Figure - available from: Frontiers in Cellular and Infection Microbiology
This content is subject to copyright.
Schematic representation of the genomic intron/exon organization of human IL-10 and the HCMV IL-10s transcripts. Boxes and horizontal lines representing exons and introns were drawn to scale. The 39- and 59-UTRs of cellular IL-10 (GenBank accession no. NP_000563) are not shown. Colored boxes represent homologous exons. The first horizontal scale represents the position in the AD169 HCMV strain genome (GenBank accession number FJ527563.1). The second horizontal scale represents the length in base pairs (bp). Finally, the asterisks represent the position of the stop codons.
Source publication
Human Cytomegalovirus (HCMV) can cause a variety of health disorders that can lead to death in immunocompromised individuals and neonates. The HCMV lifecycle comprises both a lytic (productive) and a latent (non-productive) phase. HCMV lytic infection occurs in a wide range of terminally differentiated cell types. HCMV latency has been less well-st...
Similar publications
Oral squamous cell carcinoma (OSCC) is the most encountered type of oral malignant neoplasm. P27 is a nuclear cell cycle inhibitory protein, that can be transported to the cytoplasm to deactivate it's role, Similarly the mechanism is used by cancer cells to unlock cell cycle arrest. In reaction to damage to DNA caused, either by the cell cycle arre...
Citations
... It is known to be a potent antiinflammatory and immunosuppressive cytokine [6]. IL-10 is produced by various immune cells, including dendritic cells, macrophages, B cells, and T cells [7]. IL-10 plays a crucial role in preventing inflammation-mediated tissue damage and is involved in the outcome of infections, allergies, autoimmune reactions, tumor development, and transplant tolerance [8]. ...
... For example, vIL-10 directly modulates the immune response [33] and the vIL-10-induced cellular IL-10 has been shown to contribute to the immune evasion microenvironment [34,35]. Additionally, vIL-10 mediates some aspects of cellular IL-10 signalling directly [36]. ...
Human cytomegalovirus (HCMV) infection can lead to either lytic or latent infection, which is dependent on the regulation of the viral major immediate early promoter (MIEP). Suppression of the MIEP is a pre-requisite for latency and is driven by repressive epigenetic modifications at the MIEP during latent infection. However, other viral genes are expressed during latency and this is correlated with activatory epigenetic modifications at latent gene promoters. Yet the molecular basis of the differential regulation of latent and lytic gene expression by epigenetics is unclear. LUNA, a latent viral transcript, has been suggested to be important for HCMV latency and has also been shown to be important for efficient reactivation likely through its known deSUMOylase activity. Intriguingly, we and others have also observed that LUNA enhances latency-associated expression of the viral UL138 gene. Here, we show that in the absence of LUNA, the expression of multiple latency-associated transcripts is reduced during latent infection, which is correlated with a lack of activatory marks at their promoters. Interestingly, we also show that LUNA interacts with the hematopoietic transcription factor GATA-2, which has previously been shown to bind to a number of latency-associated gene promoters, and that this interaction is dependent on the deSUMOylase domain of LUNA. Finally, we show that the deSUMOylase activity of LUNA is required for the establishment and/or maintenance of an open chromatin configuration around latency-associated gene promoters. As such, LUNA plays a key role in efficient latency-associated viral gene expression and carriage of viral genome during latent carriage.
... TGF-β inhibits the differentiation of Th22 from naïve CD4 + T cells [20,35]. Moreover, virus-encoded IL-10 homolog, capable of inducing host IL-10, synergizes with this process to make it worse and modulates the immune system [36,37]. IL-10 maintains the differentiation of monocytes to macrophages, a proper place for the proliferation of the virus, and up-regulates HCMV immediate-early genes to attenuate antiviral responses [38,39]. ...
Background
The immunity of CD4⁺ T cell subsets against human cytomegalovirus (HCMV) is considerable due to their essential role in controlling the infection in transplant individuals. Previously explained CD4⁺ subsets such as T helper (Th) 1 have been proven to have a protective role against HCMV infection, while the role of the recently identified Th22 subset has not been described yet. Here, the frequency changes of Th22 cells and the IL-22 cytokine production were investigated in kidney transplant recipients with and without HCMV infection.
Methods
Twenty kidney transplant patients and ten healthy controls were enrolled in this study. Patients were categorized into HCMV + and HCMV- groups based on the HCMV DNA real-time PCR results. After isolating CD4⁺ T cells from PBMCs, the phenotype (CCR6⁺CCR4⁺CCR10⁺) and cytokine profile (IFN-γ⁻IL-17⁻IL-22⁺) of Th22 cells were analyzed by flow cytometry. The gene expression of Aryl Hydrocarbon Receptor (AHR) transcription factor was analyzed by real-time PCR.
