Influenza A virus (H1N1) infection induces microglia activation and temporal dysbalance in glutamatergic synaptic transmission.

Influenza A virus (IAV) causes respiratory tract disease and is responsible for seasonal and reoccurring epidemics affecting all age groups. Next to typical disease symptoms such as fever and fatigue, IAV infection has been associated with behavioral alterations presumably contributing to the development of major depression. Previous experiments using IAV/H1N1 infection models have shown impaired hippocampal neuronal morphology and cognitive abilities, but the underlying pathways have not been fully described. In this study, we demonstrate that infection with a low dose non-neurotrophic H1N1 strain of IAV causes ample peripheral immune response followed by a temporary blood-brain barrier disturbance. Although histological examination did not reveal obvious pathological processes in the brains of IAV-infected mice, detailed multidimensional flow cytometric characterization of immune cells uncovered subtle alterations in the activation status of microglia cells. More specifically, we detected an altered expression pattern of major histocompatibility complex class I and II, CD80, and F4/80 accompanied by elevated mRNA levels of CD36, CD68, C1QA, and C3, suggesting evolved synaptic pruning. To closer evaluate how these profound changes affect synaptic balance, we established a highly sensitive multiplex flow cytometry-based approach called Flow Synaptometry. The introduction of this novel technique enabled us to simultaneously quantify the abundance of pre- and postsynapses from distinct brain regions. Our data reveal a significant reduction of VGLUT1 in excitatory presynaptic terminals in the Cortex and Hippocampus, identifying a subtle dysbalance in glutamatergic synapse transmission upon H1N1 infection in mice. In conclusion, our results highlight the consequences of systemic IAV-triggered inflammation on the central nervous system and the induction and progression of neuronal alterations.

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Influenza A Virus (H1N1) Infection Induces Microglial Activation and Temporal Dysbalance in Glutamatergic Synaptic Transmission

mBio ◽

10.1128/mbio.01776-21 ◽

2021 ◽

Vol 12 (5) ◽

Author(s):

Henning Peter Düsedau ◽

Johannes Steffen ◽

Caio Andreeta Figueiredo ◽

Julia Désirée Boehme ◽

Kristin Schultz ◽

...

Keyword(s):

Influenza A Virus ◽

Influenza A ◽

Microglial Activation ◽

Age Groups ◽

Virus H1n1 ◽

Respiratory Tract Disease ◽

Behavioral Alterations ◽

Disease Symptoms ◽

Glutamatergic Synaptic Transmission ◽

Tract Disease

Influenza A virus (IAV) causes respiratory tract disease and is responsible for seasonal and reoccurring epidemics affecting all age groups. Next to typical disease symptoms, such as fever and fatigue, IAV infection has been associated with behavioral alterations presumably contributing to the development of major depression.

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Clinical Investigations. Comparison of Directigen Flu A+B with Real Time PCR in the Diagnosis of Influenza / Сравнение Иммунохроматографического Метода (Directigen Flu A+B) И Теста RT-PCR При Инфекциях Гриппа

Folia Medica ◽

10.1515/folmed-2015-0027 ◽

2015 ◽

Vol 57 (2) ◽

pp. 104-110 ◽

Cited By ~ 4

Author(s):

Golubinka Bosevska ◽

Nikola Panovski ◽

Elizabeta Janceska ◽

Vladimir Mikik ◽

Irena Kondova Topuzovska ◽

...

Keyword(s):

