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1.
Int J Mol Sci ; 22(5)2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33652988

RESUMO

In this Review, we briefly describe the basic virology and pathogenesis of SARS-CoV-2, highlighting how stem cell technology and organoids can contribute to the understanding of SARS-CoV-2 cell tropisms and the mechanism of disease in the human host, supporting and clarifying findings from clinical studies in infected individuals. We summarize here the results of studies, which used these technologies to investigate SARS-CoV-2 pathogenesis in different organs. Studies with in vitro models of lung epithelia showed that alveolar epithelial type II cells, but not differentiated lung alveolar epithelial type I cells, are key targets of SARS-CoV-2, which triggers cell apoptosis and inflammation, while impairing surfactant production. Experiments with human small intestinal organoids and colonic organoids showed that the gastrointestinal tract is another relevant target for SARS-CoV-2. The virus can infect and replicate in enterocytes and cholangiocytes, inducing cell damage and inflammation. Direct viral damage was also demonstrated in in vitro models of human cardiomyocytes and choroid plexus epithelial cells. At variance, endothelial cells and neurons are poorly susceptible to viral infection, thus supporting the hypothesis that neurological symptoms and vascular damage result from the indirect effects of systemic inflammatory and immunological hyper-responses to SARS-CoV-2 infection.


Assuntos
/patologia , Organoides/virologia , Células-Tronco/virologia , Animais , Apoptose , Sistema Cardiovascular/citologia , Sistema Cardiovascular/patologia , Sistema Cardiovascular/virologia , Sistema Nervoso Central/citologia , Sistema Nervoso Central/patologia , Sistema Nervoso Central/virologia , Trato Gastrointestinal/citologia , Trato Gastrointestinal/patologia , Trato Gastrointestinal/virologia , Humanos , Inflamação/patologia , Inflamação/virologia , Pulmão/citologia , Pulmão/patologia , Pulmão/virologia , Organoides/patologia , Células-Tronco/patologia , Tropismo Viral , Internalização do Vírus
2.
Proc Natl Acad Sci U S A ; 118(12)2021 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-33658332

RESUMO

The pandemic of COVID-19, caused by SARS-CoV-2, is a major global health threat. Epidemiological studies suggest that bats (Rhinolophus affinis) are the natural zoonotic reservoir for SARS-CoV-2. However, the host range of SARS-CoV-2 and intermediate hosts that facilitate its transmission to humans remain unknown. The interaction of coronavirus with its host receptor is a key genetic determinant of host range and cross-species transmission. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as the receptor to enter host cells in a species-dependent manner. In this study, we characterized the ability of ACE2 from diverse species to support viral entry. By analyzing the conservation of five residues in two virus-binding hotspots of ACE2 (hotspot 31Lys and hotspot 353Lys), we predicted 80 ACE2 proteins from mammals that could potentially mediate SARS-CoV-2 entry. We chose 48 ACE2 orthologs among them for functional analysis, and showed that 44 of these orthologs-including domestic animals, pets, livestock, and animals commonly found in zoos and aquaria-could bind the SARS-CoV-2 spike protein and support viral entry. In contrast, New World monkey ACE2 orthologs could not bind the SARS-CoV-2 spike protein and support viral entry. We further identified the genetic determinant of New World monkey ACE2 that restricts viral entry using genetic and functional analyses. These findings highlight a potentially broad host tropism of SARS-CoV-2 and suggest that SARS-CoV-2 might be distributed much more widely than previously recognized, underscoring the necessity to monitor susceptible hosts to prevent future outbreaks.


Assuntos
/genética , Receptores Virais/genética , /genética , /metabolismo , Animais , /metabolismo , Especificidade de Hospedeiro , Humanos , Pandemias/prevenção & controle , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Filogenia , Ligação Proteica , Receptores Virais/metabolismo , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Tropismo Viral , /prevenção & controle , Ligação Viral , Internalização do Vírus
3.
Cell Host Microbe ; 29(2): 150-151, 2021 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-33571440

RESUMO

Candida auris colonizes human skin and causes life-threatening fungal bloodstream infections. In this issue of Cell Host & Microbe, Huang et al. introduce a murine model of C. auris skin colonization to explore the role of distinct clades, immune signaling pathways, antibiotics, and disinfectants on fungal persistence in or clearance from its habitat.


