KIR2DS2/KIR2DL2/HLA-C1 Haplotype Is Associated with Alzheimer’s Disease: Implication for the Role of Herpesvirus Infections

Rizzo, Roberta; Bortolotti, Daria; Gentili, Valentina; Rotola, Antonella; Bolzani, Silvia; Caselli, Elisabetta; Tola, Maria Rosaria; Luca, Dario Di

doi:10.3233/jad-180777

Cited by 34 publications

(30 citation statements)

References 59 publications

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“…As previously reported, HHV-6A and HHV-6B viruses can infect NK cells (Rizzo et al, 2019). Here we showed that NK92 cells are permissive to HHV-6A, HHV-6B, and HHV-7, with a high viral amount 3 days post infection (d.p.i.)…”

Section: Hhv-6a Hhv-6b and Hhv-7 Infect Nk Cellssupporting

confidence: 77%

DNA Sensors’ Signaling in NK Cells During HHV-6A, HHV-6B and HHV-7 Infection

et al. 2020

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Objectives: The host DNA sensor proteins TLR9, STING, IFI16 are central signaling molecules that control the innate immune response to cytosolic nucleic acids. Here we propose to investigate how Natural killer (NK) cell infection by human herpesvirus (HHV)-6A, HHV-6B or HHV-7 is able to modify DNA sensor signaling in NK cells. Methods:We infected the NK92 cell line and primary NK cells with cell-free inocula of HHV-6A, HHV-6B or HHV-7 and evaluated TLR9, STING, and IFI16 pathway expression by Real-Time PCR, Western Blot, immunofluorescence and flow cytometry for 1, 2, 3, and 6 days post-infection. We evaluated NK cell cytokine-producing by Real-Time PCR and enzyme immunosorbent assay.Results: NK92 and primary NK cells were promptly infected by three viruses, as demonstrated by virus presence (DNA) and transcription (RNA) analysis. Our data show STING/STAT6 up-modulation in HHV-6A infected NK cells. NK cells infected with HHV-6B and HHV-7 up-regulated CCL3, IFN-alpha, TNF-alpha, IL-8 and IFN-gamma and slightly induced IL-4, and CCL4. HHV-6A infected NK cells up-regulated IL-4 and IL-13 and slightly induced IL-10, TNF-alpha, IFN-alpha, and IFN-gamma.Conclusion: For the first time, we demonstrate that HHV-6A, HHV-6B, and HHV-7 infections have a differential impact on intracellular DNA sensors. HHV-6B and HHV-7 mainly lead to the active control of in vivo viral spreading by pro-inflammatory cytokine secretion via TLR9. HHV-6A infected NK cells conversely induced STING/STAT6 pathway, as a mechanism of anti-viral activation, but they were characterized by a Th2 type response and a non-cytotoxic profile, suggesting a potential novel mechanism of HHV-6A-mediated immunosuppression.

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Section: Hhv-6a Hhv-6b and Hhv-7 Infect Nk Cellssupporting

confidence: 77%

DNA Sensors’ Signaling in NK Cells During HHV-6A, HHV-6B and HHV-7 Infection

et al. 2020

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“…HHV-6A DNA extraction and analysis was performed as previously described (Rizzo et al, 2019). Briefly, real-time quantitative polymerase chain reaction (qPCR) specific for the U94 gene was used to determine HHV-6A DNA presence and load.…”

Section: Hhv-6a Cell Infection and Assays For Hhv-6 Detectionmentioning

confidence: 99%

The P2X7 Receptor 489C>T Gain of Function Polymorphism Favors HHV-6A Infection and Associates With Female Idiopathic Infertility