Results
The phenotype frequency of these cells was lower in recipients with infection than in those without infection and healthy controls (1.88 ± 0.51 vs. 4.31 ± 1.05; P = 0.03 and 4.22 ± 0.72; P = 0.01, respectively). A lower Th22 cytokine profile was observed in patients with infection than in the two other groups (0.18 ± 0.03 vs. 0.20 ± 0.03; P = 0.96 and 0.33 ± 0.05; P = 0.04, respectively). AHR expression was also lower in patients with active infection.
Conclusions
Overall, this study for the first time suggests that the reduced levels of Th22 subset and IL-22 cytokine in patients with active HCMV infection might indicate the protective role of these cells against HCMV.
... A third mechanism linking CMV reactivation to clinical outcomes is secondary immunosuppression. CMV is known to encode a viral homolog of the im-mune-suppressive cytokine IL-10, which can modulate the host's immune response and contribute to secondary immunosuppression in infected individuals [48]. Moreover, CMV can alter the expression of human leukocyte antigens, which play a crucial role in the immune system's ability to recognize and eliminate infected cells [49]. ...
Cytomegalovirus (CMV) reactivation has been linked to adverse clinical outcomes in critically ill patients, with emerging evidence suggesting a potential connection with severe COVID-19. Mechanisms driving this association may include primary lung injury, amplification of systemic inflammation, and secondary immunosuppression. Diagnostic challenges in detecting and assessing CMV reactivation necessitate a comprehensive approach to improve accuracy and inform treatment decisions. Currently, there is limited evidence on the efficacy and safety of CMV pharmacotherapy in critically ill COVID-19 patients. Although insights from non-COVID-19 critical illness studies suggest a potential role for antiviral treatment or prophylaxis, the risks and benefits must be carefully balanced in this vulnerable patient population. Understanding the pathophysiological role of CMV in the context of COVID-19 and exploring the advantages of antiviral treatment are crucial for optimizing care in critically ill patients. This review provides a comprehensive synthesis of available evidence, emphasizing the need for additional investigation to establish the role of CMV treatment or prophylaxis in the management of severe COVID-19 and to develop a framework for future research on this topic.
... The reason for this observation is unclear, but the authors proposed that it could be related to different immunologic compartmentalization of each of the latent viruses. For example, they suggested that CMVassociated immunoregulatory pathways could decrease inflammation and modulate other potential pathophysiologic mechanisms (e.g., autoantibody formation) (132). In addition, they speculated that CMV seropositivity could be associated with heightened adaptive immune responses as it is with regard to influenza vaccination (133). ...
Although most individuals recover from acute SARS-CoV-2 infection, a significant number continue to suffer from Post-Acute Sequelae of SARS-CoV-2 (PASC), including the unexplained symptoms that are frequently referred to as long COVID, which could last for weeks, months, or even years after the acute phase of illness. The National Institutes of Health is currently funding large multi-center research programs as part of its Researching COVID to Enhance Recover (RECOVER) initiative to understand why some individuals do not recover fully from COVID-19. Several ongoing pathobiology studies have provided clues to potential mechanisms contributing to this condition. These include persistence of SARS-CoV-2 antigen and/or genetic material, immune dysregulation, reactivation of other latent viral infections, microvascular dysfunction, and gut dysbiosis, among others. Although our understanding of the causes of long COVID remains incomplete, these early pathophysiologic studies suggest biological pathways that could be targeted in therapeutic trials that aim to ameliorate symptoms. Repurposed medicines and novel therapeutics deserve formal testing in clinical trial settings prior to adoption. While we endorse clinical trials, especially those that prioritize inclusion of the diverse populations most affected by COVID-19 and long COVID, we discourage off-label experimentation in uncontrolled and/or unsupervised settings. Here, we review ongoing, planned, and potential future therapeutic interventions for long COVID based on the current understanding of the pathobiological processes underlying this condition. We focus on clinical, pharmacological, and feasibility data, with the goal of informing future interventional research studies.
... For example, CMV seropositivity in younger adults is actually associated with heightened adaptive immune responses to influenza vaccination (48), despite earlier studies in the aging literature linking CMV to immunosenescence phenotypes (49). Alternatively, CMV-induced immunoregulatory pathways, including secretion of its own viral IL-10, might dampen local inflammation in areas of CMV reactivation, decreasing the risk of autoantibody formation (to the extent that autoantibodies may contribute to the risk of neurologic LC symptoms) (50,51). It is also unclear whether these associations reflect a direct causal effect of CMV on LC risk or host factors that affect the risk of CMV infection and LC independently. ...
BACKGROUND. The presence and reactivation of chronic viral infections, such as EBV, CMV, and HIV, have been proposed as potential contributors to long COVID (LC), but studies in well-characterized postacute cohorts of individuals with COVID-19 over a longer time course consistent with current case definitions of LC are limited.
