antibodies (mAbs) have been successfully used to treat various diseases, particularly cancer and immunological disorders. Antigen-specific mAbs have been isolated using several different approaches, including hybridoma, transgenic mice, phage display, yeast display, and single B-cell isolation. Consequently, an increasing number of mAbs, which exhibit high potency against emerging viruses in vitro and in animal models of infection, have been developed. In this paper, we summarize historical trends and recent developments in mAb discovery, compare the advantages and disadvantages of various approaches to mAb production, and discuss the potential use of such strategies for the development of antivirals against emerging diseases. We also review the application of recently developed human mAbs against SARS-CoV, MERS-CoV, and Ebola virus and discuss prospects for the development of mAbs as therapeutic agents against emerging viral diseases.

Universal influenza virus vaccines: what can we learn from the human immune response following exposure to H7 subtype viruses?

Several universal influenza virus vaccine candidates based on eliciting antibodies against the hemagglutinin stalk domain are in development. Typically, these vaccines induce responses that target group 1 or group 2 hemagglutinins with little to no cross-group reactivity and protection. Similarly, the majority of human anti-stalk monoclonal antibodies that have been isolated are directed against group 1 or group 2 hemagglutinins with very few that bind to hemagglutinins of both groups. Here we review what is known about the human humoral immune response to vaccination and infection with H7 subtype influenza viruses on a polyclonal and monoclonal level. It seems that unlike vaccination with H5 hemagglutinin, which induces antibody responses mostly restricted to the group 1 stalk domain, H7 exposure induces both group 2 and cross-group antibody responses. A better understanding of this phenomenon and the underlying mechanisms might help to develop future universal influenza virus vaccine candidates.

Trade-Offs for Viruses in Overcoming Innate Immunities in Plants.

Plants recognize viral infection via an immune receptor, i.e., nucleotide-binding site (NB)-leucine-rich repeat (LRR) proteins. Another immune receptor, receptor-like kinase proteins, which share an LRR domain with NB-LRRs, perceive conserved molecules of pathogens called pathogen- or microbe-associated molecular patterns, but NB-LRRs generally perceive particular viral proteins. As viruses can evolve more rapidly than the host immune system, how do plant immune systems, which rely on the perception of proteins, remain effective? Viral adaptive evolution may be controlled by penalties that result from mutations in viral proteins that are perceived by NB-LRRs. Our recent studies in pea (Pisum sativum) suggest a penalty of increased susceptibility to another immune system. When a viral protein mutates to evade one immune system, the virus with the mutated protein becomes more susceptible to another. Such antagonistic pleiotropy of a viral protein by two independent plant immune systems may have precedents. Plants may rely on pairs of immune systems to constrain adaptive evolution by viruses and thereby maintain durable antiviral immunity. [Formula: see text] Copyright © 2016 The Author(s). This is an open access article distributed under the CC BY-NC 4.0 International license .

Ejercicios resistidos, parámetros hematológicos, virológicos y perfil antropométrico en personas que viven con VIH/SIDA / Exercícios resistidos, parâmetros hematologicos e virologicos, e perfil antropometrico em pessoas com HIV/AIDS / Resisted exercises, hematological and virological parameters, and anthropometric profiles in people living with HIV/AIDS

Objetivo. El objetivo de este estudio descriptivo fue analizar la relación entre los ejercicios de fuerza y los parámetros hematológicos, virológicos y antropométricos. Método. Fueron analizadas 40 personas de ambos sexos que viven con VIH/SIDA, con edades entre 20 y 50 años, de la ciudad de Mossoró (Rio Grande do Norte, Brasil). Todas fueron evaluadas antes y después de ser sometidas a un programa de ejercicios de fuerza. Los datos fueron analizados con el programa SPSS 20.0 en su versión en portugués. Resultados. Fue posible encontrar diferencia significativa (p<0.05) en el porcentaje de grasa, la urea y la hemoglobina. Conclusiones. Se concluye que al participar en un programa de ejercicios de fuerza, las personas que viven con VIH/ SIDA obtuvieron mejorías en los parámetros hematológicos, virológicos y en su perfil antropométrico (AU)

Objective. The objective of this descriptive study was to analyze the relationship between strength exercises and hematological, virological and anthropometric parameters. Method. A total of 40 people living with HIV/AIDS from both genders, aged between 20 to 50 years old, and residents in the city of Mossoró-RN (Brazil) were analyzed. All of them were evaluated before and after being subjected to a program of resisted exercises. The data were analyzed with the SPSS program version 20.0 in Portuguese. Results. A significant difference (p<0.05) was observed in the fat percentage, urea, and hemoglobin. Conclusions. It was concluded that by participating in a program of resisted exercises, people living with HIV/AIDS achieved improved hematological and virological parameters and anthropometric profile (AU)

