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Periodontology 2000 Feb 2024Localized juvenile (aggressive) periodontitis starts at puberty in otherwise healthy individuals and involves the proximal surfaces of permanent incisors and first... (Review)
Review
Localized juvenile (aggressive) periodontitis starts at puberty in otherwise healthy individuals and involves the proximal surfaces of permanent incisors and first molars. The disease destroys a sizeable amount of periodontal bone within a few months despite minimal dental plaque and gingival tissue inflammation. Cytomegalovirus and Epstein-Barr virus, as well as the two main periodontopathic bacteria Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis, are linked to juvenile periodontitis. Juvenile periodontitis-affected teeth show cementum hypoplasia. We hypothesize that an active herpesvirus infection, at the time of root formation, hampers cementum formation and, at puberty, herpesvirus reactivation triggers an upgrowth of bacterial pathogens which produce rapid periodontal destruction on teeth with a defective periodontium. A pathogenic interaction between active herpesviruses and bacterial pathogens can potentially explain the etiology and incisor-first molar destructive pattern of juvenile periodontitis. Effective treatment of juvenile periodontitis may target the herpesvirus-bacteria co-infection.
Topics: Humans; Aggressive Periodontitis; Aggregatibacter actinomycetemcomitans; Porphyromonas gingivalis; Coinfection; Cytomegalovirus; Herpesviridae Infections; Herpesviridae; Herpesvirus 4, Human
PubMed: 37345343
DOI: 10.1111/prd.12501 -
PloS One 2023Dippity Pig Syndrome (DPS) is a well-known but rare complex of clinical signs affecting minipigs, which has not been thoroughly investigated yet. Clinically affected...
Dippity Pig Syndrome (DPS) is a well-known but rare complex of clinical signs affecting minipigs, which has not been thoroughly investigated yet. Clinically affected animals show acute appearance of red, exudating lesions across the spine. The lesions are painful, evidenced by arching of the back (dipping), and the onset of clinical signs is generally sudden. In order to understand the pathogenesis, histological and virological investigations were performed in affected and unaffected Göttingen Minipigs (GöMPs). The following DNA viruses were screened for using PCR-based methods: Porcine cytomegalovirus (PCMV), which is a porcine roseolovirus (PCMV/PRV), porcine lymphotropic herpesviruses (PLHV-1, PLHV-2, PLHV-3), porcine circoviruses (PCV1, PCV2, PCV3, PCV4), porcine parvovirus 1 (PPV1), and Torque Teno sus viruses (TTSuV1, TTSuV2). Screening was also performed for integrated porcine endogenous retroviruses (PERV-A, PERV-B, PERV-C) and recombinant PERV-A/C and their expression as well as for the RNA viruses hepatitis E virus (HEV) and SARS-CoV-2. Eight clinically affected and one unaffected GöMPs were analyzed. Additional unaffected minipigs had been analyzed in the past. The analyzed GöMPs contained PERV-A and PERV-B integrated in the genome, which are present in all pigs and PERV-C, which is present in most, but not all pigs. In one affected GöMPs recombinant PERV-A/C was detected in blood. In this animal a very high expression of PERV mRNA was observed. PCMV/PRV was found in three affected animals, PCV1 was found in three animals with DPS and in the unaffected minipig, and PCV3 was detected in two animals with DPS and in the unaffected minipig. Most importantly, in one animal only PLHV-3 was detected. It was found in the affected and unaffected skin, and in other organs. Unfortunately, PLHV-3 could not be studied in all other affected minipigs. None of the other viruses were detected and using electron microscopy, no virus particles were found in the affected skin. No porcine virus RNA with exception of PERV and astrovirus RNA were detected in the affected skin by next generation sequencing. This data identified some virus infections in GöMPs with DPS and assign a special role to PLHV-3. Since PCMV/PRV, PCV1, PCV3 and PLHV-3 were also found in unaffected animals, a multifactorial cause of DPS is suggested. However, elimination of the viruses from GöMPs may prevent DPS.
Topics: Swine; Animals; Swine, Miniature; Transplantation, Heterologous; Endogenous Retroviruses; COVID-19; SARS-CoV-2; Betaherpesvirinae
PubMed: 37319233
DOI: 10.1371/journal.pone.0281521 -
International Journal of Oncology Nov 2023Colorectal cancer (CRC) is one of the most common and fatal types of cancer. Inflammation promotes CRC development, however, the underlying etiological factors are...
