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2.
Front Immunol ; 11: 1979, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32973803

RESUMO

The new pandemic virus SARS-CoV-2 emerged in China and spread around the world in <3 months, infecting millions of people, and causing countries to shut down public life and businesses. Nearly all nations were unprepared for this pandemic with healthcare systems stretched to their limits due to the lack of an effective vaccine and treatment. Infection with SARS-CoV-2 can lead to Coronavirus disease 2019 (COVID-19). COVID-19 is respiratory disease that can result in a cytokine storm with stark differences in morbidity and mortality between younger and older patient populations. Details regarding mechanisms of viral entry via the respiratory system and immune system correlates of protection or pathogenesis have not been fully elucidated. Here, we provide an overview of the innate immune responses in the lung to the coronaviruses MERS-CoV, SARS-CoV, and SARS-CoV-2. This review provides insight into key innate immune mechanisms that will aid in the development of therapeutics and preventive vaccines for SARS-CoV-2 infection.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Imunidade Inata , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Pneumonia Viral/imunologia , Vírus da SARS/imunologia , Síndrome Respiratória Aguda Grave/imunologia , Idoso , Idoso de 80 Anos ou mais , Animais , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Feminino , Humanos , Evasão da Resposta Imune , Masculino , Pandemias , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Mucosa Respiratória/imunologia , Síndrome Respiratória Aguda Grave/virologia
3.
Viruses ; 12(9)2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32961897

RESUMO

Some coronaviruses are zoonotic viruses of human and veterinary medical importance. The novel coronavirus, severe acute respiratory symptoms coronavirus 2 (SARS-CoV-2), associated with the current global pandemic, is characterized by pneumonia, lymphopenia, and a cytokine storm in humans that has caused catastrophic impacts on public health worldwide. Coronaviruses are known for their ability to evade innate immune surveillance exerted by the host during the early phase of infection. It is important to comprehensively investigate the interaction between highly pathogenic coronaviruses and their hosts. In this review, we summarize the existing knowledge about coronaviruses with a focus on antiviral immune responses in the respiratory and intestinal tracts to infection with severe coronaviruses that have caused epidemic diseases in humans and domestic animals. We emphasize, in particular, the strategies used by these coronaviruses to circumvent host immune surveillance, mainly including the hijack of antigen-presenting cells, shielding RNA intermediates in replication organelles, 2'-O-methylation modification for the evasion of RNA sensors, and blocking of interferon signaling cascades. We also provide information about the potential development of coronavirus vaccines and antiviral drugs.


Assuntos
Antivirais/imunologia , Infecções por Coronavirus/virologia , Coronavirus/imunologia , Evasão da Resposta Imune , Pneumonia Viral/virologia , Antivirais/uso terapêutico , Betacoronavirus/imunologia , Coronavirus/classificação , Coronavirus/fisiologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Citocinas/imunologia , Imunidade Inata , Imunidade nas Mucosas , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Transdução de Sinais , Tropismo Viral
4.
Nat Commun ; 11(1): 3810, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32733001

RESUMO

The pandemic of COVID-19 has posed an unprecedented threat to global public health. However, the interplay between the viral pathogen of COVID-19, SARS-CoV-2, and host innate immunity is poorly understood. Here we show that SARS-CoV-2 induces overt but delayed type-I interferon (IFN) responses. By screening 23 viral proteins, we find that SARS-CoV-2 NSP1, NSP3, NSP12, NSP13, NSP14, ORF3, ORF6 and M protein inhibit Sendai virus-induced IFN-ß promoter activation, whereas NSP2 and S protein exert opposite effects. Further analyses suggest that ORF6 inhibits both type I IFN production and downstream signaling, and that the C-terminus region of ORF6 is critical for its antagonistic effect. Finally, we find that IFN-ß treatment effectively blocks SARS-CoV-2 replication. In summary, our study shows that SARS-CoV-2 perturbs host innate immune response via both its structural and nonstructural proteins, and thus provides insights into the pathogenesis of SARS-CoV-2.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/virologia , Evasão da Resposta Imune , Interferon Tipo I/metabolismo , Pneumonia Viral/virologia , Transdução de Sinais , Betacoronavirus/genética , Betacoronavirus/imunologia , Betacoronavirus/metabolismo , Linhagem Celular , Infecções por Coronavirus/imunologia , Humanos , Imunidade Inata , Interferon beta/genética , Interferon beta/metabolismo , Interferon beta/farmacologia , Mutação , Fases de Leitura Aberta , Pandemias , Pneumonia Viral/imunologia , Regiões Promotoras Genéticas , Transdução de Sinais/efeitos dos fármacos , Proteínas Virais/genética , Proteínas Virais/metabolismo , Replicação Viral/efeitos dos fármacos
5.
Front Immunol ; 11: 1949, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32849654