METHODS. In a cohort of 280 adults with prior SARS-CoV-2 infection, we assessed the presence and types of LC symptoms and prior medical history (including COVID-19 history and HIV status) and performed serological testing for EBV and CMV using a commercial laboratory. We used covariate-adjusted binary logistic regression models to identify independent associations between variables and LC symptoms.
RESULTS. We observed that LC symptoms, such as fatigue and neurocognitive dysfunction, at a median of 4 months following initial diagnosis were independently associated with serological evidence suggesting recent EBV reactivation (early antigen–diffuse IgG positivity) or high nuclear antigen (EBNA) IgG levels but not with ongoing EBV viremia. Serological evidence suggesting recent EBV reactivation (early antigen–diffuse IgG positivity) was most strongly associated with fatigue (OR = 2.12). Underlying HIV infection was also independently associated with neurocognitive LC (OR = 2.5). Interestingly, participants who had serologic evidence of prior CMV infection were less likely to develop neurocognitive LC (OR = 0.52).
CONCLUSION. Overall, these findings suggest differential effects of chronic viral coinfections on the likelihood of developing LC and association with distinct syndromic patterns. Further assessment during the acute phase of COVID-19 is warranted.
... HCMV also expresses several different isoforms of a homologue of IL-10 (which is not affected by pUL11). These cmvIL-10 proteins exert immunosuppressive functions via their interactions with the IL-10 receptor and are expressed during both lytic and latent infections, indicating the importance of this pathway for the virus (73). IL-10-producing CD4 T cells that are specific for both latently and lytically expressed proteins have been described in blood and mucosal tissue samples from HCMV seropositive individuals, with the secreted IL-10 having the ability to inhibit polyclonal T cell proliferation (8,22,74). ...
Human cytomegalovirus (HCMV) encodes numerous immunomodulatory genes that facilitate its persistence. Previously described mechanisms by which HCMV avoids T cell control typically involve evasion of detection by infected cells. Here, we show that the virus also inhibits T cells directly via an interaction between the pUL11 glycoprotein on infected cells and the CD45 phosphatase on T cells. The antiviral functions of CD4 T cells are impaired as a result of this interaction, largely via induced interleukin 10 (IL-10) secretion in the CD4 T cell central memory compartment, resulting in enhanced viral spread. This establishes CD45 as an inhibitory receptor that regulates antiviral T cell functions and has parallels with the manipulation of natural killer (NK) cells by HCMV. By coculturing donor T cells with HCMV-infected epithelial cells, we observed that CD4 T cells can respond to epithelial cell antigen presentation and can control HCMV spread via cytolytic and cytokine-dependent mechanisms. pUL11 impairs both mechanisms. We showed that pUL11-induced IL-10 secretion requires IL-2, mTOR, and T cell receptor signaling. This characterization of the effects of the pUL11-CD45 interaction may allow for the development of new antiviral therapies and treatments for inflammatory disorders. IMPORTANCE Human cytomegalovirus (HCMV) is adept at avoiding its host's immune defenses, both by evading detection and by directly inhibiting immune cells. This can lead to a loss of control of the infection, and dangerous disease can result, particularly in cases in which an individual's immune system is immature, weak, or suppressed. T cells form a crucial part of the response to HCMV and are used in cellular HCMV therapies. We show that an interaction between a viral glycoprotein (pUL11) and a T cell surface receptor (CD45) impairs T cell memory functions and allows for increased viral spread. This defines a new immunomodulatory strategy for the virus as well as a new T cell regulatory mechanism. These results are important, as they increase our understanding of how T cells function and how HCMV disrupts them. This will allow for the development of new antiviral therapies that restore T cell functions and indicates a new target for controlling pathological T cell disorders.
... These interactions trigger the induction of STAT3 signalling via the phosphorylation of the cytoplasmic tails of IL-10R1 and IL-10R2 by JAK1 and Tyk2, respectively [53]. Regarding the HCMV IL-10 proteins, cmvIL-10 encoded by transcript A is the characterized the best characterized [54], and the only isoform with a reported crystal structure (Jones et al, 2002). cmvIL-10 binds to the receptor (IL-10R1) with the same affinity as cIL-10, inducing signalling that closely resembles that of cIL-10, despite low amino acid sequence identity between the two homologs (27%). ...