Real Time ◽

Influenza A Virus ◽

Real Time Pcr ◽

Influenza A ◽

Age Groups ◽

Influenza Viruses ◽

Influenza B Virus ◽

Influenza B ◽

B Virus ◽

Nose And Throat

AbstractEarly diagnosis and treatment of patients with influenza is the reason why physicians need rapid high-sensitivity influenza diagnostic tests that require no complex lab equipment and can be performed and interpreted within 15 min. The Aim of this study was to compare the rapid Directigen Flu A+B test with real time PCR for detection of influenza viruses in the Republic of Macedonia. MATERIALS AND METHODS: One-hundred-eight respiratory samples (combined nose and throat swabs) were routinely collected for detection of influenza virus during influenza seasons. Forty-one patients were pediatric cases and 59 were adult. Their mean age was 23 years. The patients were allocated into 6 age groups: 0 - 4 yrs, 5 - 9 yrs, 10 - 14 yrs, 15 - 19 yrs, 20-64 yrs and > 65 yrs. Each sample was tested with Directigen Flu A+B and CDC real time PCR kit for detection and typisation/subtypisation of influenza according to the lab diagnostic protocol. RESULTS: Directigen Flu A+B identified influenza A virus in 20 (18.5%) samples and influenza B virus in two 2 (1.9%) samples. The high specificity (100%) and PPV of Directigen Flu A+B we found in our study shows that the positive results do not need to be confirmed. The overall sensitivity of Directigen Flu A+B is 35.1% for influenza A virus and 33.0% for influenza B virus. The sensitivity for influenza A is higher among children hospitalized (45.0%) and outpatients (40.0%) versus adults. CONCLUSION: Directigen Flu A+B has relatively low sensitivity for detection of influenza viruses in combined nose and throat swabs. Negative results must be confirmed.

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Red ginseng and vitamin C increase immune cell activity and decrease lung inflammation induced by influenza A virus/H1N1 infection

Journal of Pharmacy and Pharmacology ◽

10.1111/jphp.12529 ◽

2016 ◽

Vol 68 (3) ◽

pp. 406-420 ◽

Cited By ~ 23

Author(s):

Hyemin Kim ◽

Mirim Jang ◽

Yejin Kim ◽

Jiyea Choi ◽

Jane Jeon ◽

...

Keyword(s):

Vitamin C ◽

Influenza A Virus ◽

Lung Inflammation ◽

Influenza A ◽

Immune Cell ◽

Cell Activity ◽

Virus H1n1 ◽

H1n1 Infection ◽

Red Ginseng

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Δ12-Prostaglandin J2 Is a Potent Inhibitor of Influenza A Virus Replication

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.44.1.200-204.2000 ◽

2000 ◽

Vol 44 (1) ◽

pp. 200-204 ◽

Cited By ~ 21

Author(s):

Francesca Pica ◽

Anna Teresa Palamara ◽

Antonio Rossi ◽

Alessandra De Marco ◽

Carla Amici ◽

...

Keyword(s):

Influenza Virus ◽

Heat Shock ◽

Influenza A Virus ◽

Influenza A ◽

Potent Inhibitor ◽

Influenza Virus Infection ◽

H1n1 Infection ◽

Shock Proteins

ABSTRACT 9-Deoxy-Δ9,Δ12-13,14-dihydro-prostaglandin D2 (Δ12-PGJ2), a natural cyclopentenone metabolite of prostaglandin D2, is shown to possess therapeutic efficacy against influenza A virus A/PR8/34 (H1N1) infection in vitro and in vivo. The results indicate that the antiviral activity is associated with induction of cytoprotective heat shock proteins and suggest novel strategies for treatment of influenza virus infection.

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Severe Influenza A Virus (H1N1) Infection in Pregnancy

Obstetrics and Gynecology ◽

10.1097/aog.0b013e3181cbc7c5 ◽

2010 ◽

Vol 115 (Supplement) ◽

pp. 412-414 ◽

Cited By ~ 13

Author(s):

Cathleen M. Brown

Keyword(s):

Influenza A Virus ◽

Influenza A ◽

Virus H1n1 ◽

H1n1 Infection ◽

Severe Influenza ◽

In Pregnancy

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C4b Binding Protein Acts as an Innate Immune Effector Against Influenza A Virus

Frontiers in Immunology ◽

10.3389/fimmu.2020.585361 ◽

2021 ◽

Vol 11 ◽

Author(s):

Praveen M. Varghese ◽

Valarmathy Murugaiah ◽

Nazar Beirag ◽

Nigel Temperton ◽

Haseeb A. Khan ◽

...