RESUMO

After the 1918 flu pandemic, the world is again facing a similar situation. However, the advancement in medical science has made it possible to identify that the novel infectious agent is from the coronavirus family. Rapid genome sequencing by various groups helped in identifying the structure and function of the virus, its immunogenicity in diverse populations, and potential preventive measures. Coronavirus attacks the respiratory system, causing pneumonia and lymphopenia in infected individuals. Viral components like spike and nucleocapsid proteins trigger an immune response in the host to eliminate the virus. These viral antigens can be either recognized by the B cells or presented by MHC complexes to the T cells, resulting in antibody production, increased cytokine secretion, and cytolytic activity in the acute phase of infection. Genetic polymorphism in MHC enables it to present some of the T cell epitopes very well over the other MHC alleles. The association of MHC alleles and its downregulated expression has been correlated with disease severity against influenza and coronaviruses. Studies have reported that infected individuals can, after recovery, induce strong protective responses by generating a memory T-cell pool against SARS-CoV and MERS-CoV. These memory T cells were not persistent in the long term and, upon reactivation, caused local damage due to cross-reactivity. So far, the reports suggest that SARS-CoV-2, which is highly contagious, shows related symptoms in three different stages and develops an exhaustive T-cell pool at higher loads of viral infection. As there are no specific treatments available for this novel coronavirus, numerous small molecular drugs that are being used for the treatment of diseases like SARS, MERS, HIV, ebola, malaria, and tuberculosis are being given to COVID-19 patients, and clinical trials for many such drugs have already begun. A classical immunotherapy of convalescent plasma transfusion from recovered patients has also been initiated for the neutralization of viremia in terminally ill COVID-19 patients. Due to the limitations of plasma transfusion, researchers are now focusing on developing neutralizing antibodies against virus particles along with immuno-modulation of cytokines like IL-6, Type I interferons (IFNs), and TNF-α that could help in combating the infection. This review highlights the similarities of the coronaviruses that caused SARS and MERS to the novel SARS-CoV-2 in relation to their pathogenicity and immunogenicity and also focuses on various treatment strategies that could be employed for curing COVID-19.


Assuntos
Betacoronavirus/genética , Infecções por Coronavirus/imunologia , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Pneumonia Viral/imunologia , Vírus da SARS/genética , Síndrome Respiratória Aguda Grave/imunologia , Animais , Apresentação do Antígeno/imunologia , Antivirais/uso terapêutico , Betacoronavirus/química , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Citocinas/biossíntese , Genoma Viral , Humanos , Evasão da Resposta Imune , Imunização Passiva/métodos , Camundongos , Coronavírus da Síndrome Respiratória do Oriente Médio/química , Pandemias , Filogenia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Vírus da SARS/química , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Síndrome Respiratória Aguda Grave/virologia , Linfócitos T/imunologia , Replicação Viral
6.
Monoclon Antib Immunodiagn Immunother ; 39(4): 107-111, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32762609

RESUMO

In this hypothesis, we address the biological/immunological pathway leading to severe disease or death after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The underlying immune response is described with "original antigenic sin" (OAS) whereby previous infections influence the response to future virus encounters. We cite evidence for OAS-induced immunopathology in HIV-1 disease. We hypothesize that similar immune abnormalities can occur after infection with SARS-CoV-2. This hypothesis is supported by recent analysis of the antibodies in infected patients demonstrating serological and B cell abnormalities. The concept of symmetrical clonal regulation developed earlier for the immune network illustrates the pathway suggested by our hypothesis and may be helpful to develop strategies avoiding severe coronavirus disease 2019.


