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1.
Front Immunol ; 15: 1352022, 2024.
Article in English | MEDLINE | ID: mdl-38698856

ABSTRACT

The complement system is an innate immune mechanism against microbial infections. It involves a cascade of effector molecules that is activated via classical, lectin and alternative pathways. Consequently, many pathogens bind to or incorporate in their structures host negative regulators of the complement pathways as an evasion mechanism. Factor H (FH) is a negative regulator of the complement alternative pathway that protects "self" cells of the host from non-specific complement attack. FH has been shown to bind viruses including human influenza A viruses (IAVs). In addition to its involvement in the regulation of complement activation, FH has also been shown to perform a range of functions on its own including its direct interaction with pathogens. Here, we show that human FH can bind directly to IAVs of both human and avian origin, and the interaction is mediated via the IAV surface glycoprotein haemagglutinin (HA). HA bound to common pathogen binding footprints on the FH structure, complement control protein modules, CCP 5-7 and CCP 15-20. The FH binding to H1 and H3 showed that the interaction overlapped with the receptor binding site of both HAs, but the footprint was more extensive for the H3 HA than the H1 HA. The HA - FH interaction impeded the initial entry of H1N1 and H3N2 IAV strains but its impact on viral multicycle replication in human lung cells was strain-specific. The H3N2 virus binding to cells was significantly inhibited by preincubation with FH, whereas there was no alteration in replicative rate and progeny virus release for human H1N1, or avian H9N2 and H5N3 IAV strains. We have mapped the interaction between FH and IAV, the in vivo significance of which for the virus or host is yet to be elucidated.


Subject(s)
Complement Factor H , Hemagglutinin Glycoproteins, Influenza Virus , Influenza A virus , Influenza, Human , Protein Binding , Humans , Complement Factor H/metabolism , Complement Factor H/immunology , Animals , Influenza, Human/immunology , Influenza, Human/virology , Influenza, Human/metabolism , Influenza A virus/immunology , Influenza A virus/physiology , Hemagglutinin Glycoproteins, Influenza Virus/metabolism , Hemagglutinin Glycoproteins, Influenza Virus/immunology , Binding Sites , Influenza in Birds/virology , Influenza in Birds/immunology , Influenza in Birds/metabolism , Birds/virology , Host-Pathogen Interactions/immunology , Influenza A Virus, H3N2 Subtype/immunology , Influenza A Virus, H9N2 Subtype/immunology
2.
J Gen Virol ; 104(5)2023 05.
Article in English | MEDLINE | ID: mdl-37167079

ABSTRACT

The 2021/2022 epizootic of high pathogenicity avian influenza (HPAIV) remains one of the largest ever in the UK, being caused by a clade 2.3.4.4b H5N1 HPAIV. This epizootic affected more than 145 poultry premises, most likely through independent incursion from infected wild birds, supported by more than 1700 individual detections of H5N1 from wild bird mortalities. Here an H5N1 HPAIV, representative of this epizootic (H5N1-21), was used to investigate its virulence, pathogenesis and transmission in layer chickens and Pekin ducks, two species of epidemiological importance. We inoculated both avian species with decreasing H5N1-21 doses. The virus was highly infectious in ducks, with high infection levels and accompanying shedding of viral RNA, even in ducks inoculated with the lowest dose, reflecting the strong waterfowl adaptation of the clade 2.3.4.4 HPAIVs. Duck-to-duck transmission was very efficient, coupled with high environmental contamination. H5N1-21 was frequently detected in water sources, serving as likely sources of infection for ducks, but inhalable dust and aerosols represented low transmission risks. In contrast, chickens inoculated with the highest dose exhibited lower rates of infection compared to ducks. There was no evidence for experimental H5N1-21 transmission to any naive chickens, in two stocking density scenarios, coupled with minimal and infrequent contamination being detected in the chicken environment. Systemic viral dissemination to multiple organs reflected the pathogenesis and high mortalities in both species. In summary, the H5N1-21 virus is highly infectious and transmissible in anseriformes, yet comparatively poorly adapted to galliformes, supporting strong host preferences for wild waterfowl. Key environmental matrices were also identified as being important in the epidemiological spread of this virus during the continuing epizootic.