Keyword(s):

Influenza A Virus ◽

Influenza A ◽

Matrix Protein ◽

Binding Protein ◽

Fluid Phase ◽

Factor H ◽

Epithelial Cell Line ◽

Mrna Levels ◽

Dependent Manner ◽

Independent Manner

C4b Binding Protein (C4BP) is a major fluid phase inhibitor of the classical and lectin pathways of the complement system. Complement inhibition is achieved by binding to and restricting the role of activated complement component C4b. C4BP functions as a co-factor for factor I in proteolytic inactivation of both soluble and cell surface-bound C4b, thus restricting the formation of the C3-convertase, C4b2a. C4BP also accelerates the natural decay/dissociation of the C3 convertase. This makes C4BP a prime target for exploitation by pathogens to escape complement attack, as seen in Streptococcus pyogenes or Flavivirus. Here, we examined whether C4BP can act on its own in a complement independent manner, against pathogens. C4BP bound H1N1 and H3N2 subtypes of Influenza A Virus (IAV) most likely via multiple sites in Complement Control Protein (CCP) 1-2, 4-5, and 7-8 domains of its α-chain. In addition, C4BP CCP1-2 bound H3N2 better than H1N1. C4BP bound three IAV envelope proteins: Haemagglutinin (~70 kDa), Neuraminidase (~55 kDa), and Matrix protein 1 (~25kDa). C4BP suppressed H1N1 subtype infection into the lung epithelial cell line, A549, while it promoted infection by H3N2 subtype. C4BP restricted viral entry for H1N1 but had the opposite effect on H3N2, as evident from experiments using pseudo-typed viral particles. C4BP downregulated mRNA levels of pro-inflammatory IFN-α, IL-12, and NFκB in the case of H1N1, while it promoted a pro-inflammatory immune response by upregulating IFN- α, TNF-α, RANTES, and IL-6 in the case of H3N2. We conclude that C4BP differentially modulates the efficacy of IAV entry, and hence, replication in a target cell in a strain-dependent manner, and acts as an entry inhibitor for H1N1. Thus, CCP containing complement proteins such as factor H and C4BP may have additional defense roles against IAV that do not rely on the regulation of complement activation.

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Mutational Analysis of the Influenza Virus cRNA Promoter and Identification of Nucleotides Critical for Replication

Journal of Virology ◽

10.1128/jvi.78.12.6263-6270.2004 ◽

2004 ◽

Vol 78 (12) ◽

pp. 6263-6270 ◽

Cited By ~ 37

Author(s):

Mandy Crow ◽

Tao Deng ◽

Mark Addley ◽

George G. Brownlee

Keyword(s):

Secondary Structure ◽

Influenza A Virus ◽

Influenza A ◽

Promoter Activity ◽

Mrna Levels ◽

Structure Model ◽

Hairpin Loop ◽

Base Pairing ◽

Secondary Structure Model

ABSTRACT Replication of the influenza A virus virion RNA (vRNA) requires the synthesis of full-length cRNA, which in turn is used as a template for the synthesis of more vRNA. A “corkscrew” secondary-structure model of the cRNA promoter has been proposed recently. However the data in support of that model were indirect, since they were derived from measurement, by use of a chloramphenicol acetyltransferase (CAT) reporter in 293T cells, of mRNA levels from a modified cRNA promoter rather than the authentic cRNA promoter found in influenza A viruses. Here we measured steady-state cRNA and vRNA levels from a CAT reporter in 293T cells, directly measuring the replication of the authentic influenza A virus wild-type cRNA promoter. We found that (i) base pairing between the 5′ and 3′ ends and (ii) base pairing in the stems of both the 5′ and 3′ hairpin loops of the cRNA promoter were required for in vivo replication. Moreover, nucleotides in the tetraloop at positions 4, 5, and 7 and nucleotides forming the 2-9 base pair of the 3′ hairpin loop were crucial for promoter activity in vivo. However, the 3′ hairpin loop was not required for polymerase binding in vitro. Overall, our results suggest that the corkscrew secondary-structure model is required for authentic cRNA promoter activity in vivo, although the precise role of the 3′ hairpin loop remains unknown.

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