Assuntos
Candida , Tropismo Viral , Animais , Modelos Animais de Doenças , Ecossistema , Humanos , Camundongos , Fatores de Risco
4.
ACS Chem Neurosci ; 12(4): 573-580, 2021 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-33538586

RESUMO

Long-COVID is a postviral illness that can affect survivors of COVID-19, regardless of initial disease severity or age. Symptoms of long-COVID include fatigue, dyspnea, gastrointestinal and cardiac problems, cognitive impairments, myalgia, and others. While the possible causes of long-COVID include long-term tissue damage, viral persistence, and chronic inflammation, the review proposes, perhaps for the first time, that persistent brainstem dysfunction may also be involved. This hypothesis can be split into two parts. The first is the brainstem tropism and damage in COVID-19. As the brainstem has a relatively high expression of ACE2 receptor compared with other brain regions, SARS-CoV-2 may exhibit tropism therein. Evidence also exists that neuropilin-1, a co-receptor of SARS-CoV-2, may be expressed in the brainstem. Indeed, autopsy studies have found SARS-CoV-2 RNA and proteins in the brainstem. The brainstem is also highly prone to damage from pathological immune or vascular activation, which has also been observed in autopsy of COVID-19 cases. The second part concerns functions of the brainstem that overlap with symptoms of long-COVID. The brainstem contains numerous distinct nuclei and subparts that regulate the respiratory, cardiovascular, gastrointestinal, and neurological processes, which can be linked to long-COVID. As neurons do not readily regenerate, brainstem dysfunction may be long-lasting and, thus, is long-COVID. Indeed, brainstem dysfunction has been implicated in other similar disorders, such as chronic pain and migraine and myalgic encephalomyelitis or chronic fatigue syndrome.


Assuntos
Encefalopatias/fisiopatologia , Tronco Encefálico/fisiopatologia , Inflamação/fisiopatologia , Trombose/fisiopatologia , /metabolismo , Encefalopatias/metabolismo , Encefalopatias/virologia , Tronco Encefálico/irrigação sanguínea , Tronco Encefálico/metabolismo , Tronco Encefálico/virologia , /fisiopatologia , Humanos , Inflamação/metabolismo , Inflamação/virologia , Neuropilina-1/metabolismo , RNA Viral/isolamento & purificação , RNA Viral/metabolismo , /genética , Trombose/metabolismo , Trombose/virologia , Tropismo Viral
5.
PLoS Pathog ; 17(2): e1009225, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33596266

RESUMO

Since the initial report of the novel Coronavirus Disease 2019 (COVID-19) emanating from Wuhan, China, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has spread globally. While the effects of SARS-CoV-2 infection are not completely understood, there appears to be a wide spectrum of disease ranging from mild symptoms to severe respiratory distress, hospitalization, and mortality. There are no Food and Drug Administration (FDA)-approved treatments for COVID-19 aside from remdesivir; early efforts to identify efficacious therapeutics for COVID-19 have mainly focused on drug repurposing screens to identify compounds with antiviral activity against SARS-CoV-2 in cellular infection systems. These screens have yielded intriguing hits, but the use of nonhuman immortalized cell lines derived from non-pulmonary or gastrointestinal origins poses any number of questions in predicting the physiological and pathological relevance of these potential interventions. While our knowledge of this novel virus continues to evolve, our current understanding of the key molecular and cellular interactions involved in SARS-CoV-2 infection is discussed in order to provide a framework for developing the most appropriate in vitro toolbox to support current and future drug discovery efforts.


Assuntos
Descoberta de Drogas , Tropismo Viral , Internalização do Vírus , Replicação Viral , /tratamento farmacológico , Catepsinas , Linhagem Celular , Desenvolvimento de Medicamentos , Endocitose , Furina , Humanos , Serina Endopeptidases
6.
mSphere ; 6(1)2021 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-33597174

RESUMO

Many viruses, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human immunodeficiency virus (HIV), have a structure consisting of spikes protruding from an underlying spherical surface. Research in biological and colloidal sciences has revealed secrets of why spikes exist on virus surfaces. Specifically, the spikes favor virus attachment on surfaces via receptor-specific interactions (RSIs), mediate the membrane fusion, and determine or change viral tropism. The spikes also facilitate viruses to approach surfaces before attachment and subsequently escape back to the environment if RSIs do not occur (i.e., easy come and easy go). Therefore, virus spikes create the paradox of having a large capacity for binding with cells (high infectivity) and meanwhile great mobility in the environment. Such structure-function relationships have important implications for the fabrication of virus-like particles and analogous colloids (e.g., hedgehog- and raspberry-like particles) for applications such as the development of antiviral vaccines and drug delivery.


