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1.
Zool Res ; 44(3): 505-521, 2023 May 18.
Article in English | MEDLINE | ID: covidwho-2306427

ABSTRACT

Bacterial or viral infections, such as Brucella, mumps virus, herpes simplex virus, and Zika virus, destroy immune homeostasis of the testes, leading to spermatogenesis disorder and infertility. Of note, recent research shows that SARS-CoV-2 can infect male gonads and destroy Sertoli and Leydig cells, leading to male reproductive dysfunction. Due to the many side effects associated with antibiotic therapy, finding alternative treatments for inflammatory injury remains critical. Here, we found that Dmrt1 plays an important role in regulating testicular immune homeostasis. Knockdown of Dmrt1 in male mice inhibited spermatogenesis with a broad inflammatory response in seminiferous tubules and led to the loss of spermatogenic epithelial cells. Chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) revealed that Dmrt1 positively regulated the expression of Spry1, an inhibitory protein of the receptor tyrosine kinase (RTK) signaling pathway. Furthermore, immunoprecipitation-mass spectrometry (IP-MS) and co-immunoprecipitation (Co-IP) analysis indicated that SPRY1 binds to nuclear factor kappa B1 (NF-κB1) to prevent nuclear translocation of p65, inhibit activation of NF-κB signaling, prevent excessive inflammatory reaction in the testis, and protect the integrity of the blood-testis barrier. In view of this newly identified Dmrt1- Spry1-NF-κB axis mechanism in the regulation of testicular immune homeostasis, our study opens new avenues for the prevention and treatment of male reproductive diseases in humans and livestock.


Subject(s)
COVID-19 , Rodent Diseases , Zika Virus Infection , Zika Virus , Humans , Male , Mice , Animals , Testis , NF-kappa B/metabolism , COVID-19/veterinary , SARS-CoV-2/metabolism , Homeostasis , Fertility , Zika Virus/metabolism , Zika Virus Infection/metabolism , Zika Virus Infection/veterinary , Membrane Proteins/metabolism , Phosphoproteins/metabolism , Phosphoproteins/pharmacology , Adaptor Proteins, Signal Transducing/metabolism , Adaptor Proteins, Signal Transducing/pharmacology , Rodent Diseases/metabolism
2.
Exp Neurol ; 363: 114375, 2023 05.
Article in English | MEDLINE | ID: covidwho-2271639

ABSTRACT

Microglia, the resident macrophage of the central nervous system, are increasingly recognized as contributing to diverse aspects of human development, health, and disease. In recent years, numerous studies in both mouse and human models have identified microglia as a "double edged sword" in the progression of neurotropic viral infections: protecting against viral replication and cell death in some contexts, while acting as viral reservoirs and promoting excess cellular stress and cytotoxicity in others. It is imperative to understand the diversity of human microglial responses in order to therapeutically modulate them; however, modeling human microglia has been historically challenging due to significant interspecies differences in innate immunity and rapid transformation upon in vitro culture. In this review, we discuss the contribution of microglia to the neuropathogenesis of key neurotropic viral infections: human immunodeficiency virus 1 (HIV-1), Zika virus (ZIKV), Japanese encephalitis virus (JEV), West Nile virus (WNV), Herpes simplex virus (HSV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We pay special attention to recent work with human stem cell-derived microglia and propose strategies to leverage these powerful models to further uncover species- and disease-specific microglial responses and novel therapeutic interventions for neurotropic viral infections.


