RESUMO
Severe influenza is often associated with disease manifestations outside the respiratory tract. While proinflammatory cytokines can be detected in the lungs and blood of infected patients, the role of extra-respiratory organs in the production of proinflammatory cytokines is unknown. Here, we show that both 2009 pandemic H1N1 influenza A (H1N1) virus and highly pathogenic avian influenza A (H5N1) virus induce expression of tumor necrosis factor α, interleukin-6, and interleukin-8 in the respiratory tract and central nervous system. In addition, H5N1 virus induced cytokines in the heart, pancreas, spleen, liver, and jejunum. Together, these data suggest that extra-respiratory tissues contribute to systemic cytokine responses, which may increase the severity of influenza.
Assuntos
Citocinas/metabolismo , Vírus da Influenza A Subtipo H1N1 , Virus da Influenza A Subtipo H5N1 , Infecções por Orthomyxoviridae/veterinária , Animais , Citocinas/biossíntese , Citocinas/genética , Furões , Infecções por Orthomyxoviridae/patologia , Infecções por Orthomyxoviridae/virologiaRESUMO
Central nervous system (CNS) disease is the most common extrarespiratory complication of influenza in humans. However, the pathogenesis, including the route of virus entry, is largely unknown. Here we present, for the first time, evidence of influenza virus entry into the CNS via the olfactory route in an immune-compromised infant. Since the nasal cavity is a primary site of influenza virus replication and is directly connected to the CNS via the olfactory nerve, these results imply that influenza virus invasion of the CNS may occur more often than previously believed.
Assuntos
Infecções do Sistema Nervoso Central/virologia , Vírus da Influenza A/isolamento & purificação , Influenza Humana/imunologia , Influenza Humana/virologia , Bulbo Olfatório/virologia , Orthomyxoviridae/fisiologia , Evolução Fatal , Feminino , Humanos , Hospedeiro Imunocomprometido , Lactente , Vírus da Influenza A/classificação , Vírus da Influenza A/fisiologia , PancitopeniaRESUMO
Highly pathogenic avian influenza H5N1 virus causes a severe, often fatal, pneumonia in humans. The tropism and pathogenesis of highly pathogenic avian influenza H5N1 virus can partly be explained by the presence of H5N1 virus receptors in the human alveoli, which are the site of inflammation during pneumonia. Although studies on the distribution of influenza virus receptors in normal respiratory tract tissues have provided significant insights into the cell tropism and pathogenesis of influenza viruses, the distribution of influenza virus receptors have not been studied during influenza virus infection. Therefore, we studied the distribution of H5N1 virus receptors, by virus and lectin histochemistry, during highly pathogenic avian influenza H5N1 virus infection in alveolar tissues of humans, macaques, ferrets, and cats. In all species, we observed a decrease of H5N1 virus receptors in influenza virus-infected and neighboring cells. The observed decrease of H5N1 virus receptors was associated with the presence of MxA, a known marker for interferon activity. Taken together, our data suggest that the decrease of H5N1 virus receptors might be part of a defense mechanism that limits viral replication in the lower respiratory tract.
Assuntos
Virus da Influenza A Subtipo H5N1/patogenicidade , Influenza Humana/virologia , Mamíferos/virologia , Infecções por Orthomyxoviridae/virologia , Receptores Virais/metabolismo , Animais , Antígenos Virais/imunologia , Gatos , Contagem de Células , Furões/virologia , Humanos , Virus da Influenza A Subtipo H5N1/imunologia , Influenza Humana/patologia , Macaca/virologia , Infecções por Orthomyxoviridae/patologia , Coloração e Rotulagem , Ligação ViralRESUMO
BACKGROUND: Exposure to neurotropic pathogens has been proposed as an environmental risk factor for schizophrenia and can be evaluated by measuring pathogen-specific immunoglobulin G (IgG). Seroprevalence of pathogen-specific IgG reflects prior exposure, whereas IgG levels are associated with reactivity or reinfection. Several studies have examined these parameters in schizophrenia. However, results still remain inconclusive, as several previous studies did not correct for important confounding factors. AIMS: To investigate whether schizophrenia is associated with prior exposure to neurotropic pathogens, or with their reactivation. METHODS: We examined the seroprevalence and titer of IgG antibodies against herpes simplex virus-1 and -2 (HSV-1/HSV-2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), and Toxoplasma gondii (TG) in plasma of 368 adult patients with a schizophrenia spectrum disorder and 282 controls using ELISA. RESULTS: We did not find evidence for an increased exposure to HSV-1, HSV-2, EBV, and TG in patients. There was a significantly higher seroprevalence of VZV (98.9% vs. 95.6%, P<0.05) and CMV (40.4% vs. 27.7%, P<0.001) in controls as compared with patients, which did not remain statistically significant after adjustment for various potential confounders. We did not find significant differences in antibody titers of seropositive patients and controls for any of the six pathogens. CONCLUSIONS: Our results do not support the hypothesis that increased exposure to neurotropic pathogens after birth is associated with schizophrenia.
