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1.
Front Immunol ; 15: 1439789, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39439800

RESUMO

Granulocyte-macrophage colony stimulating factor (GM-CSF) is a pleiotropic cytokine, able to promote both myelopoiesis and activation of immune cells. Particularly in the lung, GM-CSF plays an important homeostatic role in the development and maintenance of alveolar macrophages, and is therefore considered to play a role in respiratory virus infections such as influenza and SARS-CoV-2, although the benefits of GM-CSF treatment in clinical studies remain inconclusive. To address this, we tested inhaled GM-CSF treatment in the Pneumonia Virus of Mice (PVM) mouse model. Our findings show that local GM-CSF therapy during PVM disease increased local neutrophilia and monocyte-derived cell influx, but diminished CD8+ T cells responses. Despite this, the observed effects on T cells and myeloid cells did not result in an altered clinical outcome during PVM infection. We conclude that inhaled GM-CSF therapy cannot be considered as a universal protective therapy in respiratory virus infections.


Assuntos
Linfócitos T CD8-Positivos , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Infecções por Pneumovirus , Animais , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Linfócitos T CD8-Positivos/imunologia , Camundongos , Administração por Inalação , Infecções por Pneumovirus/imunologia , Infecções por Pneumovirus/tratamento farmacológico , Modelos Animais de Doenças , Células Mieloides/imunologia , Camundongos Endogâmicos C57BL , Feminino , Pulmão/imunologia , Pulmão/virologia
2.
mBio ; 12(6): e0262121, 2021 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-34724816

RESUMO

Multiple enveloped RNA viruses of the family Paramyxoviridae and Pneumoviridae, like measles virus (MeV), Nipah virus (NiV), canine distemper virus (CDV), or respiratory syncytial virus (RSV), are of high clinical relevance. Each year a huge number of lives are lost as a result of these viral infections. Worldwide, MeV infection alone is responsible for over a hundred thousand deaths each year despite available vaccine. Therefore, there is an urgent need for treatment options to counteract these viral infections. The development of antiviral drugs in general stands as a huge challenge due to the rapid emergence of viral escape mutants. Here, we disclose the discovery of a small-molecule antiviral, compound 1 (ZHAWOC9045), active against several pneumo-/paramyxoviruses, including MeV, NiV, CDV, RSV, and parainfluenza virus type 5 (PIV-5). A series of mechanistic characterizations revealed that compound 1 targets a host factor which is indispensable for viral genome replication. Drug resistance profiling against a paramyxovirus model (CDV) demonstrated no detectable adaptation despite prolonged time of investigation, thereby mitigating the rapid emergence of escape variants. Furthermore, a thorough structure-activity relationship analysis of compound 1 led to the invention of 100-times-more potent-derivatives, e.g., compound 2 (ZHAWOC21026). Collectively, we present in this study an attractive host-directed pneumoviral/paramyxoviral replication inhibitor with potential therapeutic application. IMPORTANCE Measles virus, respiratory syncytial virus, canine distemper virus, and Nipah virus are some of the clinically significant RNA viruses that threaten substantial number of lives each year. Limited to no availability of treatment options for these viral infections makes it arduous to handle the outbreaks. This highlights the major importance of developing antivirals to fight not only ongoing infections but also potential future epidemics. Most of the discovered antivirals, in clinical trials currently, are virus targeted, which consequently poses the challenge of rapid emergence of escape variants. Here, we present compound 1 (ZHAWOC9045), discovered to target viral replication in a host-dependent manner, thereby exhibiting broad-spectrum activity against several members of the family Pneumo-/Paramyxoviridae. The inability of viruses to mutate against the inhibitor mitigated the critical issue of generation of escape variants. Importantly, compound 1 was successfully optimized to a highly potent variant, compound 2 (ZHAWOC21026), with a promising profile for pharmacological intervention.