Assuntos
/transmissão , /patogenicidade , Glicoproteína da Espícula de Coronavírus/metabolismo , Animais , HIV/metabolismo , HIV/patogenicidade , Infecções por HIV/transmissão , Humanos , Proteínas Virais/metabolismo , Tropismo Viral/fisiologia , Internalização do Vírus
7.
Br J Haematol ; 193(1): 43-51, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33538335
8.
Methods Mol Biol ; 2244: 19-38, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33555580

RESUMO

Human cytomegalovirus is routinely isolated by inoculating fibroblast cultures with clinical specimens suspected of harboring HCMV and then monitoring the cultures for cytopathic effects characteristic of this virus. Initially, such clinical isolates are usually strictly cell-associated, but continued propagation in cell culture increases the capacity of an HCMV isolate to release cell-free infectious progeny. Once cell-free infection is possible, genetically homogenous virus strains can be purified by limiting dilution infections. HCMV strains can differ greatly with regard to the titers that can be achieved, the tropism for certain cell types, and the degree to which nonessential genes have been lost during propagation. As there is no ideal HCMV strain for all purposes, the choice of the most appropriate strain depends on the requirements of the particular experiment or project. In this chapter, we provide information that can serve as a basis for deciding which strain may be the most appropriate for a given experiment.


Assuntos
Técnicas de Cultura de Células/métodos , Citomegalovirus/genética , Tropismo Viral/genética , Citomegalovirus/classificação , Citomegalovirus/isolamento & purificação , Infecções por Citomegalovirus/virologia , Fibroblastos/citologia , Humanos , Projetos de Pesquisa , Tropismo Viral/fisiologia , Replicação Viral
9.
Methods Mol Biol ; 2244: 51-81, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33555582

RESUMO

The extensive tropism of human cytomegalovirus (HCMV) results in the productive infection of multiple cell types within the human host. However, infection of other cell types, such as undifferentiated cells of the myeloid lineage, give rise to nonpermissive infections. This aspect has been used experimentally to model latent infection, which is known to be established in the pluripotent CD34+ hematopoietic progenitor cell population resident in the bone marrow in vivo. The absence of a tractable animal model for studies of HCMV has resulted in a number of laboratories employing experimental infection of cells in vitro to simulate both HCMV lytic and latent infection. Herein, we will focus on the techniques used in our laboratory for the isolation and use of primary cells to study aspects of HCMV latency, reactivation, and lytic infection.


Assuntos
Citomegalovirus/metabolismo , Cultura Primária de Células/métodos , Antígenos CD34/metabolismo , Diferenciação Celular , Infecções por Citomegalovirus/virologia , Células-Tronco Hematopoéticas/metabolismo , Monócitos/metabolismo , Transdução de Sinais , Tropismo Viral/genética , Tropismo Viral/fisiologia , Ativação Viral , Latência Viral
10.
Methods Mol Biol ; 2244: 83-101, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33555583

RESUMO

Of the many research challenges posed by the study of human cytomegalovirus (HCMV) latency, one of the most notable is the requirement for the use of primary hematopoietic cell culture. Culturing hematopoietic progenitor subpopulations requires that consideration be given to maintaining their physiological relevance. We describe a long-standing primary CD34+ hematopoietic progenitor cell (HPC) system as an in vitro model to study HCMV latent infection. Key aspects of the model include infection of primary human CD34+ HPCs prior to ex vivo expansion, a long-term culture with a stromal cell support designed to maintain the ability of stem cells to support hematopoietic reconstitution, and an assay to quantify infectious centers produced prior to and following a reactivation stimulus. Importantly, this system has been used to identify a number of viral determinants of latency or reactivation and findings have been recapitulated in vivo using a humanized mouse model for HCMV latency. Therefore, this system offers a powerful approach to defining virus-host interactions and mechanisms important for HCMV latency and reactivation.