Subject(s)
COVID-19 , Zika Virus Infection , Zika Virus , Humans , Animals , Mice , Microglia/metabolism , Host Microbial Interactions , Zika Virus Infection/metabolism , COVID-19/metabolism , SARS-CoV-2
3.
Arch Virol ; 168(4): 121, 2023 Mar 28.
Article in English | MEDLINE | ID: covidwho-2270755

ABSTRACT

Exosomes are small extracellular vesicles with a diameter of 30-150 nm that originate from endosomes and fuse with the plasma membrane. They are secreted by almost all kinds of cells and can stably transfer different kinds of cargo from donor to recipient cells, thereby altering cellular functions for assisting cell-to-cell communication. Exosomes derived from virus-infected cells during viral infections are likely to contain different microRNAs (miRNAs) that can be transferred to recipient cells. Exosomes can either promote or suppress viral infections and therefore play a dual role in viral infection. In this review, we summarize the current knowledge about the role of exosomal miRNAs during infection by six important viruses (hepatitis C virus, enterovirus A71, Epstein-Barr virus, human immunodeficiency virus, severe acute respiratory syndrome coronavirus 2, and Zika virus), each of which causes a significant global public health problem. We describe how these exosomal miRNAs, including both donor-cell-derived and virus-encoded miRNAs, modulate the functions of the recipient cell. Lastly, we briefly discuss their potential value for the diagnosis and treatment of viral infections.


Subject(s)
COVID-19 , Epstein-Barr Virus Infections , Exosomes , MicroRNAs , Zika Virus Infection , Zika Virus , Humans , MicroRNAs/genetics , MicroRNAs/metabolism , Epstein-Barr Virus Infections/metabolism , Herpesvirus 4, Human/metabolism , COVID-19/genetics , COVID-19/metabolism , Exosomes/genetics , Exosomes/metabolism , Zika Virus Infection/metabolism
4.
Essays Biochem ; 67(1): 131-145, 2023 03 03.
Article in English | MEDLINE | ID: covidwho-2289178

ABSTRACT

Key homeostasis providing cells in the central nervous system (CNS) are astrocytes, which belong to the class of cells known as atroglia, a highly heterogeneous type of neuroglia and a prominent element of the brain defence. Diseases evolve due to altered homeostatic state, associated with pathology-induced astroglia remodelling represented by reactive astrocytes, astroglial atrophy and astrodegeneration. These features are hallmarks of most infectious insults, mediated by bacteria, protozoa and viruses; they are also prominent in the systemic infection. The COVID-19 pandemic revived the focus into neurotropic viruses such as SARS-CoV2 (Coronaviridae) but also the Flaviviridae viruses including tick-borne encephalitis (TBEV) and Zika virus (ZIKV) causing the epidemic in South America prior to COVID-19. Astrocytes provide a key response to neurotropic infections in the CNS. Astrocytes form a parenchymal part of the blood-brain barrier, the site of virus entry into the CNS. Astrocytes exhibit aerobic glycolysis, a form of metabolism characteristic of highly morphologically plastic cells, like cancer cells, hence a suitable milieu for multiplication of infectious agent, including viral particles. However, why the protection afforded by astrocytes fails in some circumstances is an open question to be studied in the future.


Subject(s)
COVID-19 , Zika Virus Infection , Zika Virus , Humans , Astrocytes/metabolism , Pandemics , RNA, Viral/metabolism , Zika Virus Infection/metabolism , COVID-19/metabolism , SARS-CoV-2
5.
Cell Stem Cell ; 29(5): 810-825.e8, 2022 05 05.
Article in English | MEDLINE | ID: covidwho-1819607

ABSTRACT

Trophoblast organoids derived from placental villi provide a 3D model system of human placental development, but access to first-trimester tissues is limited. Here, we report that trophoblast stem cells isolated from naive human pluripotent stem cells (hPSCs) can efficiently self-organize into 3D stem-cell-derived trophoblast organoids (SC-TOs) with a villous architecture similar to primary trophoblast organoids. Single-cell transcriptome analysis reveals the presence of distinct cytotrophoblast and syncytiotrophoblast clusters and a small cluster of extravillous trophoblasts, which closely correspond to trophoblast identities in the post-implantation embryo. These organoid cultures display clonal X chromosome inactivation patterns previously described in the human placenta. We further demonstrate that SC-TOs exhibit selective vulnerability to emerging pathogens (SARS-CoV-2 and Zika virus), which correlates with expression levels of their respective entry factors. The generation of trophoblast organoids from naive hPSCs provides an accessible 3D model system of the developing placenta and its susceptibility to emerging pathogens.