Objetivo. O objetivo deste estudo descritivo foi analisar os efeitos do exercício físico resistido em parâmetros hematológicos e virológicos e o perfil antropometrico de pessoas com HIV/AIDS. Método. Um total de 40 pessoas que vivem com HIV/AIDS de ambos os sexos, com idade entre 20 a 50 anos e residentes na cidade de Mossoró-RN foram analisados. Todos foram avaliados antes e depois de ser submetido a um programa de exercícios resistidos. Os dados foram analisados com o programa SPSS versão 20.0 em Português. Resultados. Houve uma diferença significativa (p<0.05) foi observada no percentual de gordura, ureia, e hemoglobina. Conclusões. Conclui-se que, ao participar de um programa de exercícios resistidos, as pessoas que vivem com HIV/AIDS alcançaram melhorias no parâmetros hematológicos e virológicos e perfil antropométrico (AU)

Human Herpesvirus 6B Downregulates Expression of Activating Ligands during Lytic Infection To Escape Elimination by Natural Killer Cells.

The Herpesviridae family consists of eight viruses, most of which infect a majority of the human population. One of the less-studied members is human herpesvirus 6 (HHV-6) (Roseolovirus), which causes a mild, well-characterized childhood disease. Primary HHV-6 infection is followed by lifelong latency. Reactivation frequently occurs in immunocompromised patients, such as those suffering from HIV infection or cancer or following transplantation, and causes potentially life-threatening complications. In this study, we investigated the mechanisms that HHV-6 utilizes to remain undetected by natural killer (NK) cells, which are key participants in the innate immune response to infections. We revealed viral mechanisms which downregulate ligands for two powerful activating NK cell receptors: ULBP1, ULBP3, and MICB, which trigger NKG2D, and B7-H6, which activates NKp30. Accordingly, this downregulation impaired the ability of NK cells to recognize HHV-6-infected cells. Thus, we describe for the first time immune evasion mechanisms of HHV-6 that protect lytically infected cells from NK elimination. IMPORTANCE: Human herpesvirus 6 (HHV-6) latently infects a large portion of the human population and can reactivate in humans lacking a functional immune system, such as cancer or AIDS patients. Under these conditions, it can cause life-threatening diseases. To date, the actions and interplay of immune cells, and particularly cells of the innate immune system, during HHV-6 infection are poorly defined. In this study, we aimed to understand how cells undergoing lytic HHV-6 infection interact with natural killer (NK) cells, innate lymphocytes constituting the first line of defense against viral intruders. We show that HHV-6 suppresses the expression of surface proteins that alert the immune cells by triggering two major receptors on NK cells, NKG2D and NKp30. As a consequence, HHV-6 can replicate undetected by the innate immune system and potentially spread infection throughout the body. This study advances the understanding of HHV-6 biology and the measures it uses to successfully escape immune elimination.

Next-Generation Sequencing and the Crustacean Immune System: The Need for Alternatives in Immune Gene Annotation.

Next-generation sequencing has been a huge benefit to investigators studying non-model species. High-throughput gene expression studies, which were once restricted to animals with extensive genomic resources, can now be applied to any species. Transcriptomic studies using RNA-Seq can discover hundreds of thousands of transcripts from any species of interest. The power and limitation of these techniques is the sheer size of the dataset that is acquired. Parsing these large datasets is becoming easier as more bioinformatic tools are available for biologists without extensive computer programming expertise. Gene annotation and physiological pathway tools such as Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) Orthology enable the application of the vast amount of information acquired from model organisms to non-model species. While noble in nature, utilization of these tools can inadvertently misrepresent transcriptomic data from non-model species via annotation omission. Annotation followed by molecular pathway analysis highlights pathways that are disproportionately affected by disease, stress, or the physiological condition being examined. Problems occur when gene annotation procedures only recognizes a subset, often 50% or less, of the genes differently expressed from a non-model organisms. Annotated transcripts normally belong to highly conserved metabolic or regulatory genes that likely have a secondary or tertiary role, if any at all, in immunity. They appear to be disproportionately affected simply because conserved genes are most easily annotated. Evolutionarily induced specialization of physiological pathways is a driving force of adaptive evolution, but it results in genes that have diverged sufficiently to prevent their identification and annotation through conventional gene or protein databases. The purpose of this manuscript is to highlight some of the challenges faced when annotating crustacean immune genes by using an American lobster (Homarus americanus) transcriptome as an example. Immune genes have evolved rapidly over time, facilitating speciation and adaption to highly divergent ecological niches. Complete and proper annotation of immune genes from invertebrates has been challenging. Modulation of the crustacean immune system occurs in a variety of physiological responses including biotic and abiotic stressors, molting and reproduction. A simple method for the identification of a greater number of potential immune genes is proposed, along with a short introductory primer on crustacean immune response. The intended audience is not the advanced bioinformatic user, but those investigating physiological responses who require rudimentary understanding of crustacean immunological principles, but where immune gene regulation is not their primary interest.