Assuntos
Anticorpos Antivirais/imunologia , Linfócitos B/imunologia , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Evasão da Resposta Imune/imunologia , Pneumonia Viral/imunologia , Anticorpos Monoclonais/imunologia , Infecções por Coronavirus/patologia , Reações Cruzadas/imunologia , Síndrome da Liberação de Citocina/imunologia , HIV/imunologia , HIV-1/imunologia , Humanos , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Memória Imunológica/imunologia , Pandemias , Pneumonia Viral/patologia
7.
Front Immunol ; 11: 1450, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32733480

RESUMO

The complement system is a key component of innate immunity which readily responds to invading microorganisms. Activation of the complement system typically occurs via three main pathways and can induce various antimicrobial effects, including: neutralization of pathogens, regulation of inflammatory responses, promotion of chemotaxis, and enhancement of the adaptive immune response. These can be vital host responses to protect against acute, chronic, and recurrent viral infections. Consequently, many viruses (including dengue virus, West Nile virus and Nipah virus) have evolved mechanisms for evasion or dysregulation of the complement system to enhance viral infectivity and even exacerbate disease symptoms. The complement system has multifaceted roles in both innate and adaptive immunity, with both intracellular and extracellular functions, that can be relevant to all stages of viral infection. A better understanding of this virus-host interplay and its contribution to pathogenesis has previously led to: the identification of genetic factors which influence viral infection and disease outcome, the development of novel antivirals, and the production of safer, more effective vaccines. This review will discuss the antiviral effects of the complement system against numerous viruses, the mechanisms employed by these viruses to then evade or manipulate this system, and how these interactions have informed vaccine/therapeutic development. Where relevant, conflicting findings and current research gaps are highlighted to aid future developments in virology and immunology, with potential applications to the current COVID-19 pandemic.


Assuntos
Betacoronavirus/imunologia , Complexo de Ataque à Membrana do Sistema Complemento/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Evasão da Resposta Imune , Pandemias/prevenção & controle , Pneumonia Viral/imunologia , Pneumonia Viral/prevenção & controle , Vacinas Virais/imunologia , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Ativação do Complemento/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Flavivirus/imunologia , Infecções por Flavivirus/imunologia , Infecções por Flavivirus/virologia , Humanos , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Internalização do Vírus
8.
Viruses ; 12(8)2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32731335

RESUMO

Non-structural protein 1 (nsp1) is only characterized in alphacoronaviruses (α-CoVs) and betacoronaviruses (ß-CoVs). There have been extensive researches on how the ß-CoVs nsp1 regulates viral virulence by inhibiting host protein synthesis, but the regulatory mechanism of the α-CoVs nsp1 is still unclear. Here, we report the 2.1-Å full-length crystal structure of nsp1 in emerging porcine SADS-CoV and the 1.8-Å full-length crystal structure of nsp1 in the highly lethal cat FIPV. Although they belong to different subtypes of α-CoVs, these viruses all have a bucket-shaped fold composed of six ß-sheets, similar to the crystal structure of PEDV and TGEV nsp1. Comparing the above four structures, we found that the structure of α-CoVs nsp1 in the same subtype was more conserved. We then selected mammalian cells that were treated with SADS-CoV and FIPV nsp1 for RNA sequencing analysis and found that nsp1 had a specific inhibitory effect on interferon (IFN) and cell cycle genes. Using the Renilla luciferase (Rluc) assay and Western blotting, we confirmed that seven representative α-CoVs nsp1s could significantly inhibit the phosphorylation of STAT1-S727 and interfere with the effect of IFN-I. Moreover, the cell cycle experiment confirmed that α-CoVs nsp1 could encourage host cells to stay in the G0/G1 phase. Based on these findings, we not only greatly improved the crystal structure data on α-CoVs nsp1, but we also speculated that α-CoVs nsp1 regulated host proliferation and immune evasion-related biological functions by inhibiting the synthesis of host proteins, thus creating an environment conducive to the virus.