et al. 2020

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The P2X7 receptor (P2X7R) is an ATP-gated ion channel known for its proinflammatory activity. Despite its participation in host defense against pathogens, the role played in viral infections, notably those caused by herpes viruses, has been seldom studied. Here we investigated the effect of P2X7R expression on human herpes virus 6 A (HHV-6A) infection of P2X7R-expressing HEK293 cells. We show that functional P2X7R increases while its blockade decreases viral load. Interestingly, HHV-6A infection was enhanced in HEK293 cells transfected with P2X7R cDNA bearing the gain of function 489C>T SNP (rs208294, replacing a histidine for tyrosine at position 155). The P2X7R 489C>T polymorphism correlated with HHV-6A infection also in a cohort of 50 women affected with idiopathic infertility, a condition previously shown to correlate with HHV-6A infection. None of the infertile women infected by HHV-6A was homozygote for 489CC genotype, while on the contrary HHV-6A infection significantly associated with the presence of the rs208294 allele. Levels of soluble human leukocyte antigen G (sHLA-G), a factor promoting embryo implant, measured in uterine flushings negatively correlated with the 489TT genotype and HHV-6A infection, while proinflammatory cytokines interleukins 1a (IL-1a), 1b (IL-1b), and 8 (IL-8) positively correlated with both the 489T allele presence and viral infection. Taken together these data point to the P2X7R as a new therapeutic target to prevent HHV-6A infection and the associated infertility.

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“…Genetic analysis of late‐onset AD has uncovered a number of single nucleotide polymorphisms (SNPs) that are associated with the risk for AD, including KIR2DS2/KIR2DL2/HLA‐C1, apolipoprotein E (APOE), phosphatidylinositol binding clathrin assembly protein (PICALM), complement receptor 1 (CR1) and clusterin (CLU), glycoprotein carcinoembryonic antigen‐related cell adhesion molecule‐16, B‐cell lymphoma‐3, translocase of outer mitochondrial membrane 40 homolog (TOMM‐40), apolipoprotein C‐I (APOC1), and C‐type lectin domain A family‐16 member, paired immunoglobulin‐like type 2 receptor (PILRα), nectin‐2 (also known as poliovirus receptor‐related 2, PVRL‐2) . Nectin‐2, TOMM‐40, APOE, and APOC1 are closely located in chromosome 19.…”

Section: Susceptible Genetic Factors Of Ad Facilitate Herpesviral Infmentioning

confidence: 99%

Herpesviral infections and antimicrobial protection for Alzheimer's disease: Implications for prevention and treatment

Qin

2019

Journal of Medical Virology

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Accumulating evidence suggests that infections by herpesviruses might be closely linked to Alzheimer's disease (AD). Pathological hallmarks of AD brains include senile plaques induced by amyloid β peptide (Aβ) in the extracellular space and intracellular neurofibrillary tangles (NFTs) consisting of phosphorylated tau protein. The prevailing hypothesis for the mechanism of AD is amyloid cascade reaction. Recent studies revealed that infections by herpesviruses induce the similar pathological hallmarks of AD, including Aβ production, phosphorylation of tau (P-tau), oxidative stress, neuroinflammation, etc. Aβ peptide is regarded as one of the antimicrobial peptides, which inhibits HSV-1 replication. In the elderly, reactivation of herpesviruses might act as an initiator for amyloid cascade reaction in vulnerable individuals, triggering the neurofibrillary formation of phosphorylated tau and inducing oxidative stress and neuroinflammation, which can further contribute to the accumulation of Aβ and P-tau by impairing mitochondria and autophagosome. Epidemiological studies have shown AD susceptibility genes, such as APOE-ε4 allele, are highly linked to infections by herpesviruses. Interestingly, anti-herpesviral therapy significantly reduced the risk of AD in a large population study. Given that herpesviruses are arguably the most prevalent opportunistic pathogens and often reactivate in the elderly, it is reasonable to argue reactivation of herpesviruses might be major culprits for initiating AD in individuals carrying AD susceptibility genes. In this review, we summarize epidemiological and molecular evidence that support for a hypothesis of herpesviral infections and antimicrobial protection in the development of AD, and discuss the implications for future prevention and treatment of the disease.

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KIR2DS2/KIR2DL2/HLA-C1 Haplotype Is Associated with Alzheimer’s Disease: Implication for the Role of Herpesvirus Infections

Cited by 34 publications

References 59 publications

DNA Sensors’ Signaling in NK Cells During HHV-6A, HHV-6B and HHV-7 Infection

DNA Sensors’ Signaling in NK Cells During HHV-6A, HHV-6B and HHV-7 Infection

The P2X7 Receptor 489C>T Gain of Function Polymorphism Favors HHV-6A Infection and Associates With Female Idiopathic Infertility

Herpesviral infections and antimicrobial protection for Alzheimer's disease: Implications for prevention and treatment

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