Assuntos
Citomegalovirus/metabolismo , Cultura Primária de Células/métodos , Latência Viral/fisiologia , Antígenos CD34/metabolismo , Diferenciação Celular , Infecções por Citomegalovirus/virologia , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Transdução de Sinais , Proteínas Virais , Tropismo Viral/genética , Tropismo Viral/fisiologia , Ativação Viral/genética , Ativação Viral/fisiologia
11.
J Infect Dis ; 223(5): 752-764, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33502471

RESUMO

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic continues to produce substantial morbidity and mortality. To understand the reasons for the wide-spectrum complications and severe outcomes of COVID-19, we aimed to identify cellular targets of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) tropism and replication in various tissues. METHODS: We evaluated RNA extracted from formalin-fixed, paraffin-embedded autopsy tissues from 64 case patients (age range, 1 month to 84 years; 21 COVID-19 confirmed, 43 suspected COVID-19) by SARS-CoV-2 reverse-transcription polymerase chain reaction (RT-PCR). For cellular localization of SARS-CoV-2 RNA and viral characterization, we performed in situ hybridization (ISH), subgenomic RNA RT-PCR, and whole-genome sequencing. RESULTS: SARS-CoV-2 was identified by RT-PCR in 32 case patients (21 COVID-19 confirmed, 11 suspected). ISH was positive in 20 and subgenomic RNA RT-PCR was positive in 17 of 32 RT-PCR-positive case patients. SARS-CoV-2 RNA was localized by ISH in hyaline membranes, pneumocytes, and macrophages of lungs; epithelial cells of airways; and endothelial cells and vessel walls of brain stem, leptomeninges, lung, heart, liver, kidney, and pancreas. The D614G variant was detected in 9 RT-PCR-positive case patients. CONCLUSIONS: We identified cellular targets of SARS-CoV-2 tropism and replication in the lungs and airways and demonstrated its direct infection in vascular endothelium. This work provides important insights into COVID-19 pathogenesis and mechanisms of severe outcomes.


Assuntos
/virologia , Endotélio Vascular/virologia , Sistema Respiratório/virologia , Replicação Viral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Autopsia , Criança , Pré-Escolar , Feminino , Humanos , Hibridização In Situ , Lactente , Pulmão/virologia , Masculino , Pessoa de Meia-Idade , RNA Viral/isolamento & purificação , Reação em Cadeia da Polimerase em Tempo Real , /isolamento & purificação , Tropismo Viral , Sequenciamento Completo do Genoma , Adulto Jovem
12.
Drug Discov Ther ; 14(6): 262-272, 2021 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-33390561

RESUMO

The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified in 2019 in Wuhan, China. Clinically, respiratory tract symptoms as well as other organs disorders are observed in patients positively diagnosed coronavirus disease 2019 (COVID-19). In addition, neurological symptoms, mainly anosmia, ageusia and headache were observed in many patients. Once in the central nervous system (CNS), the SARS-CoV-2 can reside either in a quiescent latent state, or eventually in actively state leading to severe acute encephalitis, characterized by neuroinflammation and prolonged neuroimmune activation. SRAS-CoV-2 requires angiotensin-converting enzyme 2 (ACE2) as a cell entry receptor. The expression of this receptor in endothelial cells of blood-brain barrier (BBB) shows that SRAS-CoV-2 may have higher neuroinvasive potential compared to known coronaviruses. This review summarizes available information regarding the impact of SRAS-CoV-2 in the brain and tended to identify its potential pathways of neuroinvasion. We offer also an understanding of the long-term impact of latently form of SARS-CoV-2 on the development of neurodegenerative disorders. As a conclusion, the persistent infection of SRAS-CoV-2 in the brain could be involved on human neurodegenerative diseases that evolve a gradual process, perhapes, over several decades.


Assuntos
/virologia , Viroses do Sistema Nervoso Central/virologia , Doenças Neurodegenerativas/virologia , Neurônios/virologia , Tropismo Viral , Animais , Viroses do Sistema Nervoso Central/metabolismo , Viroses do Sistema Nervoso Central/patologia , Interações Hospedeiro-Patógeno , Humanos , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Neurônios/metabolismo , Neurônios/patologia , Latência Viral
13.
PLoS Pathog ; 17(1): e1009233, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33476327

RESUMO

The spike (S) protein of Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) binds to a host cell receptor which facilitates viral entry. A polybasic motif detected at the cleavage site of the S protein has been shown to broaden the cell tropism and transmissibility of the virus. Here we examine the properties of SARS-CoV-2 variants with mutations at the S protein cleavage site that undergo inefficient proteolytic cleavage. Virus variants with S gene mutations generated smaller plaques and exhibited a more limited range of cell tropism compared to the wild-type strain. These alterations were shown to result from their inability to utilize the entry pathway involving direct fusion mediated by the host type II transmembrane serine protease, TMPRSS2. Notably, viruses with S gene mutations emerged rapidly and became the dominant SARS-CoV-2 variants in TMPRSS2-deficient cells including Vero cells. Our study demonstrated that the S protein polybasic cleavage motif is a critical factor underlying SARS-CoV-2 entry and cell tropism. As such, researchers should be alert to the possibility of de novo S gene mutations emerging in tissue-culture propagated virus strains.


