Tree Shrew Is a Suitable Animal Model for the Study of Epstein Barr Virus

Epstein-Barr virus (EBV) is a human herpesvirus that latently infects approximately 95% of adults and is associated with a spectrum of human diseases including Infectious Mononucleosis and a variety of malignancies. However, understanding the pathogenesis, vaccines and antiviral drugs for EBV-associated disease has been hampered by the lack of suitable animal models. Tree shrew is a novel laboratory animal with a close phylogenetic relationship to primates, which is a critical advantage for many animal models for human disease, especially viral infections. Herein, we first identified the key residues in the CR2 receptor that bind the gp350 protein and facilitate viral entry. We found that tree shrew shares 100% sequence identity with humans in these residues, which is much higher than rabbits (50%) and rats (25%). In vitro analysis showed that B lymphocytes of tree shrews are susceptible to EBV infection and replication, as well as EBV-enhanced cell proliferation. Moreover, results of in vivo experiments show that EBV infection in tree shrews resembles EBV infection in humans. The infected animals exhibited transient fever and loss of weight accompanied by neutropenia and high viremia levels during the acute phase of the viral infection. Thereafter, tree shrews acted as asymptomatic carriers of the virus in most cases that EBV-related protein could be detected in blood and tissues. However, a resurgence of EBV infection occurred at 49 dpi. Nanopore transcriptomic sequencing of peripheral blood in EBV-infected animals revealed the dynamic changes in biological processes occurring during EBV primary infection. Importantly, we find that neutrophil function was impaired in tree shrew model as well as human Infectious Mononucleosis datasets (GSE85599 and GSE45918). In addition, retrospective case reviews suggested that neutropenia may play an important role in EBV escaping host innate immune response, leading to long-term latent infection. Our findings demonstrated that tree shrew is a suitable animal model to evaluate the mechanisms of EBV infection, and for developing vaccines and therapeutic drugs against EBV.

Clinical Characteristics and the Risk Factors of Hepatic Injury in 221 Children With Infectious Mononucleosis

Background: Infectious mononucleosis caused by Epstein-Barr Virus infection is a common acute infectious disease in children. About 40–80% of children with infectious mononucleosis have hepatic injury, and hepatic failure is one of the main causes of death in patients with fatal infectious mononucleosis. Identifying the demographics, presenting clinical characteristics and the risk factors of hepatic injury in infectious mononucleosis children are helpful to remind clinicians which patients are prone to have hepatic damage.Methods: A descriptive, cross-sectional study with a 31-month retrospective review was performed on all infectious mononucleosis children hospitalized in the pediatric department of Fuyang People's Hospital. Demographic data, presenting features, radiology imaging, clinical and laboratory parameters, and clinical outcomes of infectious mononucleosis children were collected.Results: Two-hundred twenty-one infectious mononucleosis inpatients were enrolled, and 43.9% (97/221) patients were considered to have a hepatic injury (defined as alanine amino transaminase > 40 U/L). Compared with patients without hepatic injury, hepatic injury patients were marked with a significantly higher percentage of hepatomegaly (31 vs. 49%), splenomegaly (58 vs. 81%) and palpebral edema (47 vs. 63%), higher age (3.05 ± 2.12 vs. 3.84 ± 2.44), hospitalization days (6.85 ± 2.64 vs. 8.08 ± 2.83), leukocyte (14.24 ± 5.32 vs. 18.53 ± 8.63), lymphocytes (9.48 ± 4.49 vs. 13.80 ± 7.47), the proportion of atypical lymphocytes (0.12 ± 0.07 vs. 0.15 ± 0.08) and aspartate aminotransferase (33.71 ± 10.94 vs. 107.82 ± 93.52). The results of correlation analysis and multiple linear regression analysis indicated that age (OR = 1.185; 95% CI = 1.035–1.357, p = 0.014), female (OR = 2.002, 95% CI: 0.261–0.955, p = 0.036) and splenomegaly (OR = 2.171, 95% CI: 1.018–4.628, p = 0.045) were independent risk factors of hepatic injury.Conclusions: In this study, the hepatic injury was associated with gender, age, and splenomegaly, which improved our understanding of risk factors about hepatic injury among infectious mononucleosis children.

