Tag: herpesviruses

Selective inhibition of miRNA processing by a herpesvirus-encoded miRNA

Abstract:

Herpesviruses have mastered host cell modulation and immune evasion to augment productive infection, life-long latency and reactivation1,2. A long appreciated, yet undefined relationship exists between the lytic-latent switch and viral non-coding RNAs3,4. Here we identify viral microRNA (miRNA)-mediated inhibition of host miRNA processing as a cellular mechanism that human herpesvirus 6A (HHV-6A) exploits to disrupt mitochondrial architecture, evade intrinsic host defences and drive the switch from latent to lytic virus infection.

We demonstrate that virus-encoded miR-aU14 selectively inhibits the processing of multiple miR-30 family members by direct interaction with the respective primary (pri)-miRNA hairpin loops. Subsequent loss of miR-30 and activation of the miR-30-p53-DRP1 axis triggers a profound disruption of mitochondrial architecture. This impairs induction of type I interferons and is necessary for both productive infection and virus reactivation.

Ectopic expression of miR-aU14 triggered virus reactivation from latency, identifying viral miR-aU14 as a readily druggable master regulator of the herpesvirus lytic-latent switch. Our results show that miRNA-mediated inhibition of miRNA processing represents a generalized cellular mechanism that can be exploited to selectively target individual members of miRNA families. We anticipate that targeting miR-aU14 will provide new therapeutic options for preventing herpesvirus reactivations in HHV-6-associated disorders.

Source: Hennig T, Prusty AB, Kaufer BB, Whisnant AW, Lodha M, Enders A, Thomas J, Kasimir F, Grothey A, Klein T, Herb S, Jürges C, Sauer M, Fischer U, Rudel T, Meister G, Erhard F, Dölken L, Prusty BK. Selective inhibition of miRNA processing by a herpesvirus-encoded miRNA. Nature. 2022 May;605(7910):539-544. doi: 10.1038/s41586-022-04667-4. Epub 2022 May 4. PMID: 35508655.  https://pubmed.ncbi.nlm.nih.gov/35508655/

Tissue specific signature of HHV-6 infection in ME/CFS

Abstract:

First exposure to various human herpesviruses (HHVs) including HHV-6, HCMV and EBV does not cause a life-threatening disease. In fact, most individuals are frequently unaware of their first exposure to such pathogens. These herpesviruses acquire lifelong latency in the human body where they show minimal genomic activity required for their survival. We hypothesized that it is not the latency itself but a timely, regionally restricted viral reactivation in a sub-set of host cells that plays a key role in disease development.

HHV-6 (HHV-6A and HHV-6B) and HHV-7 are unique HHVs that acquire latency by integration of the viral genome into sub-telomeric region of human chromosomes. HHV-6 reactivation has been linked to Alzheimer’s Disease, Chronic Fatigue Syndrome, and many other diseases. However, lack of viral activity in commonly tested biological materials including blood or serum strongly suggests tissue specific localization of active HHV-6 genome.

Here in this paper, we attempted to analyze active HHV-6 transcripts in postmortem tissue biopsies from a small cohort of ME/CFS patients and matched controls by fluorescence in situ hybridization using a probe against HHV-6 microRNA (miRNA), miR-aU14. Our results show abundant viral miRNA in various regions of the human brain and associated neuronal tissues including the spinal cord that is only detected in ME/CFS patients and not in controls.

Our findings provide evidence of tissue-specific active HHV-6 and EBV infection in ME/CFS, which along with recent work demonstrating a possible relationship between herpesvirus infection and ME/CFS, provide grounds for renewed discussion on the role of herpesviruses in ME/CFS.

Source: Prusty, Bhupesh K.; Kasimir, Francesca; Toomey, Danny; Liu, Zheng; Agnes Kaiping and Ariza, Maria Eugenia. Tissue specific signature of HHV-6 infection in ME/CFS. Front. Mol. Biosci. Sec. Molecular Diagnostics and Therapeutics. doi: 10.3389/fmolb.2022.1044964 https://www.frontiersin.org/articles/10.3389/fmolb.2022.1044964/abstract

Saliva antibody-fingerprint of reactivated latent viruses after mild/asymptomatic COVID-19 is unique in patients with myalgic-encephalomyelitis/chronic fatigue syndrome

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic disease considered to be triggered by viral infections in a majority of cases. Symptoms overlap largely with those of post-acute sequelae of COVID-19/long-COVID implying common pathogenetic mechanisms. SARS-CoV-2 infection is risk factor for sustained latent virus reactivation that may account for the symptoms of post-viral fatigue syndromes. The aim of this study was first to investigate whether patients with ME/CFS and healthy donors (HDs) differed in their antibody response to mild/asymptomatic SARS-CoV-2 infection. Secondly, to analyze whether COVID-19 imposes latent virus reactivation in the cohorts.