Subject(s)
COVID-19 , Pluripotent Stem Cells , Zika Virus Infection , Zika Virus , Cell Differentiation , Female , Humans , Organoids , Placenta/metabolism , Placentation , Pluripotent Stem Cells/metabolism , Pregnancy , SARS-CoV-2 , Trophoblasts/metabolism , Zika Virus Infection/metabolism
6.
FEBS Lett ; 595(23): 2854-2871, 2021 12.
Article in English | MEDLINE | ID: covidwho-1508599

ABSTRACT

SARS-CoV-2 has infected hundreds of millions of people with over four million dead, resulting in one of the worst global pandemics in recent history. Neurological symptoms associated with COVID-19 include anosmia, ageusia, headaches, confusion, delirium, and strokes. These may manifest due to viral entry into the central nervous system (CNS) through the blood-brain barrier (BBB) by means of ill-defined mechanisms. Here, we summarize the abilities of SARS-CoV-2 and other neurotropic RNA viruses, including Zika virus and Nipah virus, to cross the BBB into the CNS, highlighting the role of magnetic resonance imaging (MRI) in assessing presence and severity of brain structural changes in COVID-19 patients. We present new insight into key mutations in SARS-CoV-2 variants B.1.1.7 (P681H) and B.1.617.2 (P681R), which may impact on neuropilin 1 (NRP1) binding and CNS invasion. We postulate that SARS-CoV-2 may infect both peripheral cells capable of crossing the BBB and brain endothelial cells to traverse the BBB and spread into the brain. COVID-19 patients can be followed up with MRI modalities to better understand the long-term effects of COVID-19 on the brain.


Subject(s)
Blood-Brain Barrier , Henipavirus Infections , Nipah Virus , SARS-CoV-2 , Zika Virus Infection , Zika Virus , Blood-Brain Barrier/metabolism , Blood-Brain Barrier/physiopathology , Blood-Brain Barrier/virology , COVID-19/epidemiology , COVID-19/genetics , COVID-19/metabolism , COVID-19/physiopathology , Henipavirus Infections/epidemiology , Henipavirus Infections/genetics , Henipavirus Infections/metabolism , Henipavirus Infections/physiopathology , Humans , Mutation , Nipah Virus/genetics , Nipah Virus/metabolism , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , Zika Virus/genetics , Zika Virus/metabolism , Zika Virus Infection/epidemiology , Zika Virus Infection/genetics , Zika Virus Infection/metabolism , Zika Virus Infection/physiopathology
7.
Biochim Biophys Acta Mol Basis Dis ; 1867(12): 166264, 2021 12 01.
Article in English | MEDLINE | ID: covidwho-1385051

ABSTRACT

The molecular evolution of life on earth along with changing environmental, conditions has rendered mankind susceptible to endemic and pandemic emerging infectious diseases. The effects of certain systemic viral and bacterial infections on morbidity and mortality are considered as examples of recent emerging infections. Here we will focus on three examples of infections that are important in pregnancy and early childhood: SARS-CoV-2 virus, Zika virus, and Mycoplasma species. The basic structural characteristics of these infectious agents will be examined, along with their general pathogenic mechanisms. Coronavirus infections, such as caused by the SARS-CoV-2 virus, likely evolved from zoonotic bat viruses to infect humans and cause a pandemic that has been the biggest challenge for humanity since the Spanish Flu pandemic of the early 20th century. In contrast, Zika Virus infections represent an expanding infectious threat in the context of global climate change. The relationship of these infections to pregnancy, the vertical transmission and neurological sequels make these viruses highly relevant to the topics of this special issue. Finally, mycoplasmal infections have been present before mankind evolved, but they were rarely identified as human pathogens until recently, and they are now recognized as important coinfections that are able to modify the course and prognosis of various infectious diseases and other chronic illnesses. The infectious processes caused by these intracellular microorganisms are examined as well as some general aspects of their pathogeneses, clinical presentations, and diagnoses. We will finally consider examples of treatments that have been used to reduce morbidity and mortality of these infections and discuss briefly the current status of vaccines, in particular, against the SARS-CoV-2 virus. It is important to understand some of the basic features of these emerging infectious diseases and the pathogens involved in order to better appreciate the contributions of this special issue on how infectious diseases can affect human pregnancy, fetuses and neonates.