Assuntos
Antivirais/farmacologia , Paramyxoviridae/fisiologia , Pneumovirus/fisiologia , Replicação Viral/efeitos dos fármacos , Antivirais/química , Descoberta de Drogas , Humanos , Paramyxoviridae/genética , Infecções por Paramyxoviridae/tratamento farmacológico , Infecções por Paramyxoviridae/virologia , Pneumovirus/genética , Infecções por Pneumovirus/tratamento farmacológico , Infecções por Pneumovirus/virologia
3.
Immunobiology ; 226(6): 152151, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34742024

RESUMO

Resolvin D1 (RvD1), which is biosynthesized from essential long-chain fatty acids, is involved in anti-inflammatory activity and modulation of T cell response. Memory CD8+ T cells are important for controlling tumor growth and viral infections. Exacerbated inflammation has been described as impairing memory CD8+ T cell differentiation. This study aimed to verify the effects of RvD1 on memory CD8+ T cells in vitro and in vivo in a respiratory virus infection model. Peripheral blood mononuclear cells were treated at different time points with RvD1 and stimulated with anti-CD3/anti-CD28 antibodies. Pre-treatment with RvD1 increases the expansion of memory CD8+ T cells. The IL-12 level, a cytokine described to control memory CD8+ T cells, was reduced with RvD1 pre-treatment. When the mTOR axis was inhibited, the IL-12 levels were restored. In a respiratory virus infection model, Balb/c mice were treated with RvD1 before infection or after 7 days after infection. RvD1 treatment after infection increased the frequency of memory CD8+ T cells in the lung expressing II4, II10, and Ifng. During reinfection, RvD1-treated and RSV-infected mice present a high viral load in the lung and lower antibody response in the serum. Our results show that RvD1 modulates the expansion and phenotype of memory CD8+ T cells but contributed to a non-protective response after RSV reinfection.


Assuntos
Antivirais/uso terapêutico , Ácidos Docosa-Hexaenoicos/uso terapêutico , Memória Imunológica/efeitos dos fármacos , Infecções por Pneumovirus/tratamento farmacológico , Infecções por Pneumovirus/imunologia , Infecções por Pneumovirus/virologia , Carga Viral/efeitos dos fármacos , Adulto , Animais , Antivirais/farmacologia , Biomarcadores , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/farmacologia , Feminino , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunofenotipagem , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Masculino , Reinfecção , Resultado do Tratamento , Adulto Jovem
4.
Viruses ; 12(3)2020 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-32245118

RESUMO

Paramyxoviruses and pneumoviruses infect cells through fusion (F) protein-mediated merger of the viral envelope with target membranes. Members of these families include a range of major human and animal pathogens, such as respiratory syncytial virus (RSV), measles virus (MeV), human parainfluenza viruses (HPIVs), and highly pathogenic Nipah virus (NiV). High-resolution F protein structures in both the metastable pre- and the postfusion conformation have been solved for several members of the families and a number of F-targeting entry inhibitors have progressed to advanced development or clinical testing. However, small-molecule RSV entry inhibitors have overall disappointed in clinical trials and viral resistance developed rapidly in experimental settings and patients, raising the question of whether the available structural information may provide a path to counteract viral escape through proactive inhibitor engineering. This article will summarize current mechanistic insight into F-mediated membrane fusion and examine the contribution of structural information to the development of small-molecule F inhibitors. Implications are outlined for future drug target selection and rational drug engineering strategies.


Assuntos
Antivirais/química , Antivirais/farmacologia , Descoberta de Drogas , Paramyxovirinae/fisiologia , Pneumovirus/fisiologia , Internalização do Vírus/efeitos dos fármacos , Animais , Sítios de Ligação , Descoberta de Drogas/métodos , Humanos , Modelos Moleculares , Infecções por Paramyxoviridae/tratamento farmacológico , Infecções por Paramyxoviridae/virologia , Paramyxovirinae/efeitos dos fármacos , Pneumovirus/efeitos dos fármacos , Infecções por Pneumovirus/tratamento farmacológico , Infecções por Pneumovirus/virologia , Ligação Proteica , Relação Estrutura-Atividade
5.
Antiviral Res ; 171: 104594, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31470041