Methods: Anti-SARS-CoV-2 antibodies were analyzed in plasma and saliva from non-vaccinated ME/CFS (n=95) and HDs (n=110) using soluble multiplex immunoassay. Reactivation of human herpesviruses 1-6 (HSV1, HSV2, VZV, EBV, CMV, HHV6), and human endogenous retrovirus K (HERV-K) was detected by anti-viral antibody fingerprints in saliva.

Results: At 3-6 months after mild/asymptomatic SARS-CoV-2 infection, virus-specific antibodies in saliva were substantially induced signifying a strong reactivation of latent viruses (EBV, HHV6 and HERV-K) in both cohorts. In patients with ME/CFS, antibody responses were significantly stronger, in particular EBV-encoded nuclear antigen-1 (EBNA1) IgG were elevated in patients with ME/CFS, but not in HDs. EBV-VCA IgG was also elevated at baseline prior to SARS-infection in patients compared to HDs.

Conclusion: Our results denote an altered and chronically aroused anti-viral profile against latent viruses in ME/CFS. SARS-CoV-2 infection even in its mild/asymptomatic form is a potent trigger for reactivation of latent herpesviruses (EBV, HHV6) and endogenous retroviruses (HERV-K), as detected by antibody fingerprints locally in the oral mucosa (saliva samples). This has not been shown before because the antibody elevation is not detected systemically in the circulation/plasma.

Source: Apostolou Eirini, Rizwan Muhammad, Moustardas Petros, Sjögren Per, Bertilson Bo Christer, Bragée Björn, Polo Olli, Rosén Anders. Saliva antibody-fingerprint of reactivated latent viruses after mild/asymptomatic COVID-19 is unique in patients with myalgic-encephalomyelitis/chronic fatigue syndrome. Frontiers in Immunology, Vol 13, 2022. https://www.frontiersin.org/articles/10.3389/fimmu.2022.949787/full (Full text)

Detection of herpes viruses in patients with myalgic encephalomyelitis /chronic fatigue syndrome in Belarus

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multifactorial chronic disease. The etiology and pathogenesis of ME/CFS are unknown. There are many theories for the occurrence of this disease. but the most convincing is the infectious or viral theory of the emergence of CFS.

The aim of this study is to detect of herpes viruses 6, 7 types and Epstein-Barr  to examine the prevalence HHV-6, HHV-7 and EBV infections in Belarus CFS patients.

We examined 30 patients with CFS in whom fatigue during  more than 2 years (7), more than 1 year (11) and more than 6 months (12). The diagnosis was made on clinical grounds using the Fukuda criteria.

The presence of markers the active forms  infection HHV-6 and HHV-7 in CFS patients with a long period of fatigue  were detected in 16.6% and 26.6% respectively. IgM  antibodies to HHV-6 and EBV. positive, in 16.6% and 6.7% respectively in patients with long-term illness. Detection of IgG antibodies indicates a quiet carrier state, latent phase.

Source: ORLOVA, Svetlana et al. Detection of herpes viruses in patients with myalgic encephalomyelitis /chronic fatigue syndrome in Belarus. Polish Journal of Applied Sciences, [S.l.], v. 6, n. 2, p. 50-53, dec. 2021. ISSN 2451-1544. Available at: <https://pjas.pwsip.edu.pl/index.php/pjas/article/view/176>. Date accessed: 10 jan. 2022. doi: https://doi.org/10.34668/PJAS.2020.6.2.08. (Full text)

Salivary DNA Loads for Human Herpesviruses 6 and 7 Are Correlated With Disease Phenotype in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

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, but there are no clear differences in exposure to, or seroprevalence of, any particular viruses between people with ME/CFS and healthy individuals. However, herpes viruses have been repeatedly hypothesized to underlie the chronic relapsing/remitting form of MS/CFS due to their persistence in a latent form with periodic reactivation. It is possible that ME/CFS is associated with herpes virus reactivation, which has not been detectable previously due to insufficiently sensitive testing methods.