Assuntos
/genética , Serina Endopeptidases/deficiência , Glicoproteína da Espícula de Coronavírus/genética , Sequência de Aminoácidos , Animais , Células CACO-2 , Linhagem Celular , Chlorocebus aethiops , Células HEK293 , Humanos , Mutação , /crescimento & desenvolvimento , Alinhamento de Sequência , Inoculações Seriadas , Células Vero , Tropismo Viral
14.
Viruses ; 13(1)2021 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-33477379

RESUMO

Porcine deltacoronavirus (PDCoV) strain OH-FD22 infects poultry and shares high nucleotide identity with sparrow-origin deltacoronaviruses (SpDCoV) ISU73347 and HKU17 strains. We hypothesized that the spike (S) protein or receptor-binding domain (RBD) from these SpDCoVs would alter the host and tissue tropism of PDCoV. First, an infectious cDNA clone of PDCoV OH-FD22 strain (icPDCoV) was generated and used to construct chimeric icPDCoVs harboring the S protein of HKU17 (icPDCoV-SHKU17) or the RBD of ISU73347 (icPDCoV-RBDISU). To evaluate their pathogenesis, neonatal gnotobiotic pigs were inoculated orally/oronasally with the recombinant viruses or PDCoV OH-FD22. All pigs inoculated with icPDCoV or OH-FD22 developed severe diarrhea and shed viral RNA at moderate-high levels (7.62-10.56 log10 copies/mL) in feces, and low-moderate levels in nasal swabs (4.92-8.48 log10 copies/mL). No pigs in the icPDCoV-SHKU17 and icPDCoV-RBDISU groups showed clinical signs. Interestingly, low-moderate levels (5.07-7.06 log10 copies/mL) of nasal but not fecal viral RNA shedding were detected transiently at 1-4 days post-inoculation in 40% (2/5) of icPDCoV-SHKU17- and 50% (1/2) of icPDCoV-RBDISU-inoculated pigs. These results confirm that PDCoV infected both the upper respiratory and intestinal tracts of pigs. The chimeric viruses displayed an attenuated phenotype with the loss of tropism for the pig intestine. The SpDCoV S protein and RBD reduced viral replication in pigs, suggesting limited potential for cross-species spillover upon initial passage.


Assuntos
Infecções por Coronavirus/patologia , Intestinos/patologia , Sistema Respiratório/patologia , Glicoproteína da Espícula de Coronavírus/genética , Tropismo Viral/genética , Motivos de Aminoácidos , Animais , Doenças das Aves/virologia , Linhagem Celular , Intestinos/virologia , Proteínas Recombinantes/genética , Sistema Respiratório/virologia , Pardais , Suínos , Doenças dos Suínos/virologia , Virulência/genética
15.
PLoS Pathog ; 17(1): e1009292, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33507952

RESUMO

The human airway epithelium is the initial site of SARS-CoV-2 infection. We used flow cytometry and single cell RNA-sequencing to understand how the heterogeneity of this diverse cell population contributes to elements of viral tropism and pathogenesis, antiviral immunity, and treatment response to remdesivir. We found that, while a variety of epithelial cell types are susceptible to infection, ciliated cells are the predominant cell target of SARS-CoV-2. The host protease TMPRSS2 was required for infection of these cells. Importantly, remdesivir treatment effectively inhibited viral replication across cell types, and blunted hyperinflammatory responses. Induction of interferon responses within infected cells was rare and there was significant heterogeneity in the antiviral gene signatures, varying with the burden of infection in each cell. We also found that heavily infected secretory cells expressed abundant IL-6, a potential mediator of COVID-19 pathogenesis.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/farmacologia , /virologia , Tropismo Viral , Monofosfato de Adenosina/farmacologia , Alanina/farmacologia , /genética , Epitélio/imunologia , Epitélio/virologia , Humanos , Interferons/genética , Interferons/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Pulmão/imunologia , Pulmão/virologia , Tropismo Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
16.
Arch Virol ; 166(3): 733-753, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33502593