The virome in host health and disease.

The mammalian virome includes diverse commensal and pathogenic viruses that evoke a broad range of immune responses from the host. Sustained viral immunomodulation is implicated in a variety of inflammatory diseases, but also confers unexpected benefits to the host. These outcomes of viral infections are often dependent on host genotype. Moreover, it is becoming clear that the virome is part of a dynamic network of microorganisms that inhabit the body. Therefore, viruses can be viewed as a component of the microbiome, and interactions with commensal bacteria and other microbial agents influence their behavior. This piece is a review of our current understanding of how the virome, together with other components of the microbiome, affects the function of the host immune system to regulate health and disease.

The evolution and genetics of virus host shifts.

Emerging viral diseases are often the product of a host shift, where a pathogen jumps from its original host into a novel species. Phylogenetic studies show that host shifts are a frequent event in the evolution of most pathogens, but why pathogens successfully jump between some host species but not others is only just becoming clear. The susceptibility of potential new hosts can vary enormously, with close relatives of the natural host typically being the most susceptible. Often, pathogens must adapt to successfully infect a novel host, for example by evolving to use different cell surface receptors, to escape the immune response, or to ensure they are transmitted by the new host. In viruses there are often limited molecular solutions to achieve this, and the same sequence changes are often seen each time a virus infects a particular host. These changes may come at a cost to other aspects of the pathogen's fitness, and this may sometimes prevent host shifts from occurring. Here we examine how these evolutionary factors affect patterns of host shifts and disease emergence.

MicroRNAs in the regulation of TLR and RIG-I pathways.

The innate immune system recognizes invading pathogens through germline-encoded pattern recognition receptors (PRRs), which elicit innate antimicrobial and inflammatory responses and initiate adaptive immunity to control or eliminate infection. Toll-like receptors (TLRs) and retinoic acid-inducible gene I (RIG-I) are the key innate immune PRRs and are tightly regulated by elaborate mechanisms to ensure a beneficial outcome in response to foreign invaders. Although much of the focus in the literature has been on the study of protein regulators of inflammation, microRNAs (miRNAs) have emerged as important controllers of certain features of the inflammatory process. Several miRNAs are induced by TLR and RIG-I activation in myeloid cells and act as feedback regulators of TLR and RIG-I signaling. In this review, we comprehensively discuss the recent understanding of how miRNA networks respond to TLR and RIG-I signaling and their role in the initiation and termination of inflammatory responses. Increasing evidence also indicates that both virus-encoded miRNAs and cellular miRNAs have important functions in viral replication and host anti-viral immunity.

The evolutionary dynamics of within-generation immune priming in invertebrate hosts.

While invertebrates lack the machinery necessary for 'acquired immunity', there is increasing empirical evidence that exposure to low levels of disease may 'prime' an invertebrate's immune response, increasing its defence to subsequent exposure. Despite this increasing empirical data, there has been little theoretical attention paid to immune priming. Here, we investigate the evolution of immune priming, focusing on the role of the unique feedbacks generated by a newly developed susceptible-primed-infected epidemiological model. Contrasting our results with previous models on the evolution of acquired immunity, we highlight that there are important implications to the evolution of immunity through priming owing to these different epidemiological feedbacks. In particular, we find that in contrast to acquired immunity, priming is strongly selected for at high as well as intermediate pathogen virulence. We also find that priming may be greatest at either intermediate or high host lifespans depending on the severity of disease. Furthermore, hosts faced with more severe pathogens are more likely to evolve diversity in priming. Finally, we show when the evolution of priming leads to the exclusion of the pathogens or hosts experiencing population cycles. Overall the model acts as a baseline for understanding the evolution of priming in host-pathogen systems.