Saliva samples were collected from 30 people living with ME/CFS at monthly intervals for 6 months and at times when they experienced symptom exacerbation, as well as from 14 healthy control individuals. The viral DNA load of the nine humanherpes viruses was determined by digital droplet PCR. Symptoms were assessed by questionnaire at each time point. Human herpesvirus (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 herpesviruses detectable across the 6 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 DNA load correlates with ME/CFS symptoms: this is in accordance with the hypothesis that pathogenesis is related to herpesvirus reactivation state, and this should be formally tested. Herpesvirus reactivation might be a cause or consequence of dysregulated immune function seen in ME/CFS. The sampling strategy and molecular tools developed here permit such large-scale epidemiological investigations.

Source: Lee JS, Lacerda EM, Nacul L, Kingdon CC, Norris J, O’Boyle S, Roberts CH, Palla L, Riley EM, Cliff JM. Salivary DNA Loads for Human Herpesviruses 6 and 7 Are Correlated With Disease Phenotype in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Front Med (Lausanne). 2021 Aug 6;8:656692. doi: 10.3389/fmed.2021.656692. PMID: 34422848; PMCID: PMC8378328. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8378328/  (Full text)

Herpesviruses Serology Distinguishes Different Subgroups of Patients From the United Kingdom Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Biobank

Abstract:

The evidence of an association between Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and chronic herpesviruses infections remains inconclusive. Two reasons for the lack of consistent evidence are the large heterogeneity of the patients’ population with different disease triggers and the use of arbitrary cutoffs for defining seropositivity. In this work we re-analyzed previously published serological data related to 7 herpesvirus antigens. Patients with ME/CFS were subdivided into four subgroups related to the disease triggers: S0-42 patients who did not know their disease trigger; S1-43 patients who reported a non-infection trigger; S2-93 patients who reported an infection trigger, but that infection was not confirmed by a lab test; and S3-48 patients who reported an infection trigger and that infection was confirmed by a lab test.

In accordance with a sensitivity analysis, the data were compared to those from 99 healthy controls allowing the seropositivity cutoffs to vary within a wide range of possible values. We found a negative association between S1 and seropositivity to Epstein-Barr virus (VCA and EBNA1 antigens) and Varicella-Zoster virus using specific seropositivity cutoff. However, this association was not significant when controlling for multiple testing. We also found that S3 had a lower seroprevalence to the human cytomegalovirus when compared to healthy controls for all cutoffs used for seropositivity and after adjusting for multiple testing using the Benjamini-Hochberg procedure. However, this association did not reach statistical significance when using Benjamini-Yekutieli procedure. In summary, herpesviruses serology could distinguish subgroups of ME/CFS patients according to their disease trigger, but this finding could be eventually affected by the problem of multiple testing.

Source: Domingues TD, Grabowska AD, Lee JS, Ameijeiras-Alonso J, Westermeier F, Scheibenbogen C, Cliff JM, Nacul L, Lacerda EM, Mouriño H, Sepúlveda N. Herpesviruses Serology Distinguishes Different Subgroups of Patients From the United Kingdom Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Biobank. Front Med (Lausanne). 2021 Jul 5;8:686736. doi: 10.3389/fmed.2021.686736. PMID: 34291062; PMCID: PMC8287507. https://pubmed.ncbi.nlm.nih.gov/34291062/

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Human Herpesviruses Are Back!

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) or Systemic Exertion Intolerance Disease (SEID) is a chronic multisystem illness of unconfirmed etiology. There are currently no biomarkers and/or signatures available to assist in the diagnosis of the syndrome and while numerous mechanisms have been hypothesized to explain the pathology of ME/CFS, the triggers and/or drivers remain unknown. Initial studies suggested a potential role of the human herpesviruses especially Epstein-Barr virus (EBV) in the disease process but inconsistent and conflicting data led to the erroneous suggestion that these viruses had no role in the syndrome. New studies using more advanced approaches have now demonstrated that specific proteins encoded by EBV could contribute to the immune and neurological abnormalities exhibited by a subgroup of patients with ME/CFS. Elucidating the role of these herpesvirus proteins in ME/CFS may lead to the identification of specific biomarkers and the development of novel therapeutics.

Source: Ariza ME. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Human Herpesviruses Are Back! Biomolecules. 2021 Jan 29;11(2):185. doi: 10.3390/biom11020185. PMID: 33572802. https://www.mdpi.com/2218-273X/11/2/185 (Full text)

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

Abstract:

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 Field The 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.