Childcare attendance and risk of infectious mononucleosis: A population-based Danish cohort study

Background The risk of infectious mononucleosis (IM) is affected both by crowding and by sibship structure, i.e., number and signed age differential between an index child and a sibling. Siblings provide protection against IM by pre-empting delayed primary Epstein-Barr virus infection with its associated high risk of IM. The association between childcare attendance and risk of IM, on the other hand, has never been studied in a large, well-characterized cohort. Methods Danish children born in July 1992 through 2016 with a completely known simple childcare attendance history before age 1.5 years (n = 908,866) were followed up for a hospital contact with an IM diagnosis at ages 1.5–26 years. Hazard ratios (HRs) of IM for an additional year of exposure were obtained from stratified Cox regression analyses, stratified by sex and year of birth, with age as the underlying time scale, adjusted for sibship structure, and sociodemographic variables including parental ethnicity and maternal age. Results An additional year of exclusively attending a daycare home (max 5 children) yielded HR = 0.90 (95% confidence interval 0.81–1.00), and similarly, each year of exclusively attending a childcare institution (e.g., crèche) yielded HR = 0.94 (0.84–1.06). Conclusions Forwarding enrollment in childcare by a year lowers the risk of IM later in life much less than having an additional sibling of comparable age and has no practical public health implications. We find our results suggestive of a random threshold for successful Epstein-Barr virus infection that is more easily reached by a sibling than the collective of playmates in daycare homes or childcare institutions.

Structural and functional state of blood lymphocytes in patients with infectious mononucleosis with different course

The article presents the results of our own studies. The aim was to determine the structural and functional status of blood lymphocytes in patients with acute and prolonged course of infectious mononucleosis (IM) in children. Materials and methods. 102 children were under clinical and laboratory-instrumental supervision, the children were divided into groups: group 1 – 65 children with IM with an acute course of the disease; group 2 – 37 children with a prolonged course of the disease. All children underwent standard clinical laboratory and instrumental laboratory examinations. The diagnosis of IM was confirmed by PCR (detection of EBV DNA in the blood) and ELISA (anti-EBV IgM and IgG). Research results. In the study of the structural state of the cytoplasmic membrane of the lymphocytes in the blood of patients with MI in the onset of the disease, it was found that the average values of penetration rate of the electron paramagnetic resonance of spin probes (PR EPR s. p.) in children of both groups were significantly higher than normal (P < 0.001). There are also differences between groups of patients. In this case, the value of PR EPR s. p. in patients with a prolonged course by 15.8 % exceeded those in patients with acute IM (P < 0.001). According to the rate of microviscosity of the intracellular content (MV IC), its values were reduced compared with the control – by 22.1 % (P < 0.001) in patients with acute course of the disease and by 25.1 % – with a prolonged course of IM). In addition, in patients with a prolonged course of the disease, the values were 9 % lower than in the group with acute infectious mononucleosis. When considering immunological parameters, it was found that the indicators of the T-immune system for patients with a prolonged course of the disease in comparison with the alternative group was characterized by a decrease in the content of CD3 <50 % (respectively in 51.3 % and 26.2 % of patients; P < 0.05); CD4 <31 % (62.1 % and 32.4 %, respectively; P < 0.05) and CD8 <15 % (37.8 % and 10.8 %, respectively; P < 0.01). With regard to the cytokine profile, the level of IL-1 <20.0 pg/ml was determined 3.5 times more often in patients with a prolonged course of the disease compared to the acute course (64.8 % and 18.5 % of patients, respectively); TNFα <20.0 pg/ml 1.9 times more often (48.6 % and 24.6 %, respectively) and a very high (>30.1 pg/ml) level of IL4 in 40.5 % and 20 %). From the B-system of immunity in patients with a prolonged course of IM in comparison with the acute course increased content of CD22 was more often determined, as well as low levels of IgA, IgM <1.1 g/l and IgG <10.0 g/l. Conclusions. According to the results of observations, the pathogenetic role of the violation of the structural organization of blood lymphocytes in the formation of IM is established. It was found that these disorders in the form of increased permeability of their cytoplasmic membrane and reduced viscoelastic properties of their intracellular environment are more pronounced with a prolonged course of the disease, which is a factor in the prolongation of the disease. It is determined that the indicators of cellular and humoral parts of the immune system affect the course of IM. During formation of an acute course of IM in children already in the acute period of a disease activation of both cellular and humoral links of immunity, which is shown in the form of increase in relative content of CD3+, CD4+, CD8+ and CD22+ and levels of immunoglobulins M, A, is noted. For the prolonged course of the disease depression of T-cell immunity in the form of a decrease in the relative content of CD3+, CD4+ and CD8+ lymphocytes and an increase in CD22+, as well as inhibition of antibody genesis are characteristic. It was found that the variant of IM depends on the type of reaction of T-helper clones, namely – in the initial period of manifestation of IM with its acute course there is activation of T1 and T2 helper response, which manifests itself in a significant increase in IL-1, TNFα and moderate IL-4. Prolonged course of the disease is formed against the background of weak activation of pro-inflammatory interleukins (IL-1, TNFα) and significant – anti-inflammatory IL-4.