Subject(s)
Bacterial Infections/prevention & control , Communicable Diseases/transmission , Virus Diseases/prevention & control , Bacterial Infections/history , Bacterial Infections/transmission , COVID-19/metabolism , COVID-19/prevention & control , Communicable Diseases/virology , Female , History, 19th Century , History, 20th Century , History, 21st Century , Humans , Infant, Newborn , Infectious Disease Transmission, Vertical/history , Mycoplasma/pathogenicity , Mycoplasma Infections/metabolism , Mycoplasma Infections/prevention & control , Pregnancy , Pregnant Women , SARS-CoV-2/pathogenicity , Virus Diseases/history , Virus Diseases/transmission , Zika Virus/pathogenicity , Zika Virus Infection/metabolism , Zika Virus Infection/prevention & control
8.
Biochim Biophys Acta Mol Basis Dis ; 1867(12): 166244, 2021 12 01.
Article in English | MEDLINE | ID: covidwho-1356140

ABSTRACT

The placenta provides a significant physical and physiological barrier to prevent fetal infection during pregnancy. Nevertheless, it is at times breached by pathogens and leads to vertical transmission of infection from mother to fetus. This review will focus specifically on the Zika flavivirus, the HIV retrovirus and the emerging SARS-CoV2 coronavirus, which have affected pregnant women and their offspring in recent epidemics. In particular, we will address how viral infections affect the immune response at the maternal-fetal interface and how the placental barrier is physically breached and discuss the consequences of infection on various aspects of placental function to support fetal growth and development. Improved understanding of how the placenta responds to viral infections will lay the foundation for developing therapeutics to these and emergent viruses, to minimise the harms of infection to the offspring.


Subject(s)
Placenta/virology , Pregnancy Complications, Infectious/virology , Virus Diseases/physiopathology , COVID-19/metabolism , Female , Fetus/virology , HIV Infections/metabolism , HIV-1/pathogenicity , Humans , Infectious Disease Transmission, Vertical/statistics & numerical data , Placenta/metabolism , Pregnancy , Pregnancy Complications, Infectious/epidemiology , SARS-CoV-2/pathogenicity , Zika Virus/pathogenicity , Zika Virus Infection/metabolism
9.
Viruses ; 13(1)2020 12 29.
Article in English | MEDLINE | ID: covidwho-1004758

ABSTRACT

RNA viruses have gained plenty of attention during recent outbreaks of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Zika virus (ZIKV), and Ebola virus. ZIKV is a vector borne Flavivirus that is spread by mosquitoes and it mainly infects neuronal progenitor cells. One hallmark of congenital ZIKV disease is a reduced brain size in fetuses, leading to severe neurological defects. The World Health Organization (WHO) is urging the development of new antiviral treatments against ZIKV, as there are no efficient countermeasures against ZIKV disease. Previously, we presented a new class of host-targeting antivirals active against a number of pathogenic RNA viruses, such as SARS-CoV-2. Here, we show the transfer of the image-based phenotypic antiviral assay to ZIKV-infected brain cells, followed by mechanism-of-action studies and a proof-of-concept study in a three-dimensional (3D) organoid model. The novel antiviral compounds showed a therapeutic window against ZIKV in several cell models and rescued ZIKV-induced neurotoxicity in brain organoids. The compound's mechanism-of-action was pinpointed to late steps in the virus life cycle, impairing the formation of new virus particles. Collectively, in this study, we expand the antiviral activity of new small molecule inhibitors to a new virus class of Flaviviruses, but also uncover compounds' mechanism of action, which are important for the further development of antivirals.


