Influenza infection triggers disease in a genetic model of experimental autoimmune encephalomyelitis

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system. Most MS patients experience periods of symptom exacerbation (relapses) followed by periods of partial recovery (remission). Interestingly, upper-respiratory viral infections increase the risk for relapse. Here, we used an autoimmune-prone T-cell receptor transgenic mouse (2D2) and a mouse-adapted human influenza virus to test the hypothesis that upper-respiratory viral infection can cause glial activation, promote immune cell trafficking to the CNS, and trigger disease. Specifically, we inoculated 2D2 mice with influenza A virus (Puerto Rico/8/34; PR8) and then monitored them for symptoms of inflammatory demyelination. Clinical and histological experimental autoimmune encephalomyelitis was observed in ∼29% of infected 2D2 mice. To further understand how peripheral infection could contribute to disease onset, we inoculated wild-type C57BL/6 mice and measured transcriptomic alterations occurring in the cerebellum and spinal cord and monitored immune cell surveillance of the CNS by flow cytometry. Infection caused temporal alterations in the transcriptome of both the cerebellum and spinal cord that was consistent with glial activation and increased T-cell, monocyte, and neutrophil trafficking to the brain at day 8 post infection. Finally, Cxcl5 expression was up-regulated in the brains of influenza-infected mice and was elevated in cerebrospinal fluid of MS patients during relapse compared with specimens acquired during remission. Collectively, these data identify a mechanism by which peripheral infection may exacerbate MS as well as other neurological diseases."



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Synergistic effects of influenza and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can be eliminated by the use of influenza therapeutics: experimental evidence for the multi-hit hypothesis | npj Parkinson's Disease

H1N1 virus (Photo credit: Wikipedia)

"Central Nervous System inflammation has been implicated in neurodegenerative disorders including Parkinson’s disease (Ransohoff, Science 353: 777–783, 2016; Kannarkat et al. J. Parkinsons Dis. 3: 493–514, 2013). Here, we examined if the H1N1 influenza virus (Studahl et al. Drugs 73: 131–158, 2013) could synergize with the parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (Jackson-Lewis et al. in Mark LeDoux (ed) Movement Disorders: Genetics and Models: 287–306, Elsevier, 2015) to induce a greater microglial activation and loss of substantia nigra pars compacta dopaminergic neurons than either insult alone. H1N1-infected animals administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exhibit a 20% greater loss of substantia nigra pars compacta dopaminergic neurons than occurs from the additive effects of H1N1 or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine alone (p < 0.001). No synergistic effects were found in microglial activation. The synergistic dopaminergic neuron loss is eliminated by influenza vaccination or treatment with oseltamivir carboxylate. This work shows that multiple insults can induce synergistic effects; and even these small changes can be significant as it might allow one to cross a phenotypic disease threshold that would not occur from individual non-interacting exposures. Our observations also have important implications for public health, providing impetus for influenza vaccination or prompt treatment with anti-viral medications upon influenza diagnosis."



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Immune response to a flu protein yields new insights into narcolepsy

An international team of researchers has found some of the first solid
evidence that narcolepsy may be a so-called "hit-and-run" autoimmune
disease.

The authors propose a hit-and-run autoimmune mechanism for how both
swine flu and the vaccine Pandemrix might cause narcolepsy. They suggest that in
genetically predisposed people, high levels of the H1N1 protein
stimulate the production of large amounts of antibodies to both the
virus (or vaccine) and the hypocretin receptor. These antibodies may persist in the
blood for months. Either the large numbers of antibodies or inflammation
from an unrelated infection could alter the blood-brain barrier,
allowing the antibodies to enter the brain. There, the antibodies may
latch onto hypocretin receptors, possibly directing the immune system to
destroy or suppress brain cells critical to regulating sleep-wake
cycles.

Serological Documentation of Maternal Influenza Exposure and Bipolar Disorder in Adult Offspring

Objective
The authors examined whether serologically confirmed maternal
exposure to influenza was associated with an increased risk of bipolar
disorder in the offspring and with subtypes of bipolar disorder, with
and without psychotic features.

Method
The study used a nested case-control design in the Child Health
and Development Study birth cohort. In all, 85 individuals with bipolar
disorder were identified following extensive ascertainment and
diagnostic assessment and matched to 170 comparison subjects in the
analysis. Serological documentation of maternal exposure to influenza
was determined using the hemagglutination inhibition assay.

