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1.
PLoS Negl Trop Dis ; 17(11): e0010751, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-38011286

RESUMO

Chikungunya virus (CHIKV) is a human pathogen causing outbreaks of febrile illness for which vaccines and specific treatments remain unavailable. Autophagy-related (ATG) proteins and autophagy receptors are a set of host factors that participate in autophagy, but have also shown to function in other unrelated cellular pathways. Although autophagy is reported to both inhibit and enhance CHIKV replication, the specific role of individual ATG proteins remains largely unknown. Here, a siRNA screen was performed to evaluate the importance of the ATG proteome and autophagy receptors in controlling CHIKV infection. We observed that 7 out of 50 ATG proteins impact the replication of CHIKV. Among those, depletion of the mitochondrial protein and autophagy receptor BCL2 Interacting Protein 3 (BNIP3) increased CHIKV infection. Interestingly, BNIP3 controls CHIKV independently of autophagy and cell death. Detailed analysis of the CHIKV viral cycle revealed that BNIP3 interferes with the early stages of infection. Moreover, the antiviral role of BNIP3 was found conserved across two distinct CHIKV genotypes and the closely related Semliki Forest virus. Altogether, this study describes a novel and previously unknown function of the mitochondrial protein BNIP3 in the control of the early stages of the alphavirus viral cycle.


Assuntos
Febre de Chikungunya , Vírus Chikungunya , Humanos , Vírus Chikungunya/fisiologia , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Replicação Viral/fisiologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas Proto-Oncogênicas/metabolismo
2.
Antimicrob Agents Chemother ; 66(1): e0154321, 2022 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-34633839

RESUMO

Antiviral therapies are urgently needed to treat and limit the development of severe COVID-19 disease. Ivermectin, a broad-spectrum anti-parasitic agent, has been shown to have anti-SARS-CoV-2 activity in Vero cells at a concentration of 5 µM. These limited in vitro results triggered the investigation of ivermectin as a treatment option to alleviate COVID-19 disease. However, in April 2021, the World Health Organization stated the following: "The current evidence on the use of ivermectin to treat COVID-19 patients is inconclusive." It is speculated that the in vivo concentration of ivermectin is too low to exert a strong antiviral effect. Here, we performed a head-to-head comparison of the antiviral activity of ivermectin and the structurally related, but metabolically more stable moxidectin in multiple in vitro models of SARS-CoV-2 infection, including physiologically relevant human respiratory epithelial cells. Both moxidectin and ivermectin exhibited antiviral activity in Vero E6 cells. Subsequent experiments revealed that these compounds predominantly act on the steps following virus cell entry. Surprisingly, however, in human-airway-derived cell models, both moxidectin and ivermectin failed to inhibit SARS-CoV-2 infection, even at concentrations of 10 µM. These disappointing results call for a word of caution in the interpretation of anti-SARS-CoV-2 activity of drugs solely based on their activity in Vero cells. Altogether, these findings suggest that even using a high-dose regimen of ivermectin, or switching to another drug in the same class, is unlikely to be useful for treatment of SARS-CoV-2 in humans.


Assuntos
COVID-19 , Ivermectina , Animais , Antivirais/farmacologia , Chlorocebus aethiops , Células Epiteliais , Humanos , Ivermectina/farmacologia , Macrolídeos , SARS-CoV-2 , Células Vero , Replicação Viral
3.
Viruses ; 13(7)2021 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-34372541

RESUMO

The current COVID-19 pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has an enormous impact on human health and economy. In search for therapeutic options, researchers have proposed resveratrol, a food supplement with known antiviral, anti-inflammatory, and antioxidant properties as an advantageous antiviral therapy for SARS-CoV-2 infection. Here, we provide evidence that both resveratrol and its metabolically more stable structural analog, pterostilbene, exhibit potent antiviral properties against SARS-CoV-2 in vitro. First, we show that resveratrol and pterostilbene antiviral activity in African green monkey kidney cells. Both compounds actively inhibit virus replication within infected cells as reduced virus progeny production was observed when the compound was added at post-inoculation conditions. Without replenishment of the compound, antiviral activity was observed up to roughly five rounds of replication, demonstrating the long-lasting effect of these compounds. Second, as the upper respiratory tract represents the initial site of SARS-CoV-2 replication, we also assessed antiviral activity in air-liquid interface (ALI) cultured human primary bronchial epithelial cells, isolated from healthy volunteers. Resveratrol and pterostilbene showed a strong antiviral effect in these cells up to 48 h post-infection. Collectively, our data indicate that resveratrol and pterostilbene are promising antiviral compounds to inhibit SARS-CoV-2 infection. Because these results represent laboratory findings in cells, we advocate evaluation of these compounds in clinical trials before statements are made whether these drugs are advantageous for COVID-19 treatment.