Subject(s)
Antiviral Agents/pharmacology , Brain/metabolism , Organoids/metabolism , Zika Virus Infection/metabolism , Zika Virus/drug effects , Animals , Brain/pathology , COVID-19 , Cell Survival/drug effects , Humans , Organoids/pathology , RNA Viruses , Ribavirin/pharmacology , SARS-CoV-2 , Zika Virus/physiology , Zika Virus Infection/virology
10.
Biopreserv Biobank ; 18(6): 561-569, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-919312

ABSTRACT

When a new virus emerges and causes a significant epidemic, the emergency response relies on diagnostics, surveillance, testing, and proposal of treatments if they exist, and also in the longer term, redirection of research efforts toward understanding the newly discovered pathogen. To serve these goals, viral biobanks play a crucial role. The European Virus Archive (EVA) is a network of biobanks from research laboratories worldwide that has combined into a common set of practices and mutually beneficial objectives to give scientists the tools that they need to study viruses in general, and also to respond to a pandemic caused by emerging viruses. Taking the most recent outbreaks of the Zika virus and SARS-CoV-2 as examples, by looking at who orders what and when to the EVA, we illustrate how the global science community at large, public health, fundamental research and private companies, reorganize their activity toward diagnosing, understanding, and fighting the new pathogen.


Subject(s)
Biological Specimen Banks , COVID-19 , Pandemics , SARS-CoV-2/metabolism , Zika Virus Infection , Zika Virus/metabolism , COVID-19/epidemiology , COVID-19/metabolism , Europe/epidemiology , Humans , Zika Virus Infection/epidemiology , Zika Virus Infection/metabolism
11.
Biochemistry ; 60(13): 999-1018, 2021 04 06.
Article in English | MEDLINE | ID: covidwho-889110

ABSTRACT

Carbohydrate-receptor interactions are often involved in the docking of viruses to host cells, and this docking is a necessary step in the virus life cycle that precedes infection and, ultimately, replication. Despite the conserved structures of the glycans involved in docking, they are still considered "undruggable", meaning these glycans are beyond the scope of conventional pharmacological strategies. Recent advances in the development of synthetic carbohydrate receptors (SCRs), small molecules that bind carbohydrates, could bring carbohydrate-receptor interactions within the purview of druggable targets. Here we discuss the role of carbohydrate-receptor interactions in viral infection, the evolution of SCRs, and recent results demonstrating their ability to prevent viral infections in vitro. Common SCR design strategies based on boronic ester formation, metal chelation, and noncovalent interactions are discussed. The benefits of incorporating the idiosyncrasies of natural glycan-binding proteins-including flexibility, cooperativity, and multivalency-into SCR design to achieve nonglucosidic specificity are shown. These studies into SCR design and binding could lead to new strategies for mitigating the grave threat to human health posed by enveloped viruses, which are heavily glycosylated viroids that are the cause of some of the most pressing and untreatable diseases, including HIV, Dengue, Zika, influenza, and SARS-CoV-2.