RESUMO

Respiratory syncytial virus (RSV) is responsible for a large proportion of acute lower respiratory tract infections, specifically in children. Pneumonia virus of mice (PVM) causes similar lung pathology and clinical disease in rodents, and is therefore an appropriate model of RSV infection. Previously, we demonstrated that a single intranasal dose of P-I-P, a novel immunomodulator composed of the toll-like receptor 3 agonist poly(I:C), an innate defense regulator peptide and a polyphosphazene, confers protection in Balb/c mice for up to 3 days from lethal PVM-15 infection. In the present study a dual intranasal treatment with P-I-P was shown to extend the duration of the protection conferred by P-I-P from PVM-15 challenge. Balb/c mice treated twice with P-I-P showed higher survival rates and milder clinical signs when compared to animals that received a single P-I-P dose. While the mice treated with two consecutive doses of P-I-P experienced some weight loss, they all recovered. The dual P-I-P treatment mediated infiltration of several innate immune cells into the BALF and lung, including alveolar macrophages, neutrophils, and γδ T cells. Partial depletion of alveolar macrophages decreased survival rates and exacerbated clinical signs of mice subjected to the P-I-P dual treatment regime followed by PVM-15 challenge. This suggests that the alveolar macrophage is at least partially responsible for the protection elicited by this novel prophylactic treatment strategy.


Assuntos
Imunidade Inata , Fatores Imunológicos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Vírus da Pneumonia Murina/efeitos dos fármacos , Vírus da Pneumonia Murina/imunologia , Infecções por Pneumovirus/imunologia , Infecções por Pneumovirus/virologia , Animais , Linhagem Celular , Citocinas/biossíntese , Citocinas/sangue , Feminino , Interações Hospedeiro-Patógeno , Fatores Imunológicos/administração & dosagem , Macrófagos/metabolismo , Macrófagos/virologia , Camundongos , Infecções por Pneumovirus/tratamento farmacológico , Infecções por Pneumovirus/mortalidade
6.
J Allergy Clin Immunol ; 141(5): 1607-1619.e9, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-28947081

RESUMO

BACKGROUND: Rhinovirus infection triggers acute asthma exacerbations. IL-33 is an instructive cytokine of type 2 inflammation whose expression is associated with viral load during experimental rhinovirus infection of asthmatic patients. OBJECTIVE: We sought to determine whether anti-IL-33 therapy is effective during disease progression, established disease, or viral exacerbation using a preclinical model of chronic asthma and in vitro human primary airway epithelial cells (AECs). METHODS: Mice were exposed to pneumonia virus of mice and cockroach extract in early and later life and then challenged with rhinovirus to model disease onset, progression, and chronicity. Interventions included anti-IL-33 or dexamethasone at various stages of disease. AECs were obtained from asthmatic patients and healthy subjects and treated with anti-IL-33 after rhinovirus infection. RESULTS: Anti-IL-33 decreased type 2 inflammation in all phases of disease; however, the ability to prevent airway smooth muscle growth was lost after the progression phase. After the chronic phase, IL-33 levels were persistently high, and rhinovirus challenge exacerbated the type 2 inflammatory response. Treatment with anti-IL-33 or dexamethasone diminished exacerbation severity, and anti-IL-33, but not dexamethasone, promoted antiviral interferon expression and decreased viral load. Rhinovirus replication was higher and IFN-λ levels were lower in AECs from asthmatic patients compared with those from healthy subjects. Anti-IL-33 decreased rhinovirus replication and increased IFN-λ levels at the gene and protein levels. CONCLUSION: Anti-IL-33 or dexamethasone suppressed the magnitude of type 2 inflammation during a rhinovirus-induced acute exacerbation; however, only anti-IL-33 boosted antiviral immunity and decreased viral replication. The latter phenotype was replicated in rhinovirus-infected human AECs, suggesting that anti-IL-33 therapy has the additional benefit of enhancing host defense.