RESUMO

The chronic dysfunction of neuronal cells, both central and peripheral, a characteristic of neurological disorders, may be caused by irreversible damage and cell death. In 2016, more than 276 million cases of neurological disorders were reported worldwide. Moreover, neurological disorders are the second leading cause of death. Generally, the etiology of neurological diseases is not fully understood. Recent studies have related the onset of neurological disorders to viral infections, which may cause neurological symptoms or lead to immune responses that trigger these pathological signs. Currently, this relationship is mostly based on epidemiological data on infections and seroprevalence of patients who present with neurological disorders. The number of studies aiming to elucidate the mechanism of action by which viral infections may directly or indirectly contribute to the development of neurological disorders has been increasing over the years but these studies are still scarce. Comprehending the pathogenesis of these diseases and exploring novel theories may favor the development of new strategies for diagnosis and therapy in the future. Therefore, the objective of the present study was to review the main pieces of evidence for the relationship between viral infection and neurological disorders such as Alzheimer's disease, Parkinson's disease, Guillain-Barré syndrome, multiple sclerosis, and epilepsy. Viruses belonging to the families Herpesviridae, Orthomyxoviridae, Flaviviridae, and Retroviridae have been reported to be involved in one or more of these conditions. Also, neurological symptoms and the future impact of infection with SARS-CoV-2, a member of the family Coronaviridae that is responsible for the COVID-19 pandemic that started in late 2019, are reported and discussed.


Assuntos
/patologia , Doenças do Sistema Nervoso/virologia , Tropismo Viral/fisiologia , Doença de Alzheimer/virologia , Epilepsia/virologia , Flaviviridae/metabolismo , Síndrome de Guillain-Barré/virologia , Herpesviridae/metabolismo , Humanos , Esclerose Múltipla/virologia , Doenças do Sistema Nervoso/patologia , Orthomyxoviridae/metabolismo , Doença de Parkinson/virologia , Retroviridae/metabolismo , /metabolismo
17.
Viruses ; 13(1)2021 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-33477296

RESUMO

The process of Kaposi's Sarcoma Herpes Virus' (KSHV) entry into target cells is complex and engages several viral glycoproteins which bind to a large range of host cell surface molecules. Receptors for KSHV include heparan sulphate proteoglycans (HSPGs), several integrins and Eph receptors, cystine/glutamate antiporter (xCT) and Dendritic Cell-Specific Intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN). This diverse range of potential binding and entry sites allows KSHV to have a broad cell tropism, and entry into specific cells is dependent on the available receptor repertoire. Several molecules involved in KSHV entry have been well characterized, particularly those postulated to be associated with KSHV-associated pathologies such as Kaposi's Sarcoma (KS). In this review, KSHV infection of specific cell types pertinent to its pathogenesis will be comprehensively summarized with a focus on the specific cell surface binding and entry receptors KSHV exploits to gain access to a variety of cell types. Gaps in the current literature regarding understanding interactions between KSHV glycoproteins and cellular receptors in virus infection are identified which will lead to the development of virus infection intervention strategies.


Assuntos
Infecções por Herpesviridae/metabolismo , Infecções por Herpesviridae/virologia , Herpesvirus Humano 8/fisiologia , Interações Hospedeiro-Patógeno , Receptores Virais/metabolismo , Especificidade de Hospedeiro , Humanos , Proteínas do Envelope Viral/metabolismo , Tropismo Viral , Ligação Viral , Internalização do Vírus
18.
PLoS Genet ; 16(12): e1009272, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33332358

RESUMO

The Betacoronaviruses comprise multiple subgenera whose members have been implicated in human disease. As with SARS, MERS and now SARS-CoV-2, the origin and emergence of new variants are often attributed to events of recombination that alter host tropism or disease severity. In most cases, recombination has been detected by searches for excessively similar genomic regions in divergent strains; however, such analyses are complicated by the high mutation rates of RNA viruses, which can produce sequence similarities in distant strains by convergent mutations. By applying a genome-wide approach that examines the source of individual polymorphisms and that can be tested against null models in which recombination is absent and homoplasies can arise only by convergent mutations, we examine the extent and limits of recombination in Betacoronaviruses. We find that recombination accounts for nearly 40% of the polymorphisms circulating in populations and that gene exchange occurs almost exclusively among strains belonging to the same subgenus. Although experimental studies have shown that recombinational exchanges occur at random along the coronaviral genome, in nature, they are vastly overrepresented in regions controlling viral interaction with host cells.