The human cytomegalovirus (HCMV) UL111A gene encodes several homologs of the cellular interleukin 10 (cIL-10). Alternative splicing in the UL111A region produces two relatively well-characterized transcripts designated cmvIL-10 (isoform A) and LAcmvIL-10 (isoform B). The cmvIL-10 protein is the best characterized, both structurally and functionally, and has many immunosuppressive activities similar to cIL-10, while LAcmvIL-10 has more restricted biological activities. Alternative splicing also results in five less studied UL111A transcripts encoding additional proteins homologous to cIL-10 (isoforms C to G). These transcripts were identified during productive HCMV infection of MRC-5 cells with the high passage laboratory adapted AD169 strain, and the structure and properties of the corresponding proteins are largely unknown. Moreover, it is unclear whether these protein isoforms are able to bind the cellular IL-10 receptor and induce signalling. In the present study, we investigated the expression spectrum of UL111A transcripts in fully permissive MRC-5 cells and semi permissive U251 cells infected with the low passage HCMV strain TB40E. We identified a new spliced transcript (H) expressed during productive infection. Using computational methods, we carried out molecular modelling studies on the three-dimensional structures of the HCMV IL-10 proteins encoded by the transcripts detected in our work (cmvIL-10 (A), LAcmvIL-10 (B), E, F and H) and on their interaction with the human IL-10 receptor (IL-10R1). The modelling predicts clear differences between the isoform structures. Furthermore, the in silico simulations (molecular dynamics simulation and normal-mode analyses) allowed us to evaluate regions that contain potential receptor binding sites in each isoform. The analyses demonstrate that the complexes between the isoforms and IL-10R1 present different types of molecular interactions and consequently different affinities and stabilities. The knowledge about structure and expression of specific viral IL-10 isoforms has implications for understanding of their properties and role in HCMV immune evasion and pathogenesis.
... hCMV has developed various mechanisms to evade the immune response, including modulation of cytokine response [28,69,76,77]. The main one uses a CMV homolog of IL-10 to reduce the immune response [76]. ...
... hCMV has developed various mechanisms to evade the immune response, including modulation of cytokine response [28,69,76,77]. The main one uses a CMV homolog of IL-10 to reduce the immune response [76]. CMV also encodes homologs of cytokine receptors, binding RANTES, e.g., which contribute to anti-inflammatory evasion [78]. ...
Background:
Congenital cytomegalovirus (cCMV) infection is frequent and potentially severe. The immunobiology of cCMV infection is poorly understood, involving cytokines that could be carried within or on the surface of extracellular vesicles (EV). We investigated intra-amniotic cytokines, mediated or not by EV, in cCMV infection.
Methods:
Forty infected fetuses following early maternal primary infection and forty negative controls were included. Infected fetuses were classified according to severity at birth: asymptomatic, moderately or severely symptomatic. Following the capture of EV in amniotic fluid (AF), the concentrations of 38 cytokines were quantified. The association with infection and its severity was determined using univariate and multivariate analysis. A prediction analysis based on principal component analysis was conducted.
Results:
cCMV infection was nominally associated with an increase in six cytokines, mainly soluble (IP-10, IL-18, ITAC, and TRAIL). EV-associated IP-10 was also increased in cases of fetal infection. Severity of fetal infection was nominally associated with an increase in twelve cytokines, including five also associated with fetal infection. A pattern of specific increase in six proteins fitted severely symptomatic infection, including IL-18soluble, TRAILsoluble, CRPsoluble, TRAILsurface, MIGinternal, and RANTESinternal.
Conclusion:
Fetal infection and its severity are associated with an increase in pro-inflammatory cytokines involved in Th1 immune response.
... UL111A is an HCMV viral gene that is expressed in lytic and latent phases. Alternate splicing of the transcript gives rise to several isoforms of a homolog to human IL-10 (cmvIL-10) (Poole et al. 2020). IL-10 is a cytokine that provides regulatory feedback to immune activation. ...
Human cytomegalovirus (HCMV) is a major modulator of the immune system leading to long-term changes in T-lymphocytes, macrophages, and natural killer (NK) cells among others. Perhaps because of this immunomodulatory capacity, HCMV infection has been linked with a host of deleterious effects including accelerated immune aging (premature mortality, increased expression of immunosenescence-linked markers, telomere shortening, speeding-up of epigenetic "clocks"), decreased vaccine immunogenicity, and greater vulnerability to infectious diseases (e.g., tuberculosis) or infectious disease-associated pathology (e.g., HIV). Perhaps not surprisingly given the long co-evolution between HCMV and humans, the virus has also been associated with beneficial effects, such as increased vaccine responsiveness, heterologous protection against infections, and protection against relapse in the context of leukemia. Here, we provide an overview of this literature. Ultimately, we focus on one other deleterious effect of HCMV, namely the emerging literature suggesting that HCMV plays a pathophysiological role in psychiatric illness, particularly depression and schizophrenia. We discuss this literature through the lens of psychological stress and inflammation, two well-established risk factors for psychiatric illness that are also known to predispose to reactivation of HCMV.