Colorectal cancer (CRC) is one of the most common and fatal types of cancer. Inflammation promotes CRC development, however, the underlying etiological factors are unknown. Human cytomegalovirus (HCMV), a virus that induces inflammation and other cancer hallmarks, has been detected in several types of malignancy, including CRC. The present study investigated whether HCMV infection was associated with expression of the pro‑inflammatory enzymes 5‑lipoxygenase (5‑LO) and cyclooxygenase‑2 (COX‑2) and other molecular, genetic and clinicopathological CRC features. The present study assessed 146 individual paraffin‑embedded CRC tissue microarray (TMA) cores already characterized for TP53 and KRAS mutations, microsatellite instability (MSI) status, Ki‑67 index and EGFR by immunohistochemistry (IHC). The cores were further analyzed by IHC for the expression of two HCMV proteins (Immediate Early, IE and pp65) and the inflammatory markers 5‑LO and COX‑2. The CRC cell lines Caco‑2 and LS‑174T were infected with HCMV strain VR1814, treated with antiviral drug ganciclovir (GCV) and/or anti‑inflammatory drug celecoxib (CCX) and analyzed by reverse transcription‑quantitative PCR and immunofluorescence for 5‑LO, COX‑2, IE and pp65 transcripts and proteins. HCMV IE and pp65 proteins were detected in ~90% of the CRC cases tested; this was correlated with COX‑2, 5‑LO and KI‑67 expression, but not with EGFR immunostaining, TP53 and KRAS mutations or MSI status. , HCMV infection upregulated 5‑LO and COX‑2 transcript and proteins in both Caco‑2 and LS‑174T cells and enhanced cell proliferation as determined by MTT assay. Treatment with GCV and CCX significantly decreased the transcript levels of COX‑2, 5‑LO, HCMV IE and pp65 in infected cells. HCMV was widely expressed in CRC and may promote inflammation and serve as a potential new target for CRC therapy.
Topics: Humans; Arachidonate 5-Lipoxygenase; Caco-2 Cells; Cyclooxygenase 2; Ki-67 Antigen; Proto-Oncogene Proteins p21(ras); Celecoxib; Cytomegalovirus; Ganciclovir; Cytomegalovirus Infections; Colorectal Neoplasms; ErbB Receptors
PubMed: 37654195
DOI: 10.3892/ijo.2023.5564 -
Science Advances Nov 2023Circulating senescent CD8 T (Tsen) cells are characterized by a lack of proliferative capacities but retain cytotoxic activity and have been associated to resistance to...
Circulating senescent CD8 T (Tsen) cells are characterized by a lack of proliferative capacities but retain cytotoxic activity and have been associated to resistance to immunotherapy in patients with advanced non-small cell lung cancer (aNSCLC). We aimed to better characterize Tsen and to determine which factors were associated with their accumulation in patients with aNSCLC. Circulating Tsen cells were characterized by a higher expression of SA-βgal and the transcription factor T-bet, confirming their senescent status. Using whole virome profiling, cytomegalovirus (CMV) was the only virus associated with Tsen. CMV was necessary but not sufficient to explain high accumulation of Tsen (Tsen status). In CMV patients, the proportion of Tsen cells increased with cancer progression. Last, CMV-induced Tsen phenotype but not CMV seropositivity itself was associated with worse progression-free and overall survival in patients treated with anti-PD-(L)1 therapy but not with chemotherapy. Overall, CMV is the unique viral driver of Tsen-driven resistance to anti-PD-(L)1 antibodies in patients with aNSCLC.
Topics: Humans; Cytomegalovirus; CD8-Positive T-Lymphocytes; Carcinoma, Non-Small-Cell Lung; Cytomegalovirus Infections; Virome; Lung Neoplasms
PubMed: 37939189
DOI: 10.1126/sciadv.adh0708 -
Viruses Dec 2023Human cytomegalovirus (HCMV) is linked to age-related diseases like cardiovascular disease, neurodegenerative conditions, and cancer. It can also cause congenital...
Human cytomegalovirus (HCMV) is linked to age-related diseases like cardiovascular disease, neurodegenerative conditions, and cancer. It can also cause congenital defects and severe illness in immunocompromised individuals. Accurate HCMV seroprevalence assessment is essential for public health planning and identifying at-risk individuals. This is the first HCMV seroprevalence study conducted in the general Spanish adult population in 30 years. We studied HCMV seroprevalence and HCMV IgG antibody titres in healthy adult donors (HDs) and HCMV-related disease patients from 2010 to 2013 and 2020 to 2023, categorized by sex and age. We compared our data with 1993 and 1999 studies in Spain. The current HCMV seroprevalence among HDs in Spain is 73.48%. In women of childbearing age, HCMV seroprevalence has increased 1.4-fold in the last decade. HCMV-seropositive individuals comprise 89.83% of CVD patients, 69% of SMI patients, and 70.37% of COVID-19 patients. No differences in HCMV seroprevalence or HCMV IgG antibody titres were observed between patients and HDs. A significant reduction in Spanish HCMV seroprevalence among HDs was observed in 1993. However, women of childbearing age have shown an upturn in the last decade that may denote a health risk in newborns and a change in HCMV seroprevalence trends.