RESUMO
BACKGROUND: The recent West Nile virus (WNV) outbreaks in developed countries, including Europe and the United States, have been associated with significantly higher neuropathology incidence and mortality rate than previously documented. The changing epidemiology, the constant risk of (re-)emergence of more virulent WNV strains, and the lack of effective human antiviral therapy or vaccines makes understanding the pathogenesis of severe disease a priority. Thus, to gain insight into the pathophysiological processes in severe WNV infection, a kinetic analysis of protein expression profiles in the brain of WNV-infected mice was conducted using samples prior to and after the onset of clinical symptoms. METHODOLOGY/PRINCIPAL FINDINGS: To this end, 2D-DIGE and gel-free iTRAQ labeling approaches were combined, followed by protein identification by mass spectrometry. Using these quantitative proteomic approaches, a set of 148 proteins with modified abundance was identified. The bioinformatics analysis (Ingenuity Pathway Analysis) of each protein dataset originating from the different time-point comparisons revealed that four major functions were altered during the course of WNV-infection in mouse brain tissue: i) modification of cytoskeleton maintenance associated with virus circulation; ii) deregulation of the protein ubiquitination pathway; iii) modulation of the inflammatory response; and iv) alteration of neurological development and neuronal cell death. The differential regulation of selected host protein candidates as being representative of these biological processes were validated by western blotting using an original fluorescence-based method. CONCLUSION/SIGNIFICANCE: This study provides novel insights into the in vivo kinetic host reactions against WNV infection and the pathophysiologic processes involved, according to clinical symptoms. This work offers useful clues for anti-viral research and further evaluation of early biomarkers for the diagnosis and prevention of severe neurological disease caused by WNV.
Assuntos
Redes e Vias Metabólicas/fisiologia , Doenças dos Roedores/metabolismo , Febre do Nilo Ocidental/metabolismo , Animais , Encéfalo/virologia , Chlorocebus aethiops , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Doenças dos Roedores/imunologia , Doenças dos Roedores/patologia , Índice de Gravidade de Doença , Eletroforese em Gel Diferencial Bidimensional , Células Vero , Febre do Nilo Ocidental/imunologia , Febre do Nilo Ocidental/patologia , Febre do Nilo Ocidental/veterinária , Vírus do Nilo Ocidental/isolamento & purificação , Vírus do Nilo Ocidental/fisiologiaRESUMO
In April 2009 a new influenza virus was discovered, which spread from Mexico to the rest of the world. The new influenza A (H1N1) virus is genetically related to swine flu viruses, and differs substantially from circulating human influenza viruses. It is able to spread from person to person. Because it is a completely new virus, there is probably little immunity in the population. The course of the infection is relatively mild, but the virus will mutate and it is not yet certain whether this will affect severity of the influenza. General practitioners have an important role in surveillance and treatment. The Community Health Services must be notified of any patients who are suspected of having the new influenza. Hygiene measures and administration of antiviral drugs to patients and their contacts may slow the spread. A delay in large-scale spread in the Netherlands allows time for the development of vaccines.
Assuntos
Antivirais/uso terapêutico , Higiene , Vírus da Influenza A Subtipo H1N1/patogenicidade , Influenza Humana/prevenção & controle , Influenza Humana/virologia , Serviços de Saúde Comunitária , Humanos , Vacinas contra Influenza , Influenza Humana/imunologia , Países BaixosRESUMO
Highly pathogenic avian influenza virus (H5N1) may cause severe lower respiratory tract (LRT) disease in humans. However, the LRT cells to which the virus attaches are unknown for both humans and other mammals. We show here that H5N1 virus attached predominantly to type II pneumocytes, alveolar macrophages, and nonciliated bronchiolar cells in the human LRT, and this pattern was most closely mirrored in cat and ferret tissues. These findings may explain, at least in part, the localization and severity of H5N1 viral pneumonia in humans. They also identify the cat and the ferret as suitable experimental animals based on this criterion.