Assuntos
Antivirais/farmacologia , Asma/tratamento farmacológico , Asma/imunologia , Inflamação/imunologia , Interleucina-33/imunologia , Vírus da Pneumonia Murina/efeitos dos fármacos , Vírus da Pneumonia Murina/imunologia , Animais , Antivirais/imunologia , Asma/virologia , Suscetibilidade a Doenças/imunologia , Suscetibilidade a Doenças/virologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Células Epiteliais/virologia , Inflamação/tratamento farmacológico , Inflamação/virologia , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Pneumovirus/tratamento farmacológico , Infecções por Pneumovirus/imunologia , Infecções por Pneumovirus/virologia , Carga Viral/efeitos dos fármacos , Carga Viral/imunologia
7.
PLoS One ; 9(7): e102749, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25047452

RESUMO

BACKGROUND: Pulmonary edema plays a pivotal role in the pathophysiology of respiratory syncytial virus (RSV)-induced respiratory failure. In this study we determined whether treatment with TIP (AP301), a synthetic cyclic peptide that mimics the lectin-like domain of human TNF, decreases pulmonary edema in a mouse model of severe human RSV infection. TIP is currently undergoing clinical trials as a therapy for pulmonary permeability edema and has been shown to decrease pulmonary edema in different lung injury models. METHODS: C57BL/6 mice were infected with pneumonia virus of mice (PVM) and received TIP or saline (control group) by intratracheal instillation on day five (early administration) or day seven (late administration) after infection. In a separate set of experiments the effect of multiple dose administration of TIP versus saline was tested. Pulmonary edema was determined by the lung wet-to-dry (W/D) weight ratio and was assessed at different time-points after the administration of TIP. Secondary outcomes included clinical scores and lung cellular response. RESULTS: TIP did not have an effect on pulmonary edema in different dose regimens at different time points during PVM infection. In addition, TIP administration did not affect clinical severity scores or lung cellular response. CONCLUSION: In this murine model of severe RSV infection TIP did not affect pulmonary edema nor course of disease.


Assuntos
Vírus da Pneumonia Murina/isolamento & purificação , Peptídeos Cíclicos/uso terapêutico , Infecções por Pneumovirus/tratamento farmacológico , Edema Pulmonar/tratamento farmacológico , Edema Pulmonar/virologia , Animais , Humanos , Masculino , Camundongos Endogâmicos C57BL , Vírus da Pneumonia Murina/efeitos dos fármacos , Peptídeos Cíclicos/química , Infecções por Pneumovirus/complicações , Infecções por Pneumovirus/patologia , Edema Pulmonar/patologia , Infecções por Vírus Respiratório Sincicial/complicações , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/patologia , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Vírus Sinciciais Respiratórios/isolamento & purificação , Fator de Necrose Tumoral alfa/química
8.
Viruses ; 5(1): 406-22, 2013 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-23344499

RESUMO

Pneumovirus infections cause a wide spectrum of respiratory disease in humans and animals. The airway epithelium is the major site of pneumovirus replication. Apoptosis or regulated cell death, may contribute to the host anti-viral response by limiting viral replication. However, apoptosis of lung epithelial cells may also exacerbate lung injury, depending on the extent, the timing and specific location in the lungs. Differential apoptotic responses of epithelial cells versus innate immune cells (e.g., neutrophils, macrophages) during pneumovirus infection can further contribute to the complex and delicate balance between host defense and disease pathogenesis. The purpose of this manuscript is to give an overview of the role of apoptosis in pneumovirus infection. We will examine clinical and experimental data concerning the various pro-apoptotic stimuli and the roles of apoptotic epithelial and innate immune cells during pneumovirus disease. Finally, we will discuss potential therapeutic interventions targeting apoptosis in the lungs.


Assuntos
Apoptose , Infecções por Pneumovirus/fisiopatologia , Pneumovirus/fisiologia , Animais , Antivirais/farmacologia , Humanos , Pneumovirus/efeitos dos fármacos , Pneumovirus/genética , Infecções por Pneumovirus/tratamento farmacológico , Infecções por Pneumovirus/imunologia , Infecções por Pneumovirus/virologia
9.
Curr Med Chem ; 19(10): 1424-31, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22360479

RESUMO

Respiratory syncytial virus (RSV; Family Paramyxoviridae, Genus Pneumovirus) is a major respiratory pathogen of infants and children and an emerging pathogen of the elderly. Current management of RSV disease includes monoclonal antibody prophylaxis for infants identified as high risk and supportive care for those with active infection; there is no vaccine, although several are under study. In this manuscript, we review published findings from human autopsy studies, as well as experiments that focus on human clinical samples and mouse models of acute pneumovirus infection that elucidate basic principles of disease pathogenesis. Consideration of these data suggests that the inflammatory responses to RSV and related pneumoviral pathogens can be strong, persistent, and beyond the control of conventional antiviral and anti-inflammatory therapies, and can have profound negative consequences to the host. From this perspective, we consider the case for specific immunomodulatory strategies that may have the potential to alleviate some of the more serious sequelae of this disease.