Assuntos
Alphacoronavirus/imunologia , Alphacoronavirus/fisiologia , Evasão da Resposta Imune/imunologia , Interferon Tipo I/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismo , Alphacoronavirus/genética , Sequência de Aminoácidos , Animais , Gatos , Linhagem Celular , Cristalografia por Raios X , Pontos de Checagem da Fase G1 do Ciclo Celular/fisiologia , Regulação da Expressão Gênica/genética , Células HEK293 , Humanos , Fosforilação , Estrutura Terciária de Proteína , Fator de Transcrição STAT1/metabolismo , Homologia de Sequência , Suínos , Proteínas não Estruturais Virais/genética , Replicação Viral/genética
9.
Proc Natl Acad Sci U S A ; 117(32): 19299-19309, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32737161

RESUMO

Schistosomes are parasitic flatworms that cause schistosomiasis, a neglected tropical disease affecting over 200 million people. Schistosomes develop multiple body plans while navigating their complex life cycle, which involves two different hosts: a mammalian definitive host and a molluscan intermediate host. Their survival and propagation depend upon proliferation and differentiation of stem cells necessary for parasite homeostasis and reproduction. Infective larvae released from snails carry a handful of stem cells that serve as the likely source of new tissues as the parasite adapts to life inside the mammalian host; however, the role of these stem cells during this critical life cycle stage remains unclear. Here, we characterize stem cell fates during early intramammalian development. Surprisingly, we find that the esophageal gland, an accessory organ of the digestive tract, develops before the rest of the digestive system is formed and blood feeding is initiated, suggesting a role in processes beyond nutrient uptake. To explore such a role, we examine schistosomes that lack the esophageal gland due to knockdown of a forkhead-box transcription factor, Sm-foxA, which blocks development and maintenance of the esophageal gland, without affecting the development of other somatic tissues. Intriguingly, schistosomes lacking the esophageal gland die after transplantation into naive mice, but survive in immunodeficient mice lacking B cells. We show that parasites lacking the esophageal gland are unable to lyse ingested immune cells within the esophagus before passing them into the gut. These results unveil an immune-evasion mechanism mediated by the esophageal gland, which is essential for schistosome survival and pathogenesis.


Assuntos
Esôfago/parasitologia , Evasão da Resposta Imune , Schistosoma mansoni/imunologia , Esquistossomose mansoni/imunologia , Animais , Esôfago/imunologia , Feminino , Proteínas de Helminto/genética , Proteínas de Helminto/imunologia , Interações Hospedeiro-Parasita , Humanos , Estágios do Ciclo de Vida , Masculino , Camundongos , Schistosoma mansoni/genética , Schistosoma mansoni/crescimento & desenvolvimento , Esquistossomose mansoni/parasitologia , Esquistossomose mansoni/fisiopatologia
10.
J Mol Med (Berl) ; 98(10): 1369-1383, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32808094

RESUMO

Occasional zoonotic viral attacks on immunologically naive populations result in massive death tolls that are capable of threatening human survival. Currently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the infectious agent that causes coronavirus disease (COVID-19), has spread from its epicenter in Wuhan China to all parts of the globe. Real-time mapping of new infections across the globe has revealed that variable transmission patterns and pathogenicity are associated with differences in SARS-CoV-2 lineages, clades, and strains. Thus, we reviewed how changes in the SARS-CoV-2 genome and its structural architecture affect viral replication, immune evasion, and transmission within different human populations. We also looked at which immune dominant regions of SARS-CoV-2 and other coronaviruses are recognized by Major Histocompatibility Complex (MHC)/Human Leukocyte Antigens (HLA) genes and how this could impact on subsequent disease pathogenesis. Efforts were also placed on understanding immunological changes that occur when exposed individuals either remain asymptomatic or fail to control the virus and later develop systemic complications. Published autopsy studies that reveal alterations in the lung immune microenvironment, morphological, and pathological changes are also explored within the context of the review. Understanding the true correlates of protection and determining how constant virus evolution impacts on host-pathogen interactions could help identify which populations are at high risk and later inform future vaccine and therapeutic interventions.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/epidemiologia , Interações Hospedeiro-Patógeno/imunologia , Evasão da Resposta Imune/imunologia , Pneumonia Viral/epidemiologia , Replicação Viral/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/virologia , Humanos , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/fisiopatologia , Pneumonia Viral/virologia
11.
Infection ; 48(5): 665-669, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32737833