Results
No association was observed between serologically documented
maternal exposure to influenza and bipolar disorder in offspring.
However, maternal serological influenza exposure was related to a
significant fivefold greater risk of bipolar disorder with psychotic
features.

Conclusions
The results suggest that maternal influenza exposure may
increase the risk for offspring to develop bipolar disorder with
psychotic features. Taken together with earlier associations between
prenatal influenza exposure and schizophrenia, these results may suggest
that prenatal influenza is a risk factor for psychosis rather than for a
specific psychotic disorder diagnosis.

Seasonal flu vaccine may cut stroke risk -- ScienceDaily

Having the seasonal flu jab could reduce the risk of suffering a stroke
by almost a quarter, researchers have found. Academics discovered that
patients who had been vaccinated against influenza were 24% less likely
to suffer a stroke in the same flu season. In 2010, the same research
team showed a similar link between flu vaccination and reduced risk of
heart attack. "Further experimental studies would be needed to better
understand the relationship between flu vaccination and stroke risk.
However, these findings reinforce the value of the U.K.'s national flu
vaccination program with reduced risk of stroke appearing to be an added
health benefit," the authors noted.

Transcriptional de-repression of ERVWE1 following influenza A virus infection.

Syncytin-1, a fusogenic protein encoded by a human endogenous retrovirus
(HERV-W) element (ERVWE1), is expressed in the syncytiotrophoblast
layer of the placenta. This locus is transcriptionally repressed in
adult tissues through promoter CpG methylation and suppressive histone
modifications. Whereas syncytin-1 appears crucial for the development
and functioning of the human placenta, its ectopic expression has been
associated with pathological conditions such as multiple sclerosis and
schizophrenia. We previously reported on the transactivation of HERV-W
elements, including ERVWE1, during influenza A/WSN/33 virus infection in
a range of human cell-lines. We here report qPCR analyses of
transcripts encoding syncytin-1 in both cell-lines and primary
fibroblast cells. We observed that spliced ERVWE1 transcripts and those
encoding the transcription factor glial cells missing 1 (GCM1), acting
as an enhancer element upstream of ERVWE1, are prominently up-regulated
in response to influenza A/WSN/33 virus infection in non-placental
cells. Knock-down of GCM1 by siRNA, followed by infection suppressed the
transactivation of ERVWE1. While the infection had no influence on CpG
methylation in the ERVWE1 promoter, chromatin immunoprecipitation assays
detected decreased H3K9 trimethylation (H3K9me3) and histone
methytransferase SETDB1 levels along with viral proteins associated with
ERVWE1 and other HERV-W loci in infected CCF-STTG1 cells. The present
findings suggest that an exogenous influenza virus infection can
transactivate ERVWE1 by increasing transcription of GCM1 and reducing
H3K9me3 in this region and in other regions harboring HERV-W
elements.Importance Syncytin-1, a protein encoded by the env gene in the
HERV-W locus ERVWE1 appears crucial for the development and functioning
of the human placenta and is transcriptionally repressed in
non-placental tissues. Nevertheless, its ectopic expression has been
associated with pathological conditions such as multiple sclerosis and
schizophrenia. In the present paper we report findings suggesting that
an exogenous influenza A virus infection can transactivate ERVWE1 by
increasing transcription of GCM1 and reducing the repressive histone
mark H3K9me3 in this region and in other regions harboring HERV-W
elements. These observations have implications of potential relevance
for viral pathogenesis and for conditions associated with aberrant
transcription of HERV-W loci.

H1N1-Flu triggered narcolepsy may stem from 'molecular mimicry'

In genetically susceptible people, narcolepsy can sometimes be triggered by a similarity between a region of a protein called hypocretin and a portion of a protein from the pandemic H1N1 virus, according to a new study by researchers at the Stanford University School of Medicine.

Immunosuppressant Drug Rapamycin Widens Immunity to Flu | The Scientist Magazine®

The immunosuppressant drug rapamycin paradoxically helped to protect mice against a diverse range of influenza viruses after the animals were vaccinated against just one flu strain.