Assuntos
Fatores Imunológicos/uso terapêutico , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/imunologia , Vírus Sincicial Respiratório Humano/imunologia , Animais , Anticorpos Monoclonais/uso terapêutico , Antivirais/uso terapêutico , Citocinas/antagonistas & inibidores , Citocinas/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Oligodesoxirribonucleotídeos Antissenso/uso terapêutico , Pneumovirus/genética , Pneumovirus/imunologia , Infecções por Pneumovirus/tratamento farmacológico , Infecções por Pneumovirus/imunologia , Infecções por Pneumovirus/patologia , Infecções por Vírus Respiratório Sincicial/patologia , Vírus Sincicial Respiratório Humano/genética
10.
Curr Opin Oncol ; 21(2): 171-6, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19532020

RESUMO

PURPOSE OF REVIEW: Several epidemiologic studies have enhanced our understanding of the impact of respiratory viruses on bone marrow transplant recipients. RECENT FINDINGS: Respiratory viral infections occur frequently following stem cell transplantation but present atypically. Many patients have asymptomatic infections. There is a growing armamentarium of antiviral agents currently under development, although prospective studies in transplant patients are needed. SUMMARY: Respiratory viral infections occur frequently after hematopoietic stem cell transplant. Newer agents may prove useful in the prevention and treatment of respiratory viral infections in this population.


Assuntos
Transplante de Medula Óssea/efeitos adversos , Infecções por Pneumovirus/etiologia , Respirovirus , Antivirais/uso terapêutico , Humanos , Infecções por Pneumovirus/tratamento farmacológico , Infecções por Pneumovirus/fisiopatologia , Complicações Pós-Operatórias/tratamento farmacológico , Vírus Sincicial Respiratório Humano
11.
Immunol Lett ; 118(1): 6-12, 2008 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-18471897

RESUMO

Pneumonia virus of mice (PVM; family Paramyxoviridae, genus Pneumovirus) is a natural mouse pathogen that is closely related to human and bovine respiratory syncytial viruses. Among the prominent features of this infection, robust replication of PVM takes place in bronchial epithelial cells in response to a minimal virus inoculum. Virus replication in situ results in local production of proinflammatory cytokines (MIP-1alpha, MIP-2, MCP-1 and IFNgamma) and granulocyte recruitment to the lung. If left unchecked, PVM infection and the ensuing inflammatory response ultimately lead to pulmonary edema, respiratory compromise and death. In this review, we consider the recent studies using the PVM model that have provided important insights into the role of the inflammatory response in the pathogenesis of severe respiratory virus infection. We also highlight several works that have elucidated acquired immune responses to this pathogen, including T cell responses and the development of humoral immunity. Finally, we consider several immunomodulatory strategies that have been used successfully to reduce morbidity and mortality when administered to PVM-infected, symptomatic mice, and thus hold promise as realistic therapeutic strategies for severe respiratory virus infections in human subjects.


Assuntos
Pneumovirus/fisiologia , Infecções Respiratórias/virologia , Animais , Genoma Viral/genética , Humanos , Hipersensibilidade/imunologia , Camundongos , Pneumovirus/patogenicidade , Infecções por Pneumovirus/tratamento farmacológico , Infecções por Pneumovirus/imunologia , Infecções por Pneumovirus/metabolismo , Infecções por Pneumovirus/virologia , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/imunologia , Infecções Respiratórias/metabolismo , Linfócitos T/imunologia
12.
Antiviral Res ; 69(2): 53-9, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16337014