Subject(s)
Antiviral Agents/chemistry , Drug Design , Receptors, Artificial/chemistry , Receptors, Virus/metabolism , Small Molecule Libraries/chemistry , Virus Attachment/drug effects , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , COVID-19/metabolism , Carbohydrate Metabolism/drug effects , Chlorocebus aethiops , Humans , Molecular Docking Simulation , Receptors, Artificial/chemical synthesis , Receptors, Virus/antagonists & inhibitors , SARS-CoV-2/drug effects , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/pharmacology , Vero Cells , Virus Diseases/drug therapy , Virus Diseases/metabolism , Zika Virus/drug effects , Zika Virus Infection/drug therapy , Zika Virus Infection/metabolism , COVID-19 Drug Treatment
12.
Viruses ; 12(10)2020 10 21.
Article in English | MEDLINE | ID: covidwho-887617

ABSTRACT

Most cells can release extracellular vesicles (EVs), membrane vesicles containing various proteins, nucleic acids, enzymes, and signaling molecules. The exchange of EVs between cells facilitates intercellular communication, amplification of cellular responses, immune response modulation, and perhaps alterations in viral pathogenicity. EVs serve a dual role in inhibiting or enhancing viral infection and pathogenesis. This review examines the current literature on EVs to explore the complex role of EVs in the enhancement, inhibition, and potential use as a nanotherapeutic against clinically relevant viruses, focusing on neurotropic viruses: Zika virus (ZIKV) and human immunodeficiency virus (HIV). Overall, this review's scope will elaborate on EV-based mechanisms, which impact viral pathogenicity, facilitate viral spread, and modulate antiviral immune responses.


Subject(s)
Extracellular Vesicles/metabolism , Virus Diseases/metabolism , Antiviral Agents/pharmacology , Cell Communication/physiology , Coronavirus/metabolism , Coronavirus/pathogenicity , Exosomes/metabolism , HIV/metabolism , HIV/pathogenicity , HIV Infections/metabolism , Humans , Retroviridae/metabolism , Simplexvirus/metabolism , Therapeutics/methods , Virus Diseases/drug therapy , Virus Diseases/virology , Zika Virus/metabolism , Zika Virus/pathogenicity , Zika Virus Infection/metabolism
13.
Brain Behav Immun ; 89: 480-490, 2020 10.
Article in English | MEDLINE | ID: covidwho-669660

ABSTRACT

The incidence of infectious diseases affecting the central nervous system (CNS) has been increasing over the last several years. Among the reasons for the expansion of these diseases and the appearance of new neuropathogens are globalization, global warming, and the increased proximity between humans and wild animals due to human activities such as deforestation. Neurotropism affecting normal brain function is shared by organisms such as viruses, bacteria, fungi, and parasites. Neuroinfections caused by these agents activate immune responses, inducing neuroinflammation, excitotoxicity, and neurodegeneration. Purinergic signaling is an evolutionarily conserved signaling pathway associated with these neuropathologies. During neuroinfections, host cells release ATP as an extracellular danger signal with pro-inflammatory activities. ATP is metabolized to its derivatives by ectonucleotidases such as CD39 and CD73; ATP and its metabolites modulate neuronal and immune mechanisms through P1 and P2 purinergic receptors that are involved in pathophysiological mechanisms of neuroinfections. In this review we discuss the beneficial or deleterious effects of various components of the purinergic signaling pathway in infectious diseases that affect the CNS, including human immunodeficiency virus (HIV-1) infection, herpes simplex virus type 1 (HSV-1) infection, bacterial meningitis, sepsis, cryptococcosis, toxoplasmosis, and malaria. We also provide a description of this signaling pathway in emerging viral infections with neurological implications such as Zika and SARS-CoV-2.


Subject(s)
Central Nervous System Infections/metabolism , Receptors, Purinergic P1/metabolism , Receptors, Purinergic P2X/metabolism , Receptors, Purinergic P2Y/metabolism , AIDS Dementia Complex/metabolism , Betacoronavirus , COVID-19 , Coronavirus Infections/metabolism , Encephalitis, Herpes Simplex/metabolism , Humans , Malaria/metabolism , Meningitis, Bacterial/metabolism , Meningitis, Cryptococcal/metabolism , Pandemics , Pneumonia, Viral/metabolism , SARS-CoV-2 , Sepsis/metabolism , Signal Transduction , Toxoplasmosis, Cerebral/metabolism , Zika Virus Infection/metabolism
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