Assuntos
Betacoronavirus/classificação , Betacoronavirus/genética , Recombinação Genética/genética , Glicoproteína da Espícula de Coronavírus/genética , Troca Genética/genética , Genes Virais/genética , Genoma Viral/genética , Especificidade de Hospedeiro/genética , Modelos Genéticos , Polimorfismo Genético , /genética , Tropismo Viral/genética
19.
Viruses ; 12(12)2020 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-33352888

RESUMO

The viral protein 1 unique region (VP1u) of human parvovirus B19 (B19V) is a multifunctional capsid protein with essential roles in virus tropism, uptake, and subcellular trafficking. These functions reside on hidden protein domains, which become accessible upon interaction with cell membrane receptors. A receptor-binding domain (RBD) in VP1u is responsible for the specific targeting and uptake of the virus exclusively into cells of the erythroid lineage in the bone marrow. A phospholipase A2 domain promotes the endosomal escape of the incoming virus. The VP1u is also the immunodominant region of the capsid as it is the target of neutralizing antibodies. For all these reasons, the VP1u has raised great interest in antiviral research and vaccinology. Besides the essential functions in B19V infection, the remarkable erythroid specificity of the VP1u makes it a unique erythroid cell surface biomarker. Moreover, the demonstrated capacity of the VP1u to deliver diverse cargo specifically to cells around the proerythroblast differentiation stage, including erythroleukemic cells, offers novel therapeutic opportunities for erythroid-specific drug delivery. In this review, we focus on the multifunctional role of the VP1u in B19V infection and explore its potential in diagnostics and erythroid-specific therapeutics.


Assuntos
Biotecnologia , Proteínas do Capsídeo/fisiologia , Sítios de Ligação , Proteínas do Capsídeo/química , Proteínas do Capsídeo/imunologia , Epitopos Imunodominantes , Sinais de Localização Nuclear , Parvovirus B19 Humano/fisiologia , Fosfolipases A2/química , Receptores Virais , Tropismo Viral , Vírion/fisiologia
20.
Viruses ; 12(12)2020 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-33322850

RESUMO

A number of characteristics including lack of virulence and the ability to grow to high titers, have made bovine adenovirus-3 (BAdV-3) a vector of choice for further development as a vaccine-delivery vehicle for cattle. Despite the importance of blood leukocytes, including dendritic cells (DC), in the induction of protective immune responses, little is known about the interaction between BAdV-3 and bovine blood leukocytes. Here, we demonstrate that compared to other leukocytes, bovine blood monocytes and neutrophils are significantly transduced by BAdV404a (BAdV-3, expressing enhanced yellow green fluorescent protein [EYFP]) at a MOI of 1-5 without a significant difference in the mean fluorescence of EYFP expression. Moreover, though expression of some BAdV-3-specific proteins was observed, no progeny virions were detected in the transduced monocytes or neutrophils. Interestingly, addition of the "RGD" motif at the C-terminus of BAdV-3 minor capsid protein pIX (BAV888) enhanced the ability of the virus to enter the monocytes without altering the tropism of BAdV-3. The increased uptake of BAV888 by monocytes was associated with a significant increase in viral genome copies and the abundance of EYFP and BAdV-3 19K transcripts compared to BAdV404a-transduced monocytes. Our results suggest that BAdV-3 efficiently transduces monocytes and neutrophils in the absence of viral replication. Moreover, RGD-modified capsid significantly increases vector uptake without affecting the initial interaction with monocytes.


Assuntos
Infecções por Adenoviridae/veterinária , Doenças dos Bovinos/virologia , Leucócitos/virologia , Mastadenovirus/fisiologia , Tropismo Viral , Animais , Bovinos , Doenças dos Bovinos/imunologia , Doenças dos Bovinos/metabolismo , Linhagem Celular , Expressão Gênica , Regulação Viral da Expressão Gênica , Leucócitos/imunologia , Leucócitos/metabolismo , Transdução Genética , Proteínas Virais/genética , Proteínas Virais/metabolismo , Replicação Viral
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