Source: Ji-Sook Lee, Eliana M. Lacerda, Luis Nacul, Caroline C. Kingdon, Jasmin Norris, Shennae O’Boyle, Chrissy H. Roberts, Luigi Palla, Eleanor M. Riley, Jacqueline M. Cliff. Salivary DNA loads for human herpes viruses 6 and 7 are correlated with disease phenotype in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome.
medRxiv 2021.01.06.20248486; doi: https://doi.org/10.1101/2021.01.06.20248486 https://www.medrxiv.org/content/10.1101/2021.01.06.20248486v1.full-text  (Full text)

Commentary: Antibodies to Human Herpesviruses in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients

Introduction: Studies to ascertain a possible relationship between herpesviruses and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have relied heavily on classical approaches, specifically, serological examination for antibodies against virus proteins, primarily structural, and/or increases in viral load (1–21). These data have been conflicting due in part to several features: the heterogeneity of the disease, high prevalence of the herpesviruses in the population since they can establish lifelong infections, and differences between laboratories. Two additional problems lead to conflicting data in serological studies: which viral antigens are to be used for detection, and what is the possible relationship, if any, of these viral antigens to ME/CFS? These are important questions that must be addressed for any data to provide meaningful insight into the possible contribution of a virus to the pathophysiology of ME/CFS. Although the experimental techniques used in Blomberg’s serological study were appropriate, the selection of specific herpesviruses and viral antigens studied gives a limited view of the humoral response in ME/CFS.

Discussion: Blomberg et al. (22) used a suspension multiplex immunoassay to detect antibodies against various herpesviruses’ antigens, derived from proteins expressed during latency or late lytic replication (Figure 1), with the goal of determining differences in antibody titers against these antigens between ME/CFS patients and controls. However, no rationale was given as to why these particular antigens were chosen and what association, if any, they may have with ME/CFS. This is important because the antigenic properties of the different virus proteins are not the same. As demonstrated in an eloquent study by Vaider-Shalt et al. (23), over the course of their evolution, herpes simplex virus 1 (HSV-1), Epstein-Barr virus (EBV), human herpesvirus 8 (HHV-8), and human cytomegalovirus have decreased the number of epitopes present in virus proteins in order to help them avoid immune detection. Thus, the ability of a virus protein to generate an antibody response is dependent upon the amount of protein present in the host and its antigenicity. It is also not clear why Blomberg et al. (22) included HSV-1/2, human cytomegalovirus, HHV-7, and varicella zoster virus (VZV) in their study since there are no up-to-date literature reports establishing a serological relationship between these viruses and ME/CFS.

Source: Ariza ME. Commentary: Antibodies to Human Herpesviruses in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. Front Immunol. 2020;11:1400. Published 2020 Jul 23. doi:10.3389/fimmu.2020.01400 https://www.frontiersin.org/articles/10.3389/fimmu.2020.01400/full (Full text)

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome as a Hyper-Regulated Immune System Driven by an Interplay Between Regulatory T Cells and Chronic Human Herpesvirus Infections

Abstract:

Autoimmunity and chronic viral infections are recurrent clinical observations in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a complex disease with an unknown cause. Given these observations, the regulatory CD4+ T cells (Tregs) show promise to be good candidates for the underlying pathology due to their capacity to suppress the immune responses against both self and microbial antigens. Here, we discussed the overlooked role of these cells in the chronicity of Human Herpes Virus 6 (HHV6), Herpes Simplex 1 (HSV1), and Epstein-Barr virus (EBV), as often reported as triggers of ME/CFS.

Using simulations of the cross-regulation model for the dynamics of Tregs, we illustrated that mild infections might lead to a chronically activated immune responses under control of Tregs if the responding clone has a high autoimmune potential. Such infections promote persistent inflammation and possibly fatigue. We then hypothesized that ME/CFS is a condition characterized by a predominance of this type of infections under control of Tregs. In contrast, healthy individuals are hypothesized to trigger immune responses of a virus-specific clone with a low autoimmune potential.

According to this hypothesis, simple model simulations of the CD4+ T-cell repertoire could reproduce the increased density and percentages of Tregs observed in patients suffering from the disease, when compared to healthy controls. A deeper analysis of Tregs in the pathogenesis of ME/CFS will help to assess the validity of this hypothesis.

Copyright © 2019 Sepúlveda, Carneiro, Lacerda and Nacul.

Source: Sepúlveda N, Carneiro J, Lacerda E, Nacul L. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome as a Hyper-Regulated Immune System Driven by an Interplay Between Regulatory T Cells and Chronic Human Herpesvirus Infections. Front Immunol. 2019 Nov 21;10:2684. doi: 10.3389/fimmu.2019.02684. eCollection 2019. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883905/ (Full article)