Assuntos
Brônquios/virologia , COVID-19/virologia , Células Epiteliais/virologia , Resveratrol/farmacologia , SARS-CoV-2/efeitos dos fármacos , Estilbenos/farmacologia , Replicação Viral/efeitos dos fármacos , Animais , Antivirais/farmacologia , COVID-19/epidemiologia , Linhagem Celular , Células Cultivadas , Chlorocebus aethiops , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/fisiologia , Células Vero , Tratamento Farmacológico da COVID-19
4.
Sci Rep ; 6: 28768, 2016 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-27385443

RESUMO

Antibody-dependent enhancement of dengue virus (DENV) infection plays an important role in the exacerbation of DENV-induced disease. To understand how antibodies influence the fate of DENV particles, we explored the cell entry pathway of DENV in the absence and presence of antibodies in macrophage-like P388D1 cells. Recent studies unraveled that both mature and immature DENV particles contribute to ADE, hence, both particles were studied. We observed that antibody-opsonized DENV enters P388D1 cells through a different pathway than non-opsonized DENV. Antibody-mediated DENV entry was dependent on FcγRs, pH, Eps15, dynamin, actin, PI3K, Rab5, and Rab7. In the absence of antibodies, DENV cell entry was FcγR, PI3K, and Rab5-independent. Live-cell imaging of fluorescently-labeled particles revealed that actin-mediated membrane protrusions facilitate virus uptake. In fact, actin protrusions were found to actively search and capture antibody-bound virus particles distantly located from the cell body, a phenomenon that is not observed in the absence of antibodies. Overall, similar results were seen for antibody-opsonized standard and antibody-bound immature DENV preparations, indicating that the maturation status of the virus does not control the entry pathway. Collectively, our findings suggest that antibodies alter the cell entry pathway of DENV and trigger a novel mechanism of initial virus-cell contact.


Assuntos
Anticorpos/fisiologia , Vírus da Dengue/fisiologia , Dengue/virologia , Macrófagos/virologia , Citoesqueleto de Actina/patologia , Animais , Anticorpos Facilitadores , Linhagem Celular , Membrana Celular/patologia , Membrana Celular/virologia , Culicidae , Endocitose , Humanos , Cinética , Camundongos , Receptores de IgG/metabolismo , Internalização do Vírus
5.
Sci Rep ; 6: 29201, 2016 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-27380892

RESUMO

The dogma is that the human immune system protects us against pathogens. Yet, several viruses, like dengue virus, antagonize the hosts' antibodies to enhance their viral load and disease severity; a phenomenon called antibody-dependent enhancement of infection. This study offers novel insights in the molecular mechanism of antibody-mediated enhancement (ADE) of dengue virus infection in primary human macrophages. No differences were observed in the number of bound and internalized DENV particles following infection in the absence and presence of enhancing concentrations of antibodies. Yet, we did find an increase in membrane fusion activity during ADE of DENV infection. The higher fusion activity is coupled to a low antiviral response early in infection and subsequently a higher infection efficiency. Apparently, subtle enhancements early in the viral life cycle cascades into strong effects on infection, virus production and immune response. Importantly, and in contrast to other studies, the antibody-opsonized virus particles do not trigger immune suppression and remain sensitive to interferon. Additionally, this study gives insight in how human macrophages interact and respond to viral infections and the tight regulation thereof under various conditions of infection.


Assuntos
Anticorpos Antivirais/imunologia , Antivirais/farmacologia , Vírus da Dengue/fisiologia , Dengue/imunologia , Dengue/virologia , Macrófagos/virologia , Internalização do Vírus/efeitos dos fármacos , Células Cultivadas , Dengue/genética , Vírus da Dengue/efeitos dos fármacos , Perfilação da Expressão Gênica , Humanos , Interferon Tipo I/metabolismo , Macrófagos/efeitos dos fármacos , Biossíntese de Proteínas/efeitos dos fármacos , Transcrição Gênica/efeitos dos fármacos , Carga Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
6.
PLoS Negl Trop Dis ; 9(3): e0003564, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25760350

RESUMO

Humoral immunity plays an important role in controlling dengue virus (DENV) infection. Antibodies (Abs) developed during primary infection protect against subsequent infection with the same dengue serotype, but can enhance disease following secondary infection with a heterologous serotype. A DENV virion has two surface proteins, envelope protein E and (pre)-membrane protein (pr)M, and inefficient cleavage of the prM protein during maturation of progeny virions leads to the secretion of immature and partially immature particles. Interestingly, we and others found that historically regarded non-infectious prM-containing DENV particles can become highly infectious in the presence of E- and prM-Abs. Accordingly, we hypothesized that these virions contribute to the exacerbation of disease during secondary infection. Here, we tested this hypothesis and investigated the ability of acute sera of 30 DENV2-infected patients with different grades of disease severity, to bind, neutralize and/or enhance immature DENV2. We found that a significant fraction of serum Abs bind to the prM protein and to immature virions, but we observed no significant difference between the disease severity groups. Furthermore, functional analysis of the Abs did not underscore any specific correlation between the neutralizing/enhancing activity towards immature DENV2 and the development of more severe disease. Based on our analysis of acute sera, we conclude that Abs binding to immature virions are not a discriminating factor in dengue pathogenesis.


Assuntos
Anticorpos Antivirais/imunologia , Vírus da Dengue/imunologia , Vírion/imunologia , Dengue/imunologia , Humanos , Soros Imunes/imunologia , Imunoglobulina G/sangue , Proteínas do Envelope Viral/imunologia
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