RESUMO

In this work we have evaluated the clinical responses of pneumovirus-infected mice to combination therapy with the antiviral agent, ribavirin, and the CysLT1 cysteinyl leukotriene receptor antagonist, montelukast. We observed substantial virus replication in our mouse model of pneumovirus infection and significant accumulation of cysteinyl leukotrienes in lung tissue, the latter detected at levels that correlate directly with granulocyte recruitment to the airways. While administration of the nucleoside analog, ribavirin, reduced virus replication approximately 2,000-fold, the clinical outcomes as measured by morbidity and mortality, in response to ribavirin monotherapy were indistinguishable from those of the no-treatment controls. Similarly, montelukast therapy alone did not reduce granulocyte recruitment nor did it improve the clinical outcome. However, combined therapy with ribavirin and montelukast resulted in a significant reduction in morbidity and a substantial reduction in mortality (50% survival at t = 14 days and onward, compared to 10-20% survival in response to montelukast alone or to ribavirin alone, respectively, p < 0.01). These findings define further the independent contributions made by virus replication and by the ensuing inflammatory response to the detrimental sequelae of pneumovirus infection in vivo.


Assuntos
Acetatos/uso terapêutico , Antivirais/uso terapêutico , Bronquiolite Viral/tratamento farmacológico , Antagonistas de Leucotrienos/uso terapêutico , Vírus da Pneumonia Murina/patogenicidade , Quinolinas/uso terapêutico , Ribavirina/uso terapêutico , Acetatos/administração & dosagem , Animais , Antivirais/administração & dosagem , Bronquiolite Viral/mortalidade , Bronquiolite Viral/virologia , Ciclopropanos , Cisteína/antagonistas & inibidores , Modelos Animais de Doenças , Quimioterapia Combinada , Humanos , Antagonistas de Leucotrienos/administração & dosagem , Leucotrienos , Pulmão/virologia , Camundongos , Camundongos Endogâmicos C57BL , Vírus da Pneumonia Murina/efeitos dos fármacos , Vírus da Pneumonia Murina/fisiologia , Infecções por Pneumovirus/tratamento farmacológico , Infecções por Pneumovirus/mortalidade , Infecções por Pneumovirus/virologia , Quinolinas/administração & dosagem , Ribavirina/administração & dosagem , Sulfetos , Resultado do Tratamento , Replicação Viral
13.
Pharmacol Ther ; 105(1): 1-6, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15626452

RESUMO

Pneumonia virus of mice (PVM) is the first infection model that replicates features of severe human respiratory syncytial virus (hRSV) disease in the mouse. The PVM model has highlighted the importance of inflammation to the pathogenesis of severe disease, demonstrating that the inflammatory response remains active and acute even when virus replication ceases in response to appropriate antiviral therapy. The fact that the inflammatory response continues and is not completely linked to ongoing virus replication indicates the need for concurrent anti-inflammatory or, ideally, specific immunomodulatory therapy. The chemokine macrophage inflammatory protein-1alpha (MIP-1alpha) and its receptor, CC chemokine receptor 1 (CCR1), have been identified as crucial to the inflammatory response to PVM and hRSV and thus as elements to exploit for potential immunomodulatory control. Biochemical blockade of MIP-1alpha signaling with the CCR1 antagonist met-RANTES prevents the inflammatory response to PVM and results in reduced morbidity and mortality when administered in conjunction with the antiviral agent ribavirin. Ongoing exploration into the biology of PVM infection will identify other pathways and targets to be exploited for immunomodulatory control of hRSV and related severe respiratory virus infections.


Assuntos
Antivirais/uso terapêutico , Vírus da Pneumonia Murina , Infecções por Pneumovirus/tratamento farmacológico , Infecções por Pneumovirus/patologia , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/patologia , Animais , Humanos , Camundongos , Infecções por Pneumovirus/virologia , Infecções por Vírus Respiratório Sincicial/virologia , Ribavirina/uso terapêutico
14.
J Virol ; 78(15): 7984-9, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15254170