Subject(s)
Influenza A Virus, H5N1 Subtype , Influenza A virus , Influenza in Birds , Animals , Ducks , Chickens , Influenza A Virus, H5N1 Subtype/genetics , Virulence , Influenza in Birds/epidemiology , Animals, Wild
3.
mBio ; 12(5): e0178521, 2021 10 26.
Article in English | MEDLINE | ID: mdl-34488450

ABSTRACT

Avian influenza viruses pose a continuous threat to both poultry and human health, with significant economic impact. The ability of viruses to reassort and jump the species barrier into mammalian hosts generates a constant pandemic threat. H10Nx avian viruses have been shown to replicate in mammalian species without prior adaptation and have caused significant human infection and fatalities. They are able to rapidly reassort with circulating poultry strains and go undetected due to their low pathogenicity in chickens. Novel detections of both human reassortant strains and increasing endemicity of H10Nx poultry infections highlight the increasing need for heightened surveillance and greater understanding of the distribution, tropism, and infection capabilities of these viruses. In this minireview, we highlight the gap in the current understanding of this subtype and its prevalence across a vast range of host species and geographical locations.


Subject(s)
Influenza in Birds/transmission , Poultry/virology , Viral Zoonoses/transmission , Animals , Australia , Birds , Chickens , Host Specificity , Humans , Influenza in Birds/classification , Influenza in Birds/genetics , Influenza, Human/virology , Orthomyxoviridae Infections/virology , Pandemics , Swine
4.
Neurochem Res ; 44(1): 228-233, 2019 Jan.
Article in English | MEDLINE | ID: mdl-29299811

ABSTRACT

Impaired interactions between Calcineurin (Cn) and (Cu/Zn) superoxide dismutase (SOD1) are suspected to be responsible for the formation of hyperphosphorylated protein aggregation in amyotrophic lateral sclerosis (ALS). Serine (Ser)- enriched phosphorylated TDP-43 protein aggregation appears in the spinal cord of ALS animal models, and may be linked to the reduced phosphatase activity of Cn. The mutant overexpressed SOD1G93A protein does not properly bind zinc (Zn) in animal models; hence, mutant SOD1G93A-Cn interaction weakens. Consequently, unstable Cn fails to dephosphorylate TDP-43 that yields hyperphosphorylated TDP-43 aggregates. Our previous studies had suggested that Cn and SOD1 interaction was necessary to keep Cn enzyme functional. We have observed low Cn level, increased Zn concentrations, and increased TDP-43 protein levels in cervical, thoracic, lumbar, and sacral regions of the spinal cord tissue homogenates. This study further supports our previously published work indicating that Cn stability depends on functional Cn-SOD1 interaction because Zn is crucial for maintaining the Cn stability. Less active Cn did not efficiently dephosphorylate TDP-43; hence TDP-43 aggregations appeared in the spinal cord tissue.


Subject(s)
Amyotrophic Lateral Sclerosis/metabolism , Calcineurin/metabolism , DNA-Binding Proteins/metabolism , Spinal Cord/metabolism , Superoxide Dismutase/metabolism , Zinc/metabolism , Amyotrophic Lateral Sclerosis/genetics , Animals , Calcineurin/genetics , DNA-Binding Proteins/genetics , Rats , Rats, Transgenic , Superoxide Dismutase/genetics
5.
Br J Health Psychol ; 13(Pt 4): 683-99, 2008 Nov.
Article in English | MEDLINE | ID: mdl-17958929

ABSTRACT

OBJECTIVES: Hope is important in determining positive outcomes in a range of chronic illnesses. This study examined the role of hope in adjustment to end-stage renal failure (ESRF) and consequent dialysis. DESIGN: A cross-sectional design examined the ability of hope to predict adjustment to ESRF over and above other relevant variables. METHODS: Individuals receiving dialysis at 4 units in the North-West UK were invited to take part in the study. 103 questionnaire packs were included in the analysis. Multiple regression equations determined whether hope was able to predict significant variance in adjustment over and above that accounted for by other factors (demographic and illness-related factors, perceived control, and social support). Measures of anxiety, depression, and quality of life constituted a multidimensional measure of adjustment to ESRF. RESULTS: Each of the regression models was significant. Hope emerged as an independent significant predictor in five of the multiple regressions: anxiety; depression; effects and symptoms of kidney disease; and mental health quality of life. Age also emerged as an important predictor of outcome. CONCLUSIONS: It appears that hope is a significant predictor of adjustment to ESRF. Clinical implications of this research are discussed, along with suggestions for future research.


Subject(s)
Adaptation, Psychological , Hemodialysis, Home/psychology , Kidney Failure, Chronic/psychology , Motivation , Peritoneal Dialysis/psychology , Renal Dialysis/psychology , Sick Role , Adult , Aged , Aged, 80 and over , Anxiety/diagnosis , Anxiety/psychology , Cross-Sectional Studies , Depression/diagnosis , Depression/psychology , England , Female , Humans , Internal-External Control , Male , Middle Aged , Quality of Life/psychology , Social Support
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