Persistence of viral RNA in the brain of offspring to mice infected with influenza A/WSN/33 virus during pregnancy

Aronsson, Fredrik; Lannebo, Charlotta; Paucar, Martin; Brask, Johan; Kristensson, Krister; Karlsson, Håkan

doi:10.1080/13550280290100480

Cited by 69 publications

(48 citation statements)

References 27 publications

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“…Two of these proteins, AQP4 and CX43, are likewise altered in autistic brain (Fatemi et al unpublished observations) and a third may be implicated in the macrocephaly, which is commonly observed in autistic subjects (Fombonne et al 1999;Lainhart et al 2006) as well as in our animal model (Fatemi et al 2002a). Most importantly, the weight of accumulated evidence so far showing presence of gliosis (Fatemi et al 2002b), pyramidal cell atrophy (Fatemi et al 2002a), and upregulation of nucleolin, as well as previous supportive evidence (Aronsson et al 2001;Aronsson et al 2002), showing persistence of influenza viral RNA in brain implicate a potential viral effect on the developing fetal brain.…”

Section: Discussionmentioning

confidence: 77%

Viral regulation of aquaporin 4, connexin 43, microcephalin and nucleolin

Fatemi¹,

Folsom²,

Reutiman³

et al. 2008

Schizophrenia Research

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The current study investigated whether human influenza viral infection in midpregnancy leads to alterations in proteins involved in brain development. Human influenza viral infection was administered to E9 pregnant Balb/c mice. Brains of control and virally exposed littermates were subjected to microarray analysis, SDS-PAGE and western blotting at three postnatal stages. Microarray analysis of virally-exposed mouse brains showed significant, two-fold change in expression of multiple genes in both neocortex and cerebellum when compared to sham-infected controls. Levels of mRNA and protein levels of four selected genes were examined in brains of exposed mice. Nucleolin mRNA was significantly decreased in day 0 and day 35 neocortex and significantly increased in day 35 cerebellum. Protein levels were significantly upregulated at days 35 and 56 in neocortex and at day 56 in cerebellum. Connexin 43 protein levels were significantly decreased at day 56 in neocortex. Aquaporin 4 mRNA was significantly decreased in day 0 neocortex. Aquaporin 4 protein levels decreased in neocortex significantly at day 35. Finally, microcephalin mRNA was significantly decreased in day 56 neocortex and protein levels were significantly decreased at 56 cerebellum. These data suggest that influenza viral infection in midpregnancy in mice leads to long term changes in brain markers for enhanced ribosome genesis (nucleolin), increased production of immature neurons (microcephalin), and abnormal glial-neuronal communication (connexin 43 and aquaporin 4).

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Section: Discussionmentioning

confidence: 77%

Viral regulation of aquaporin 4, connexin 43, microcephalin and nucleolin

Fatemi¹,

Folsom²,

Reutiman³

et al. 2008

Schizophrenia Research

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“…However, having performed a careful review of the pertinent literature, we found that, in the majority of studies in which neural spread of the A/WSN/33 virus has been shown to occur, this was a result of i.p. infection of pregnant dams (49,50), intranasal infection of immunodeficient mice (23,51), direct intracerebral inoculation (52,53), or infection of suckling mice (54)(55)(56). Indeed, we were able to identify only two studies that described spread to the brain following intranasal administration of influenza A/WSN/33 virus to adult immunocompetent mice, and in both cases, mice were infected using an inoculum 100 or 500 times greater than that used in our studies (57,58).…”

Section: Fig 7 Lung Compliance and Airway Resistance Were Not Alteredmentioning

confidence: 71%

Activation of A ₁ -Adenosine Receptors Promotes Leukocyte Recruitment to the Lung and Attenuates Acute Lung Injury in Mice Infected with Influenza A/WSN/33 (H1N1) Virus

Aeffner

Woods

Davis

2014

J Virol

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We have shown that bronchoalveolar epithelial A 1 -adenosine receptors (A 1 -AdoR) are activated in influenza A virus-infected mice. Alveolar macrophages and neutrophils also express A 1 -AdoRs, and we hypothesized that activation of A 1 -AdoRs on these cells will promote macrophage and neutrophil chemotaxis and activation and thereby play a role in the pathogenesis of influenza virus-induced acute lung injury. Wild-type (WT) C57BL/6 mice, congenic A 1 -AdoR knockout (A 1 -KO) mice, and mice that had undergone reciprocal bone marrow transfer were inoculated intranasally with 10,000 PFU/mouse influenza A/WSN/33 (H1N1) virus. Alternatively, WT mice underwent daily treatment with the A 1 -AdoR antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) from 1 day prior to inoculation. Infection increased bronchoalveolar lining fluid (BALF) adenosine comparably in WT and A 1 -KO mice. Infection of WT mice resulted in reduced carotid arterial O 2 saturation (hypoxemia), lung pathology, pulmonary edema, reduced lung compliance, increased basal airway resistance, and hyperresponsiveness to methacholine. These effects were absent or significantly attenuated in A 1 -KO mice. Levels of BALF leukocytes, gamma interferon (IFN-␥), and interleukin 10 (IL-10) were significantly reduced in infected A 1 -KO mice, but levels of KC, IP-10, and MCP-1 were increased. Reciprocal bone marrow transfer resulted in WT-like lung injury severity, but BALF leukocyte levels increased only in WT and A 1 -KO mice with WT bone barrow. Hypoxemia, pulmonary edema, and levels of BALF alveolar macrophages, neutrophils, IFN-␥, and IL-10 were reduced in DPCPX-treated WT mice. Levels of viral replication did not differ between mouse strains or treatment groups. These findings indicate that adenosine activation of leukocyte A 1 -AdoRs plays a significant role in their recruitment to the infected lung and contributes to influenza pathogenesis. A 1 -AdoR inhibitor therapy may therefore be beneficial in patients with influenza virus-induced lung injury. IMPORTANCEBecause antiviral drugs are of limited efficacy in patients hospitalized for influenza virus-induced respiratory failure, there is an urgent need for new therapeutics that can limit the progression of lung injury and reduce influenza death rates. We show that influenza A virus infection results in increased production of the nucleoside adenosine in the mouse lung and that activation of A 1 -subtype adenosine receptors by adenosine contributes significantly to both recruitment of innate immune cells to the lung and development of acute lung injury following influenza virus infection. We also show that treatment with an A 1 -adenosine receptor antagonist reduces the severity of lung injury in influenza virus-infected mice. Our findings indicate that adenosine plays an important and previously unrecognized role in the innate immune response to influenza virus infection and suggest that drugs which can inhibit either generation of adenosine or activation of A 1 -adenosine receptors may be beneficia...