RESUMO

Novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) became pandemic by the end of March 2020. In contrast to the 2002-2003 SARS-CoV outbreak, which had a higher pathogenicity and lead to higher mortality rates, SARSCoV-2 infection appears to be much more contagious. Moreover, many SARS-CoV-2 infected patients are reported to develop low-titer neutralizing antibody and usually suffer prolonged illness, suggesting a more effective SARS-CoV-2 immune surveillance evasion than SARS-CoV. This paper summarizes the current state of art about the differences and similarities between the pathogenesis of the two coronaviruses, focusing on receptor binding domain, host cell entry and protease activation. Such differences may provide insight into possible intervention strategies to fight the pandemic.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/epidemiologia , Pandemias , Pneumonia Viral/epidemiologia , Vírus da SARS/patogenicidade , Síndrome Respiratória Aguda Grave/epidemiologia , Glicoproteína da Espícula de Coronavírus/imunologia , Anticorpos Antivirais/biossíntese , Betacoronavirus/imunologia , Catepsinas/genética , Catepsinas/imunologia , Infecções por Coronavirus/enzimologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Ativação Enzimática/imunologia , Humanos , Evasão da Resposta Imune , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/enzimologia , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Ligação Proteica , Domínios Proteicos , Vírus da SARS/imunologia , Serina Endopeptidases/genética , Serina Endopeptidases/imunologia , Síndrome Respiratória Aguda Grave/enzimologia , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/patologia , Índice de Gravidade de Doença , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Internalização do Vírus , Replicação Viral
12.
Anticancer Res ; 40(8): 4663-4674, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727790

RESUMO

BACKGROUND/AIM: Roles for mutant (mt) KRAS in the innate immune microenvironment in colorectal cancer (CRC) were explored. MATERIALS AND METHODS: Human CRC HCT116-derived, mtKRAS-disrupted (HKe3) cells that express exogenous mtKRAS and allogenic cytokine-activated killer (CAK) cells were co-cultured in 3D floating (3DF) culture. The anti-CD155 antibody was used for function blocking and immuno histochemistry. RESULTS: Infiltration of CAK cells, including NKG2D+ T cells, into the deep layer of HKe3-mtKRAS spheroids, was observed. Surface expression of CD155 was found to be up-regulated by mtKRAS in 3DF culture and CRC tissues. Further, the number of CD3+ tumor-infiltrating cells in the invasion front that show substantial CD155 expression was significantly larger than the number showing weak expression in CRC tissues with mtKRAS. CD155 blockade decreased the growth of spheroids directly and indirectly through the release of CAK cells. CONCLUSION: CD155 blockade may be useful for therapies targeting tumors containing mtKRAS.


Assuntos
Evasão da Resposta Imune/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Proteínas Proto-Oncogênicas p21(ras)/imunologia , Receptores Virais/imunologia , Linfócitos T/imunologia , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular , Linhagem Celular Tumoral , Técnicas de Cocultura/métodos , Neoplasias Colorretais/imunologia , Feminino , Humanos , Células Matadoras Naturais/imunologia , Masculino , Pessoa de Meia-Idade , Microambiente Tumoral/imunologia
13.
Immunol Lett ; 226: 38-45, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32659267