Flu virus wipes out immune system's first responders to establish infection

Confronted with a harmful virus, the immune system works to generate cells capable of producing antibodies perfectly suited to bind and disarm the hostile invader. These virus-specific B cells proliferate, secreting the antibodies that slow and eventually eradicate the virus. A population of these cells retains the information needed to neutralize the virus and takes up residence in the lung to ward off secondary infection from re-exposure to the virus via inhalation.
On the surface of these so-called memory B cells are high-affinity virus-specific receptors that bind virus particles to reduce viral spread. While such cells should serve at the body's first line of defense, it turns out that flu virus exploits the specificity of the cells' receptors, using them to gain entry, disrupt antibody production, and ultimately kill the cells. By dispatching its enemies in this fashion, the virus is able to replicate efficiently before the immune system can mount a second wave of defense. This seemingly counter-intuitive pathway to infection is described this week in the journal Nature.

Antigen-specific B-cell receptor sensitizes B cells to infection by influenza virus Dougan et al, 2013

Influenza Life Cycle Pathway map

To understand the mechanisms of influenza A viral replication and the host responses, the authors took  a literature-based manual curation approach to construct a comprehensive influenza virus-host respoce map. The infuenza A virus (IAV) comprehensive pathway map (FluMap) was constructed by manual curation with the literature as well as various pathway databases such as Reactome, KEGG and Panther Pathway database.

Yukiko Matsuoka, Hiromi Matsumae, Manami Katoh, Amie J Eisfeld, Gabriele Neumann, Takeshi Hase, Samik Ghosh,Jason E Shoemaker, Tiago JS Lopes, Tokiko Watanabe, Shinji Watanabe, Satoshi Fukuyama, Hiroaki Kitano andYoshihiro Kawaoka
A Comprehensive map of Influenza A virus replication cycle.BMC Systems Biology 2013, 7:97 
doi:10.1186/1752-0509-7-97

Bacteria and viruses cooperate to turn harmless infections to disease

"In the current study, the research team grew biofilms of pneumococci on top of human epithelial cells, where the bacteria normally grow. They then infected these bacteria with influenza A virus or exposed them to the conditions that typically accompany the flu, including increased temperature to mimic fever, increased concentrations of ATP (the energy molecule in cells), and the stress hormone norepinephrine, released during flu infection. All three stimuli triggered a sudden release and departure of bacteria from the biofilm in the nose into otherwise normally sterile organs, such as the middle ears and lungs or into the bloodstream. At the same time, the researchers found that the gene expression profile of the bacteria that had dispersed from the biofilms revealed far more virulence."

Gestational flu exposure induces changes in neurochemicals, affiliative hormones and brainstem inflammation, in addition to autism-like behaviors in mice.

 The prevalence of neurodevelopmental disorders such as autism is increasing, however the etiology of these disorders is unclear and thought to involve a combination of genetic, environmental and immune factors. A recent epidemiological study found that gestational viral exposure during the first trimester increases risk of autism in offspring by two-fold. In mice gestational viral exposures alter behavior of offspring, but the biological mechanisms which underpin these behavioral changes are unclear. We hypothesized that gestational viral exposure induces changes in affiliative hormones, brainstem autonomic nuclei and neurotransmitters which are associated with behavioral alterations in offspring. To address this hypothesis, we exposed pregnant mice to influenza A virus (H3N2) on gestational day 9 and determined behavioral, hormonal and brainstem changes in male and female offspring. We found that gestational flu exposure induced dose-dependent alterations in social and aggressive behaviors (p ⩽ 0.05) in male and female offspring and increases in locomotor behaviors particularly in male offspring (p ⩽ 0.05). We found that flu exposure was also associated with reductions in oxytocin and serotonin (p ⩽ 0.05) levels in male and female offspring and sex-specific changes in dopamine metabolism. In addition we found changes in catecholaminergic and microglia density in brainstem tissues of male flu exposed offspring only (p⩽0.05). This study demonstrates that gestational viral exposure induces behavioral changes in mice, which are associated with alterations in affiliative hormones. In addition we found sex-specific changes in locomotor behavior, which may be associated with sex-specific alterations in dopamine metabolism and brainstem inflammation. Further investigations into maternal immune responses are necessary to unravel the molecular mechanisms which underpin abnormal hormonal, immune and behavioral responses in offspring after gestational viral exposure.