Topics: Adult; Humans; Infant, Newborn; Female; Cytomegalovirus; Cytomegalovirus Infections; Seroepidemiologic Studies; Tissue Donors; Antibodies, Viral; Immunoglobulin G; Cardiovascular Diseases
PubMed: 38275940
DOI: 10.3390/v16010006 -
The Journal of Infectious Diseases Aug 2023Cytomegalovirus (CMV) infection is a major driver of accelerated immunosenescence related to CD28null T cell expansion. CMV infection and these proatherogenic T cells...
Cytomegalovirus (CMV) infection is a major driver of accelerated immunosenescence related to CD28null T cell expansion. CMV infection and these proatherogenic T cells have been independently associated with cardiovascular disease and coronavirus disease 2019 (COVID-19) severity. We investigated the potential contribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to immunosenescence and its relationship with CMV. Innate and adaptive immune subpopulations from individuals with mild or asymptomatic SARS-CoV-2 infection (mCOVID-19) and healthy donors were immunophenotyped. A significant increase in CD28nullCD57+CX3CR1+ T cell percentages (CD4+ [P ≤ .01], CD8+ [P ≤ .01], and TcRγδ (CD4-CD8-) [P ≤ .001]) was found in unnvaccinated CMV-seropositive mCOVID-19 individuals stable up to 12 months after infection. This expansion did not occur in CMV-seronegative mCOVID-19 individuals or in CMV-seropositive individuals infected after SARS-CoV-2 vaccination. There were no significant differences between mCOVID-19 and aortic stenosis groups. Thus, individuals coinfected with SARS-CoV-2 and CMV have accelerated T cell senescence, which might lead to an increased risk of cardiovascular disease.
Topics: Humans; Cytomegalovirus; T-Lymphocytes; Immunosenescence; COVID-19; Cardiovascular Diseases; COVID-19 Vaccines; SARS-CoV-2; Cytomegalovirus Infections; CD8-Positive T-Lymphocytes
PubMed: 37103009
DOI: 10.1093/infdis/jiad119 -
Nature Communications Nov 2023Immunological memory is a hallmark of the adaptive immune system. Although natural killer (NK) cells are innate immune cells important for the immediate host defence,...
Immunological memory is a hallmark of the adaptive immune system. Although natural killer (NK) cells are innate immune cells important for the immediate host defence, they can differentiate into memory NK cells. The molecular mechanisms controlling this differentiation are yet to be fully elucidated. Here we identify the scaffold protein Themis2 as a critical regulator of memory NK cell differentiation and function. Themis2-deficient NK cells expressing Ly49H, an activating NK receptor for the mouse cytomegalovirus (MCMV) antigen m157, show enhanced differentiation into memory NK cells and augment host protection against MCMV infection. Themis2 inhibits the effector function of NK cells after stimulation of Ly49H and multiple activating NK receptors, though not specific to memory NK cells. Mechanistically, Themis2 suppresses Ly49H signalling by attenuating ZAP70/Syk phosphorylation, and it also translocates to the nucleus, where it promotes Zfp740-mediated repression to regulate the persistence of memory NK cells. Zfp740 deficiency increases the number of memory NK cells and enhances the effector function of memory NK cells, which further supports the relevance of the Themis2-Zfp740 pathway. In conclusion, our study shows that Themis2 quantitatively and qualitatively regulates NK cell memory formation.
Topics: Animals; Mice; Antigens, Viral; Cell Differentiation; Cytomegalovirus; Killer Cells, Natural; Muromegalovirus; Phosphorylation
PubMed: 37938555
DOI: 10.1038/s41467-023-42578-8 -
Proceedings of the National Academy of... Jul 2023Human cytomegalovirus (CMV) has infected humans since the origin of our species and currently infects most of the world's population. Variability between CMV genomes is...