RESUMO

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative pathogen of deadly Coronavirus disease-19 (COVID-19) pandemic, which emerged as a major threat to public health across the world. Although there is no clear gender or socioeconomic discrimination in the incidence of COVID-19, individuals who are older adults and/or with comorbidities and compromised immunity have a relatively higher risk of contracting this disease. Since no specific drug has yet been discovered, strengthening immunity along with maintaining a healthy living is the best way to survive this disease. As a healthy practice, calorie restriction in the form of intermittent fasting (IF) in several clinical settings has been reported to promote several health benefits, including priming of the immune response. This dietary restriction also activates autophagy, a cell surveillance system that boosts up immunity. With these prevailing significance in priming host defense, IF could be a potential strategy amid this outbreak to fighting off SARS-CoV-2 infection. Currently, no review so far available proposing IF as an encouraging strategy in the prevention of COVID-19. A comprehensive review has therefore been planned to highlight the beneficial role of fasting in immunity and autophagy, that underlie the possible defense against SARS-CoV-2 infection. The COVID-19 pathogenesis and its impact on host immune response have also been briefly outlined. This review aimed at revisiting the immunomodulatory potential of IF that may constitute a promising preventive approach against COVID-19.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/etiologia , Infecções por Coronavirus/metabolismo , Suscetibilidade a Doenças , Jejum , Interações Hospedeiro-Patógeno , Pneumonia Viral/etiologia , Pneumonia Viral/metabolismo , Autofagia , Restrição Calórica , Resistência à Doença/imunologia , Suscetibilidade a Doenças/imunologia , Jejum/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Humanos , Evasão da Resposta Imune , Imunidade , Pandemias
14.
Rev Med Virol ; 30(5): e2123, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32648313

RESUMO

The outbreak of coronavirus disease 2019 (COVID-19) and pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a major concern globally. As of 14 April 2020, more than 1.9 million COVID-19 cases have been reported in 185 countries. Some patients with COVID-19 develop severe clinical manifestations, while others show mild symptoms, suggesting that dysregulation of the host immune response contributes to disease progression and severity. In this review, we have summarized and discussed recent immunological studies focusing on the response of the host immune system and the immunopathology of SARS-CoV-2 infection as well as immunotherapeutic strategies for COVID-19. Immune evasion by SARS-CoV-2, functional exhaustion of lymphocytes, and cytokine storm have been discussed as part of immunopathology mechanisms in SARS-CoV-2 infection. Some potential immunotherapeutic strategies to control the progression of COVID-19, such as passive antibody therapy and use of interferon αß and IL-6 receptor (IL-6R) inhibitor, have also been discussed. This may help us to understand the immune status of patients with COVID-19, particularly those with severe clinical presentation, and form a basis for further immunotherapeutic investigations.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Síndrome da Liberação de Citocina/prevenção & controle , Evasão da Resposta Imune/efeitos dos fármacos , Fatores Imunológicos/uso terapêutico , Interferon Tipo I/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/terapia , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/virologia , Progressão da Doença , Regulação da Expressão Gênica , Humanos , Evasão da Resposta Imune/genética , Evasão da Resposta Imune/imunologia , Imunização Passiva/métodos , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Linfócitos/virologia , Terapia de Alvo Molecular/métodos , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Receptores de Interleucina-6/antagonistas & inibidores , Receptores de Interleucina-6/genética , Receptores de Interleucina-6/imunologia , Índice de Gravidade de Doença , Transdução de Sinais
15.
Artigo em Inglês | MEDLINE | ID: mdl-32656094

RESUMO

As an emerging swine enteropathogenic coronavirus, porcine deltacoronavirus (PDCoV) not only causes serious diarrhea in suckling piglets but also possesses the potential for cross-species transmission, which has sparked growing interest when studying this emerging virus. We previously identified a novel accessory protein NS7a encoded by PDCoV; however, the function of NS7a was not resolved. In this study, we demonstrated that PDCoV NS7a is an interferon antagonist. Overexpression of NS7a notably inhibited Sendai virus (SeV)-induced interferon-ß (IFN-ß) production and the activation of IRF3 rather than NF-κB. NS7a also inhibited IFN-ß promoter activity induced by RIG-I, MDA5, MAVS, TBK1, and IKKε, which are key components of the RIG-I-like receptor (RLR) signaling pathway but not IRF3, the transcription factor downstream of TBK1/IKKε. Surprisingly, NS7a specifically interacts with IKKε but not with the closely related TBK1. Furthermore, NS7a interacts simultaneously with the kinase domain (KD) and the scaffold dimerization domain (SDD) of IKKε, competing with TRAF3, and IRF3 for binding to IKKε, leading to the reduction of RLR-mediated IFN-ß production. The interactions of TRAF3-IKKε and IKKε-IRF3 are also attenuated in PDCoV-infected cells. Taken together, our results demonstrate that PDCoV NS7a inhibits IFN-ß production by disrupting the association of IKKε with both TRAF3 and IRF3, revealing a new mechanism utilized by a PDCoV accessory protein to evade the host antiviral innate immune response.