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“…The lack of evidence for direct infection of the fetus (Shi et al, 2005) (but see Aronsson et al, 2002), and the fact that multiple pathogens cause similar results in humans [e.g., influenza (Brown, 2006), herpes (Babulas et al, 2006), rubella (Chess, 1977)], indicates that MIA, in general, is detrimental to the developing brain. The data presented here confirms previous reports (see Introduction) that MIA causes behavioral and geneexpression changes in the offspring of pregnant mice.…”

Section: Discussionmentioning

confidence: 99%

Maternal Immune Activation Alters Fetal Brain Development through Interleukin-6

et al. 2007

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Schizophrenia and autism are thought to result from the interaction between a susceptibility genotype and environmental risk factors. The offspring of women who experience infection while pregnant have an increased risk for these disorders. Maternal immune activation (MIA) in pregnant rodents produces offspring with abnormalities in behavior, histology, and gene expression that are reminiscent of schizophrenia and autism, making MIA a useful model of the disorders. However, the mechanism by which MIA causes long-term behavioral deficits in the offspring is unknown. Here we show that the cytokine interleukin-6 (IL-6) is critical for mediating the behavioral and transcriptional changes in the offspring. A single maternal injection of IL-6 on day 12.5 of mouse pregnancy causes prepulse inhibition (PPI) and latent inhibition (LI) deficits in the adult offspring. Moreover, coadministration of an anti-IL-6 antibody in the poly(I:C) model of MIA prevents the PPI, LI, and exploratory and social deficits caused by poly(I:C) and normalizes the associated changes in gene expression in the brains of adult offspring. Finally, MIA in IL-6 knock-out mice does not result in several of the behavioral changes seen in the offspring of wild-type mice after MIA. The identification of IL-6 as a key intermediary should aid in the molecular dissection of the pathways whereby MIA alters fetal brain development, which can shed new light on the pathophysiological mechanisms that predispose to schizophrenia and autism.Key words: schizophrenia; autism; cytokine; poly(I:C); maternal immune activation; IL-6; influenza IntroductionBirth in winter or spring months is an accepted risk factor for schizophrenia, and the preponderance of evidence suggests that the prevalence of influenza in winter months is responsible (Tochigi et al., 2004). Over 25 studies have analyzed schizophrenia incidence after influenza epidemics, and the majority have found an increased incidence among exposed offspring. More recently, Brown and colleagues (Brown and Susser, 2002;Brown et al., 2004;Brown, 2006) examined the medical records of Ͼ12,000 pregnant women and found that second-trimester respiratory infection increases the risk for schizophrenia in the offspring threefold to sevenfold. Because of the high prevalence of influenza infection, they estimate that 14 -21% of schizophrenia cases are caused by maternal infection. These findings are also supported by an association between elevated cytokines or antiinfluenza antibodies in maternal serum and schizophrenia in the offspring (Brown et al., 2004). Maternal infection may also play a role in the pathogenesis of autism (Patterson, 2002). These links are even more remarkable considering that the epidemiological studies are unable to screen for susceptibility genotype. Because of the strong genetic component in autism and schizophrenia, it is likely that only genetically susceptible individuals who were exposed to maternal infection would develop the disorder, suggesting that the risk associated with maternal infect...

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Persistence of viral RNA in the brain of offspring to mice infected with influenza A/WSN/33 virus during pregnancy

Cited by 69 publications

References 27 publications

Viral regulation of aquaporin 4, connexin 43, microcephalin and nucleolin

Viral regulation of aquaporin 4, connexin 43, microcephalin and nucleolin

Activation of A ₁ -Adenosine Receptors Promotes Leukocyte Recruitment to the Lung and Attenuates Acute Lung Injury in Mice Infected with Influenza A/WSN/33 (H1N1) Virus

Maternal Immune Activation Alters Fetal Brain Development through Interleukin-6

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Persistence of viral RNA in the brain of offspring to mice infected with influenza A/WSN/33 virus during pregnancy

Cited by 69 publications

References 27 publications

Viral regulation of aquaporin 4, connexin 43, microcephalin and nucleolin

Viral regulation of aquaporin 4, connexin 43, microcephalin and nucleolin

Activation of A 1 -Adenosine Receptors Promotes Leukocyte Recruitment to the Lung and Attenuates Acute Lung Injury in Mice Infected with Influenza A/WSN/33 (H1N1) Virus

Maternal Immune Activation Alters Fetal Brain Development through Interleukin-6

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Product

Resources

About

Activation of A ₁ -Adenosine Receptors Promotes Leukocyte Recruitment to the Lung and Attenuates Acute Lung Injury in Mice Infected with Influenza A/WSN/33 (H1N1) Virus