Human cytomegalovirus (CMV) has infected humans since the origin of our species and currently infects most of the world's population. Variability between CMV genomes is the highest of any human herpesvirus, yet large portions of the genome are conserved. Here, we show that the genome encodes 74 regions of relatively high variability each with 2 to 8 alleles. We then identified two patterns in the CMV genome. Conserved parts of the genome and a minority (32) of variable regions show geographic population structure with evidence for African or European clustering, although hybrid strains are present. We find no evidence that geographic segregation has been driven by host immune pressure affecting known antigenic sites. Forty-two variable regions show no geographical structure, with similar allele distributions across different continental populations. These "nongeographical" regions are significantly enriched for genes encoding immunomodulatory functions suggesting a core functional importance. We hypothesize that at least two CMV founder populations account for the geographical differences that are largely seen in the conserved portions of the genome, although the timing of separation and direction of spread between the two are not clear. In contrast, the similar allele frequencies among 42 variable regions of the genome, irrespective of geographical origin, are indicative of a second evolutionary process, namely balancing selection that may preserve properties critical to CMV biological function. Given that genetic differences between CMVs are postulated to alter immunogenicity and potentially function, understanding these two evolutionary processes could contribute important information for the development of globally effective vaccines and the identification of novel drug targets.
Topics: Humans; Cytomegalovirus; Cytomegalovirus Infections; Gene Frequency; Genomics
PubMed: 37459519
DOI: 10.1073/pnas.2221797120 -
Frontiers in Cellular and Infection... 2023Cancer is one of the leading causes of death worldwide. Human cytomegalovirus (HCMV), a well-studied herpesvirus, has been implicated in malignancies derived from... (Review)
Review
Cancer is one of the leading causes of death worldwide. Human cytomegalovirus (HCMV), a well-studied herpesvirus, has been implicated in malignancies derived from breast, colorectal muscle, brain, and other cancers. Intricate host-virus interactions are responsible for the cascade of events that have the potential to result in the transformed phenotype of normal cells. The HCMV genome contains oncogenes that may initiate these types of cancers, and although the primary HCMV infection is usually asymptomatic, the virus remains in the body in a latent or persistent form. Viral reactivation causes severe health issues in immune-compromised individuals, including cancer patients, organ transplants, and AIDS patients. This review focuses on the immunologic mechanisms and molecular mechanisms of HCMV-induced carcinogenesis, methods of HCMV treatment, and other studies. Studies show that HCMV DNA and virus-specific antibodies are present in many types of cancers, implicating HCMV as an important player in cancer progression. Importantly, many clinical trials have been initiated to exploit HCMV as a therapeutic target for the treatment of cancer, particularly in immunotherapy strategies in the treatment of breast cancer and glioblastoma patients. Taken together, these findings support a link between HCMV infections and cellular growth that develops into cancer. More importantly, HCMV is the leading cause of birth defects in newborns, and infection with HCMV is responsible for abortions in pregnant women.
Topics: Infant, Newborn; Pregnancy; Humans; Female; Cytomegalovirus; Cytomegalovirus Infections; Oncogenes; Neoplasms; Carcinogenesis
PubMed: 37424781
DOI: 10.3389/fcimb.2023.1202138 -
PLoS Pathogens Jun 2023Innate immune responses are crucial for limiting virus infection. However, viruses often hijack our best defenses for viral objectives. Human Cytomegalovirus (HCMV) is a...
Innate immune responses are crucial for limiting virus infection. However, viruses often hijack our best defenses for viral objectives. Human Cytomegalovirus (HCMV) is a beta herpesvirus which establishes a life-long latent infection. Defining the virus-host interactions controlling latency and reactivation is vital to the control of viral disease risk posed by virus reactivation. We defined an interaction between UL138, a pro-latency HCMV gene, and the host deubiquitinating complex, UAF1-USP1. UAF1 is a scaffold protein pivotal for the activity of ubiquitin specific peptidases (USP), including USP1. UAF1-USP1 sustains an innate immune response through the phosphorylation and activation of signal transducer and activator of transcription-1 (pSTAT1), as well as regulates the DNA damage response. After the onset of viral DNA synthesis, pSTAT1 levels are elevated in infection and this depends upon UL138 and USP1. pSTAT1 localizes to viral centers of replication, binds to the viral genome, and influences UL138 expression. Inhibition of USP1 results in a failure to establish latency, marked by increased viral genome replication and production of viral progeny. Inhibition of Jak-STAT signaling also results in increased viral genome synthesis in hematopoietic cells, consistent with a role for USP1-mediated regulation of STAT1 signaling in the establishment of latency. These findings demonstrate the importance of the UL138-UAF1-USP1 virus-host interaction in regulating HCMV latency establishment through the control of innate immune signaling. It will be important going forward to distinguish roles of UAF1-USP1 in regulating pSTAT1 relative to its role in the DNA damage response in HCMV infection.
Topics: Humans; Cytomegalovirus; Cytomegalovirus Infections; Virus Replication; Ubiquitin-Specific Proteases; Signal Transduction; Virus Latency; STAT1 Transcription Factor
PubMed: 37289831
DOI: 10.1371/journal.ppat.1011185