Assuntos
Infecções por Coronavirus/metabolismo , Coronavirus/metabolismo , Quinase I-kappa B/metabolismo , Fator Regulador 3 de Interferon/metabolismo , Interferon beta/antagonistas & inibidores , Fator 3 Associado a Receptor de TNF/metabolismo , Proteínas não Estruturais Virais/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Coronavirus/genética , Coronavirus/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Células HEK293 , Humanos , Quinase I-kappa B/imunologia , Evasão da Resposta Imune , Fator Regulador 3 de Interferon/imunologia , Helicase IFIH1 Induzida por Interferon/metabolismo , Interferon beta/biossíntese , Interferon beta/imunologia , Receptores do Ácido Retinoico/metabolismo , Vírus Sendai/imunologia , Vírus Sendai/metabolismo , Transdução de Sinais , Suínos , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/imunologia
16.
Nat Commun ; 11(1): 3382, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32636381

RESUMO

The Stimulator of Interferon Genes (STING) pathway initiates potent immune responses upon recognition of DNA. To initiate signaling, serine 365 (S365) in the C-terminal tail (CTT) of STING is phosphorylated, leading to induction of type I interferons (IFNs). Additionally, evolutionary conserved responses such as autophagy also occur downstream of STING, but their relative importance during in vivo infections remains unclear. Here we report that mice harboring a serine 365-to-alanine (S365A) mutation in STING are unexpectedly resistant to Herpes Simplex Virus (HSV)-1, despite lacking STING-induced type I IFN responses. By contrast, resistance to HSV-1 is abolished in mice lacking the STING CTT, suggesting that the STING CTT initiates protective responses against HSV-1, independently of type I IFNs. Interestingly, we find that STING-induced autophagy is a CTT- and TBK1-dependent but IRF3-independent process that is conserved in the STING S365A mice. Thus, interferon-independent functions of STING mediate STING-dependent antiviral responses in vivo.


Assuntos
Herpes Simples/imunologia , Fator Regulador 3 de Interferon/imunologia , Interferon Tipo I/imunologia , Proteínas de Membrana/genética , Animais , Autofagia , Feminino , Herpesvirus Humano 1 , Evasão da Resposta Imune , Macrófagos/imunologia , Masculino , Proteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Mutantes , Mutação Puntual , Transdução de Sinais
17.
BMC Infect Dis ; 20(1): 546, 2020 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-32711474

RESUMO

BACKGROUND: Human immunodeficiency virus (HIV-1) infection is characterized by high viral replication and a decrease in CD4+ T cells (CD4+TC), resulting in AIDS, which can lead to death. In elite controllers and viremia controllers, viral replication is naturally controlled, with maintenance of CD4+TC levels without the use of antiretroviral therapy (ART). METHODS: The aim of the present study was to describe virological and immunological risk factors among HIV-1-infected individuals according to characteristics of progression to AIDS. The sample included 30 treatment-naive patients classified into three groups based on infection duration (> 6 years), CD4+TC count and viral load: (i) 2 elite controllers (ECs), (ii) 7 viremia controllers (VCs) and (iii) 21 nonviremia controllers (NVCs). Nested PCR was employed to amplify the virus genome, which was later sequenced using the Ion PGM platform for subtyping and analysis of immune escape mutations. RESULTS: Viral samples were classified as HIV-1 subtypes B and F. Greater selection pressure on mutations was observed in the group of viremia controllers, with a higher frequency of immunological escape mutations in the genes investigated, including two new mutations in gag. The viral sequences of viremia controllers and nonviremia controllers did not differ significantly regarding the presence of immune escape mutations. CONCLUSION: The results suggest that progression to AIDS is not dependent on a single variable but rather on a set of characteristics and pressures exerted by virus biology and interactions with immunogenetic host factors.