RESUMO

We present an antiviral-immunomodulatory therapeutic strategy involving the chemokine receptor antagonist Met-RANTES, which yields significant survival in the setting of an otherwise fatal respiratory virus infection. In previous work, we demonstrated that infection with the natural rodent pathogen pneumonia virus of mice involves robust virus replication accompanied by cellular inflammation modulated by the CC chemokine macrophage inflammatory protein 1alpha (MIP-1alpha). We found that the antiviral agent ribavirin limited virus replication in vivo but had no impact on morbidity and mortality associated with this disease in the absence of immunomodulatory control. We show here that ribavirin reduces mortality, from 100% to 10 and 30%, respectively, in gene-deleted CCR1(-/-) mice and in wild-type mice treated with the small-molecule chemokine receptor antagonist, Met-RANTES. As MIP-1alpha-mediated inflammation is a common response to several distantly related respiratory virus pathogens, specific antiviral therapy in conjunction with blockade of the MIP-1alpha/CCR1 inflammatory cascade may ultimately prove to be a useful, generalized approach to severe respiratory virus infection and its pathological sequelae in human subjects.


Assuntos
Quimiocina CCL5/análogos & derivados , Quimiocina CCL5/uso terapêutico , Infecções por Pneumovirus/tratamento farmacológico , Receptores de Quimiocinas/antagonistas & inibidores , Doença Aguda , Animais , Quimiocina CCL3 , Quimiocina CCL4 , Leucócitos/fisiologia , Pulmão/patologia , Proteínas Inflamatórias de Macrófagos/biossíntese , Camundongos , Camundongos Endogâmicos C57BL , Infecções por Pneumovirus/mortalidade , Infecções por Pneumovirus/patologia , Receptores CCR1
15.
J Infect Dis ; 184(12): 1518-23, 2001 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-11740726

RESUMO

The use of glucocorticoids for the treatment of symptoms associated with respiratory syncytial virus (RSV) infection has been questioned. To evaluate the sequelae of glucocorticoid administration in the setting of pneumovirus infection in vivo, hydrocortisone was administered to mice infected with pneumonia virus of mice (PVM), a pneumovirus and natural rodent pathogen that is closely related to RSV and replicates the signs and symptoms of severe human RSV infection. Results showed that hydrocortisone spared the pulmonary neutrophilia but resulted in ablation of the pulmonary eosinophilia, despite continued production of the relevant chemoattractant, macrophage inflammatory protein-1alpha. Hydrocortisone also led to diminished production of inducible nitric oxide synthase and accumulation of reactive nitrogen species in lung tissue and bronchoalveolar lavage fluid and diminished lymphocyte recruitment. PVM-infected mice responded to hydrocortisone with enhanced viral replication and accelerated mortality. These results suggest several mechanisms to explain why glucocorticoid therapy may be of limited benefit in the overall picture of pneumovirus infection.


Assuntos
Anti-Inflamatórios/administração & dosagem , Hidrocortisona/administração & dosagem , Vírus da Pneumonia Murina/fisiologia , Pneumonia Viral/imunologia , Infecções por Pneumovirus/imunologia , Animais , Quimiocina CCL2/metabolismo , Quimiocina CCL4 , Modelos Animais de Doenças , Humanos , Pulmão/imunologia , Pulmão/virologia , Proteínas Inflamatórias de Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Vírus da Pneumonia Murina/isolamento & purificação , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Infecções por Pneumovirus/tratamento farmacológico , Infecções por Pneumovirus/mortalidade , Infecções por Pneumovirus/virologia , Resultado do Tratamento , Replicação Viral/efeitos dos fármacos
16.
Pol Merkur Lekarski ; 9 Suppl 1: 63-4, 2000 Sep.
Artigo em Polonês | MEDLINE | ID: mdl-11081351

RESUMO

Viral infections are an important factor in pathogenesis of symptom aggravation in COPD, which is usually accompanied by immunological system insufficiency, i.e. local immunity. Respiratory syncytial viruses are of vital importance. The paper presents possibilities of using active antiviral substances: amantadine, remantadine, ribavirine, zanamivir preparation. Substances isolated from natural resources have also been mentioned.


Assuntos
Antivirais/uso terapêutico , Infecções por Pneumovirus/tratamento farmacológico , Doenças Respiratórias/tratamento farmacológico , Humanos , Infecções por Pneumovirus/diagnóstico , Doenças Respiratórias/virologia
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