Apoptosis and Proinflammatory Cytokine Responses of Primary Mouse Microglia and Astrocytes Induced by Human H1N1 and Avian H5N1 Influenza Viruses

Abstract

Patients with an influenza virus infection can be complicated by acute encephalopathy and encephalitis. To investigate the immune reactions involved in the neurocomplication, mouse microglia and astrocytes were isolated, infected with human H1N1 and avian H5N1 influenza viruses, and examined for their immune responses. We observed homogeneously distributed viral receptors, sialic acid (SA)-α2,3-Galactose (Gal) and SA-α2,6-Gal, on microglia and astrocytes. Both viruses were replicative and productive in microglia and astrocytes. Virus-induced apoptosis and cytopathy in infected cells were observed at 24 h post-infection (p.i.). Expression of IL-1β, IL-6 and TNF-α mRNA examined at 6 h and 24 h p.i. was up-regulated, and their expression levels were considerably higher in H5N1 infection. The amounts of secreted proinflammatory IL-1β, IL-6 and TNF-α at 6 h and 24 h p.i. were also induced, with greater induction by H5N1 infection. This study is the first demonstration that both human H1N1 and avian H5N1 influenza viruses can infect mouse microglia and astrocytes and induce apoptosis, cytopathy, and proinflammatory cytokine production in them in vitro. Our results suggest that the direct cellular damage and the consequences of immunopathological injury in the CNS contribute to the influenza viral pathogenesis. Cellular & Molecular Immunology. 2008;5(2):113-120.

Effects of NS1 variants of H5N1 influenza virus on interferon induction, TNFα response and p53 activity

“…IFNb is capable of promoting expression of a variety of cytokines and chemokines, including IL10, RANTES(CCL5), MCP-1(CCL2), MCP-3(CCL7), MCP-2(CCL8), MIG(CXCL9) and IP-10(CXCL10). [26][27][28] Because an elevated expression of cytokines and chemokines has been proposed to contribute to the unusual severity and mortality of H5N1 infection, 29,30 our results provide evidence in support of the hypothesis that the high pathogenicity of H5N1 virus may be associated with a reduced repression on IFN production conferred by the D92E mutation.…”

Experimental Infection of Bar-Headed Geese (Anser indicus) and Ruddy Shelducks (Tadorna ferruginea) With a Clade 2.3.2 H5N1 Highly Pathogenic Avian Influenza Virus

“…30 In mice as well as humans, infection of astrocytes, microglial cells, and/or neurons with neurotropic H5N1 HPAI virus led to release of proinflammatory cytokines and apoptosis (ie, cytopathic effect) in these cells. 28,51 Apoptosis may be a more predominant feature of infection with more virulent subtypes of HPAI viruses, as TUNEL reactivity and expression of caspases were elevated in porcine alveolar epithelial cells infected in vitro with H5N1 HPAI viruses but not with other H5 influenza viruses. 8 In vitro and in vivo mouse studies suggested that neuraminidase of influenza A and B viruses activates sufficient levels of transforming growth factor-b to induce apoptosis in influenza virus-infected cells.…”

Chemokine Receptor Ccr7 Restricts Fatal West Nile Virus Encephalitis

“…At the steady state, microglia perform continuous surveillance of the CNS for danger signals and provide trophic support to neurons (46). When activated, microglia proliferate, form nodules to surround areas of damage, and secrete cytokines/chemokines to recruit immune cells (47)(48)(49)(50)(51)(52)(53). Despite different triggering events, microglia activation is a major characteristic of neurodegenerative conditions, including Alzheimer's disease, Parkinson's diseases, traumatic brain injury, and multiple sclerosis (54)(55)(56)(57).…”