Assuntos
Síndrome de Imunodeficiência Adquirida/imunologia , HIV-1/genética , Evasão da Resposta Imune/genética , Mutação/imunologia , Síndrome de Imunodeficiência Adquirida/virologia , Adulto , Brasil , Linfócitos T CD4-Positivos/imunologia , Estudos Transversais , Feminino , Genes gag/genética , Humanos , Masculino , Filogenia , Conformação Proteica , Estudos Retrospectivos , Carga Viral , Viremia/genética , Replicação Viral/genética , Produtos do Gene gag do Vírus da Imunodeficiência Humana/química , Produtos do Gene gag do Vírus da Imunodeficiência Humana/genética
18.
Nat Commun ; 11(1): 3763, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32724132

RESUMO

In both animals and plants, the perception of bacterial flagella by immune receptors elicits the activation of defence responses. Most plants are able to perceive the highly conserved epitope flg22 from flagellin, the main flagellar protein, from most bacterial species. However, flagellin from Ralstonia solanacearum, the causal agent of the bacterial wilt disease, presents a polymorphic flg22 sequence (flg22Rso) that avoids perception by all plants studied to date. In this work, we show that soybean has developed polymorphic versions of the flg22 receptors that are able to perceive flg22Rso. Furthermore, we identify key residues responsible for both the evasion of perception by flg22Rso in Arabidopsis and the gain of perception by the soybean receptors. Heterologous expression of the soybean flg22 receptors in susceptible plant species, such as tomato, enhances resistance to bacterial wilt disease, demonstrating the potential of these receptors to enhance disease resistance in crop plants.


Assuntos
Flagelina/imunologia , Imunidade Vegetal , Proteínas de Plantas/imunologia , Receptores Imunológicos/imunologia , Soja/imunologia , Antígenos de Bactérias/genética , Antígenos de Bactérias/imunologia , Antígenos de Bactérias/metabolismo , Arabidopsis/genética , Arabidopsis/imunologia , Arabidopsis/metabolismo , Resistência à Doença/genética , Resistência à Doença/imunologia , Epitopos/imunologia , Flagelina/genética , Flagelina/metabolismo , Evasão da Resposta Imune/genética , Doenças das Plantas/imunologia , Doenças das Plantas/microbiologia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas , Polimorfismo Genético/imunologia , Ralstonia solanacearum/imunologia , Ralstonia solanacearum/patogenicidade , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Soja/genética , Soja/metabolismo , Soja/microbiologia
20.
Mol Biol Evol ; 37(9): 2706-2710, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32658964

RESUMO

Due to the scope and impact of the COVID-19 pandemic there exists a strong desire to understand where the SARS-CoV-2 virus came from and how it jumped species boundaries to humans. Molecular evolutionary analyses can trace viral origins by establishing relatedness and divergence times of viruses and identifying past selective pressures. However, we must uphold rigorous standards of inference and interpretation on this topic because of the ramifications of being wrong. Here, we dispute the conclusions of Xia (2020. Extreme genomic CpG deficiency in SARS-CoV-2 and evasion of host antiviral defense. Mol Biol Evol. doi:10.1093/molbev/masa095) that dogs are a likely intermediate host of a SARS-CoV-2 ancestor. We highlight major flaws in Xia's inference process and his analysis of CpG deficiencies, and conclude that there is no direct evidence for the role of dogs as intermediate hosts. Bats and pangolins currently have the greatest support as ancestral hosts of SARS-CoV-2, with the strong caveat that sampling of wildlife species for coronaviruses has been limited.


Assuntos
Alphacoronavirus/genética , Betacoronavirus/genética , Infecções por Coronavirus/epidemiologia , Genoma Viral , Pandemias , Pneumonia Viral/epidemiologia , Vírus Reordenados/genética , Alphacoronavirus/classificação , Alphacoronavirus/patogenicidade , Animais , Betacoronavirus/classificação , Betacoronavirus/patogenicidade , Evolução Biológica , Quirópteros/virologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Ilhas de CpG , Cães , Eutérios/virologia , Humanos , Evasão da Resposta Imune/genética , Pneumonia Viral/imunologia , Pneumonia Viral/transmissão , Pneumonia Viral/virologia , Ligação Proteica , RNA Viral/genética , RNA Viral/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/imunologia , Proteínas de Ligação a RNA/metabolismo , Vírus Reordenados/classificação , Vírus Reordenados/patogenicidade , Replicação Viral
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