The TLR4 antagonist Eritoran protects mice from lethal influenza infection : Nature : Nature Publishing Group

There is a pressing need to develop alternatives to annual influenza vaccines and antiviral agents licensed for mitigating influenza infection. Previous studies reported that acute lung injury caused by chemical or microbial insults is secondary to the generation of host-derived, oxidized phospholipid that potently stimulates Toll-like receptor 4 (TLR4)-dependent inflammation1. Subsequently, we reported that Tlr4−/− mice are highly refractory to influenza-induced lethality2, and proposed that therapeutic antagonism of TLR4 signalling would protect against influenza-induced acute lung injury. Here we report that therapeutic administration of Eritoran (also known as E5564)—a potent, well-tolerated, synthetic TLR4 antagonist3, 4—blocks influenza-induced lethality in mice, as well as lung pathology, clinical symptoms, cytokine and oxidized phospholipid expression, and decreases viral titres. CD14 and TLR2 are also required for Eritoran-mediated protection, and CD14 directly binds Eritoran and inhibits ligand binding to MD2. Thus, Eritoran blockade of TLR signalling represents a novel therapeutic approach for inflammation associated with influenza, and possibly other infections.

JAMA Psychiatry | Gestational Influenza and Bipolar Disorder in Adult OffspringGestational Influenza and Bipolar Disorder

Gestational influenza has been associated previously with schizophrenia in offspring, but the relationship between this exposure and bipolar disorder (BD) is unclear. The identification of gestational influenza as a risk factor for BD may have potential for preventive approaches.

Objective  To test the hypothesis that maternal influenza during pregnancy is related to BD among offspring.

Design  Nested case-control study of a population-based birth cohort from the Child Health and Development Study (CHDS). From January 1, 1959, through December 31, 1966, the CHDS recruited nearly all pregnant women receiving obstetric care from the Kaiser Permanente Medical Care Plan, Northern California Region (KPNC). Data on treated maternal influenza from the CHDS were used. Potential cases with BD from the cohort were identified by database linkages of identifiers among the CHDS, Kaiser Permanente database, and a large county health care database; by a mailed questionnaire to the CHDS cohort with subsequent interviews; and from an earlier psychiatric follow-up study on this birth cohort.

Setting  The CHDS, Kaiser Permanente, and county health care databases.

Participants  Cases of BD (n = 92) confirmed by structured research interviews and consensus diagnosis among the 214 subjects (48% of those ascertained) who participated and control subjects (n = 722) matched on date of birth, sex, and membership in KPNC or residence in Alameda County.

Exposures  Influenza.

Main Outcome and Measures  Bipolar I or II disorder, BD not otherwise specified, or BD with psychotic features.

Results  We found a significant, nearly 4-fold increase in the risk of BD (odds ratio, 3.82 [95% CI, 1.58-9.24; P = .003]) after exposure to maternal influenza at any time during pregnancy. The findings were not confounded by maternal age, race, educational level, gestational age at birth, and maternal psychiatric disorders.

Conclusions and Relevance  Maternal influenza may be a risk factor for BD. Although replication is required, the findings suggest that prevention of maternal influenza during pregnancy may reduce the risk of BD.

Researchers find potential novel treatment for influenza

 "The scientists found that a drug called Eritoran ( a Toll receptor antagonist (TLR4) )can protect mice from death after they have been infected with a lethal dose of influenza virus. The potential value of this drug as single therapy or in combination with antivirals is further supported by previous research that found that it is safe for use in humans. The findings are of particular interest to scientists now that the latest deadly strain of flu, H7N9, is spreading in China – 82 people in China had been infected with the new strain of flu virus as of April 26, and 17 had died."

Influenza A viruses grow in human pancreatic cells and cause pancreatitis and diabetes in an animal model.

