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

Bortolotti, Daria; Gentili, Valentina; Caselli, Elisabetta; Sicolo, Mariangela; Soffritti, Irene; D’Accolti, Maria; Barão, Isabel; Rotola, Antonella; Luca, Dario Di; Rizzo, Roberta

doi:10.3389/fmicb.2020.00226

Cited by 12 publications

(16 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, HHV-7 can reactivate HHV-6A/B while HHV-6 has been found to activate Epstein-Barr virus from latency [43][44][45]. HHV-6 and HHV-7 latency within leukocytes leads to wide-ranging impacts on the immune system [4] including changes in host cell transcriptomes and metabolism [46], down-regulation of antigen presentation and modulation of cytokines and chemokines [47,48], impairment of NK cell function [49], and enhancement of proinflammatory cytokine and chemokine responses to Toll-like receptor 9 signalling [50]. HHV-6 reactivation in ME/CFS patients can also lead to mitochondrial fragmentation and severely compromised energy metabolism [51]; this may be linked to reported interactions between the HHV-6B U95 early viral protein and the mitochondrial GRIM-19 protein [52] that results in reduced mitochondrial membrane potential and pronounced mitochondrial impairment.…”

Section: Discussionmentioning

confidence: 99%

Salivary DNA loads for human herpes viruses 6 and 7 are correlated with disease phenotype in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome

Lee

Lacerda

Nacul

et al. 2021

Preprint

View full text Add to dashboard Cite

Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) is a complex chronic condition affecting multiple body systems, with unknown cause, unclear pathogenesis mechanisms, and fluctuating symptoms which may lead to severe debilitation. It is frequently reported to have been triggered by an infection, particularly with herpes virus family members; however, there are no clear differences in exposure to, or seroprevalence of, any herpes virus in people with ME/CFS and healthy individuals. Herpes viruses exist in lytic and latent forms, and it is possible that ME/CFS is associated with viral reactivation, which has not been detectable previously due to insensitive testing methods.Saliva samples were collected from 30 people living with ME/CFS at monthly intervals for six months and at times when they experienced symptom exacerbation, as well as from 14 healthy control individuals. The viral DNA load of the nine human herpes viruses was determined by digital droplet PCR. Symptoms were assessed by questionnaire at each time point.Human herpes virus (HHV) 6B, HHV-7, herpes simplex virus 1 and Epstein Barr virus were detectable within the saliva samples, with higher HHV-6B and HHV-7 viral loads detected in people with ME/CFS than in healthy controls. Participants with ME/CFS could be broadly separated into two groups: one group displayed fluctuating patterns of herpes viruses detectable across the six months while the second group displayed more stable viral presentation. In the first group, there was positive correlation between HHV-6B and HHV-7 viral load and severity of symptom scores, including pain, neurocognition and autonomic dysfunction.The results indicate that fluctuating viral load, related to herpesvirus reactivation state, may play a role in ME/CFS pathogenesis, or might be a consequence of dysregulated immune function. The sampling strategy and molecular tools developed permit large-scale epidemiological investigations.Contribution to the FieldThe cause of ME/CFS and the mechanisms underlying disease pathogenesis are not known, although symptoms are often triggered by infection. Human herpes virus (HHV) family members have been implicated, although there is no difference in the seroprevalence of any HHV in people with ME/CFS and healthy controls, showing there is similar prior infection rate. HHVs exist in either latent or active, lytic, phases in the human host, and it is possible that ME/CFS symptoms and their severity is related to HHV reactivation from a latent state. We have used droplet digital PCR, a sensitive and specific method, to measure the prevalence and DNA concentration of HHVs in the saliva of people with ME/CFS and controls, and analysed the correlation with disease over a six-month timecourse. We found that two HHVs, HHV-7 and HHV-6B, were elevated in saliva from people with ME/CFS, and that in people who were severely affected by ME/CFS, the concentration HHV DNA correlated with symptom severity over time in a subgroup of patients with fluctuating salivary HHV repertoire. Our study demonstrates the feasibility of measuring HHV concentration in readily acquired samples, enabling future large-scale studies aimed at testing the causal role of HHV reactivation in ME/CFS disease.

show abstract

Section: Discussionmentioning

confidence: 99%

Salivary DNA loads for human herpes viruses 6 and 7 are correlated with disease phenotype in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome

Lee

Lacerda

Nacul

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…NK cells are the dominant lymphocytes in the endometrium. HHV-6A (and -6B) can infect both an NK cell line ( 46 ) as well as primary NK cells ( 47 ).…”

Section: Hhv-6a/b In Reproductive Organsmentioning

confidence: 99%

“…In a non-pregnant woman, when endometrial epithelial cells are infected by HHV-6A, the NK cytotoxic attack is severe, leading to the production of proinflammatory cytokines that inhibit implantation ( 47 ). Thus, viral infection of endometrial NK cells is a plausible contributor to the pathogenesis of primary infertility.…”

Section: Hhv-6a/b In Reproductive Organsmentioning

confidence: 99%

Human Herpesviruses 6A and 6B in Reproductive Diseases

2021

Self Cite

View full text Add to dashboard Cite

Human herpesviruses 6A (HHV-6A) and human herpesvirus 6B (HHV-6B)—collectively, HHV-6A/B—are recently-discovered but ancient human viruses. The vast majority of people acquire one or both viruses, typically very early in life, producing an ineradicable lifelong infection. The viruses have been linked to several neurological, pulmonary and hematological diseases. In early human history, the viruses on multiple occasions infected a germ cell, and integrated their DNA into a human chromosome. As a result, about 1% of humans are born with the full viral genome present in every cell, with uncertain consequences for health. HHV-6A may play a role in 43% of cases of primary unexplained infertility. Both the inherited and acquired viruses may occasionally trigger several of the factors that are important in the pathogenesis of preeclampsia. Transplacental infection occurs in 1-2% of pregnancies, with some evidence suggesting adverse health consequences for the child. While emerging knowledge about these viruses in reproductive diseases is not sufficient to suggest any changes in current practice, we write this review to indicate the need for further research that could prove practice-changing.

show abstract

“…HLA-E expression was analyzed by immuno uorescence with anti-HLA-E antibody ( ), as previously described 18,19 .…”

Section: Immuno Uorescence Assaymentioning

confidence: 99%

“…In December 2019, a novel coronavirus was isoleted in Wuhan, China 1 . It was the severe acute respiratory syndrome coronavirus 2 (Sars-Cov-2) the causative agent for coronavirus disease 2019 (COVID- 19).…”

Section: Introductionmentioning

confidence: 99%

Sars-Cov-2 Spike 1 protein control Natural killer cells activation via HLA-E/NKG2A pathway.

Bortolotti

Gentili

Rizzo

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Natural killer (NK) cells are important in the control of viral infections. However, the role of NK cells during Sars-Cov-2 infection has previously not been identified. Peripheral blood NK cells from Sars-Cov and Sars-Cov-2 naïve subjects were evaluated for their activation, degranulation, interferon-gamma expression in the presence of Sars-Cov and Sars-Cov-2 spike proteins. K562 and lung epithelial cells were transfected with spike proteins and co-cultured with NK cells. The analysis was performed by flow cytometry and immune-fluorescence. Sars-Cov and Sars-Cov-2 spike proteins did not alter NK cell activation in K562 in vitro model. On the contrary, Sars-Cov-2 spike 1 protein (SP1) intracellular expression by lung epithelial cells resulted in NK cell reduced degranulation. Further experiments revealed a concomitant induction of HLA-E expression on the surface of lung epithelial cells and the recognition of a SP1-derived HLA-E-binding peptide. Simultaneously, there was the up-modulation of the inhibitory receptor NKG2A/CD94 on NK cells when SP1 is expressed in lung epithelial cells. We ruled out GATA3 transcription factor as responsible for HLA-E increased levels and HLA-E/NKG2A interaction as implicate in NK cells exhaustion. We show for the first time that NK cells are affected by SP1 expression in lung epithelial cells via HLA-E/NKG2A interaction. The resulting NK cells exhaustion might contribute to immunopathogenesis in Sars-Cov-2 infection.

show abstract

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

Cited by 12 publications

References 56 publications

Salivary DNA loads for human herpes viruses 6 and 7 are correlated with disease phenotype in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome

Salivary DNA loads for human herpes viruses 6 and 7 are correlated with disease phenotype in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome

Human Herpesviruses 6A and 6B in Reproductive Diseases

Sars-Cov-2 Spike 1 protein control Natural killer cells activation via HLA-E/NKG2A pathway.

Contact Info

Product

Resources

About