Influenza A viruses commonly cause pancreatitis in naturally and experimentally infected animals. In this study, we report the results of in vivo investigations carried out to establish whether influenza virus infection could cause metabolic disorders linked to pancreatic infection. In addition, in vitro tests in human pancreatic islets and in human pancreatic cell lines were performed to evaluate viral growth and cell damage. Infection of an avian model with two low-pathogenicity avian influenza isolates caused pancreatic damage resulting in hyperlipasemia in over 50% of subjects, which evolved into hyperglycemia and subsequently diabetes. Histopathology of the pancreas showed signs of an acute infection resulting in severe fibrosis and disruption of the structure of the organ. Influenza virus nucleoprotein was detected by immunohistochemistry (IHC) in the acinar tissue. Human seasonal H1N1 and H3N2 viruses and avian H7N1 and H7N3 influenza virus isolates were able to infect a selection of human pancreatic cell lines. Human viruses were also shown to be able to infect human pancreatic islets. In situ hybridization assays indicated that viral nucleoprotein could be detected in beta cells. The cytokine activation profile indicated a significant increase of MIG/CXCL9, IP-10/CXCL10, RANTES/CCL5, MIP1b/CCL4, Groa/CXCL1, interleukin 8 (IL-8)/CXCL8, tumor necrosis factor alpha (TNF-α), and IL-6. Our findings indicate that influenza virus infection may play a role as a causative agent of pancreatitis and diabetes in humans and other mammals.

Influenza A virus nucleoprotein induces apoptosis in human airway epithelial cells: implications of a novel interaction between nucleoprotein and host protein Clusterin.

Apoptosis induction is an antiviral host response, however, influenza A virus (IAV) infection promotes host cell death. The nucleoprotein (NP) of IAV is known to contribute to viral pathogenesis, but its role in virus-induced host cell death was hitherto unknown. We observed that NP contributes to IAV infection induced cell death and heterologous expression of NP alone can induce apoptosis in human airway epithelial cells. The apoptotic effect of IAV NP was significant when compared with other known proapoptotic proteins of IAV. The cell death induced by IAV NP was executed through the intrinsic apoptosis pathway. We screened host cellular factors for those that may be targeted by NP for inducing apoptosis and identified human antiapoptotic protein Clusterin (CLU) as a novel interacting partner. The interaction between IAV NP and CLU was highly conserved and mediated through β-chain of the CLU protein. Also CLU was found to interact specifically with IAV NP and not with any other known apoptosis modulatory protein of IAV. CLU prevents induction of the intrinsic apoptosis pathway by binding to Bax and inhibiting its movement into the mitochondria. We found that the expression of IAV NP reduced the association between CLU and Bax in mammalian cells. Further, we observed that CLU overexpression attenuated NP-induced cell death and had a negative effect on IAV replication. Collectively, these findings indicate a new function for IAV NP in inducing host cell death and suggest a role for the host antiapoptotic protein CLU in this process.

Naproxen Shows Anti-Viral Activity Against Flu

MNT: The over-the-counter anti-inflammatory drug naproxen may also exhibit antiviral activity against influenza A virus, according to a team of French scientists. The finding, the result of a structure-based investigation, is published online ahead of print in the journal Antimicrobial Agents and Chemotherapy. 

Cell - The Lipid Mediator Protectin D1 Inhibits Influenza Virus Replication and Improves Severe Influenza

 "Influenza A viruses are a major cause of mortality. Given the potential for future lethal pandemics, effective drugs are needed for the treatment of severe influenza such as that caused by H5N1 viruses. Using mediator lipidomics and bioactive lipid screen, we report that the omega-3 polyunsaturated fatty acid (PUFA)-derived lipid mediator protectin D1 (PD1) markedly attenuated influenza virus replication via RNA export machinery. Production of PD1 was suppressed during severe influenza and PD1 levels inversely correlated with the pathogenicity of H5N1 viruses. Suppression of PD1 was genetically mapped to 12/15-lipoxygenase activity. Importantly, PD1 treatment improved the survival and pathology of severe influenza in mice, even under conditions where known antiviral drugs fail to protect from death. These results identify the endogenous lipid mediator PD1 as an innate suppressor of influenza virus replication that protects against lethal influenza virus infection."

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Antiviral lipid earns patent: Lipids in lung can inhibit RSV and influenza infections

 "Dennis Voelker, PhD, professor of medicine at National Jewish Health, has been awarded a U.S. patent (#8,367,643) for various lipids and related compounds that can inhibit inflammation and infection in the lungs, especially those caused by influenza and respiratory syncytial virus (RSV). Over the past several years, Dr. Voelker has published several scientific papers describing a naturally occurring lipid in the lungs, POPG (palmitoyl-oleoyl-phosphatidylglycerol), that reduces inflammation and inhibits infection by the influenza virus and RSV. The patent covers POPG and other naturally occurring lipids in the lungs as well as related anionic lipids."

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