Transient hypertriglyceridemia: a common finding during Epstein-Barr virus-induced infectious mononucleosis

Background Hypertriglyceridemia can occur in lymphoproliferative disorders. Infectious mononucleosis is a self-limiting, benign lymphoproliferative disorder. This study aimed to investigate the serum triglyceride concentrations and their change over time in patients with infectious mononucleosis. Methods We evaluated an adult patient with severe hypertriglyceridemia (>1000 mg/dL) during infectious mononucleosis and reviewed the records of 360 patients admitted to our hospital because of infectious mononucleosis (median age, 19 years; range, 15-87 years; 51.4% male). We compared the serum triglyceride concentrations with those of a control sample from the general population (n=75). A second triglyceride measurement, obtained during convalescence (median of 30 days after the initial determination), was available for 160 patients. Results The triglyceride concentrations in the acute phase (median: 156 mg/dL) were significantly higher than those of the controls (median, 76 mg/dL; P<0.001). A total of 194 (53.9%) patients presented with hypertriglyceridemia (>150 mg/dL), which was more common in the patients older than 30 years than in the younger patients (78.6% vs. 50.6%; P<0.001). A significant correlation (P<0.005) was observed between the triglyceride levels and white blood cell counts, total cholesterol levels, and liver damage markers. The triglyceride concentrations decreased during convalescence (P<0.001) and were lower than the initial measurement in 83.7% of the cases. Conversely, the total cholesterol concentrations during the acute phase were lower than those of the controls and increased during convalescence (P<0.001). Conclusions Patients with severe infectious mononucleosis frequently show mild, transient hypertriglyceridemia. Further studies are needed to elucidate the mechanisms underlying this finding.

Clinical and immunological efficiency of different therapy regimens in patients with infectious mononucleosis caused by Epstein-Barr virus

The aim of the study was to evaluate the effectiveness of ribonucleic acid in the correction of immune disorders in patients with infectious mononucleosis (IM) caused by EBV. Materials and methods. We examined 110 patients with a mean age of 23.3±4.2 years with IM, among whom women accounted for 52.7 % (n=58). The material for the study was the serum of patients obtained during the disease course. The set of tests of patients with IM included clinical and biochemical methods, enzyme-linked immunosorbent assay, polymerase chain reaction method, immunogram. Statistical processing of the obtained data was performed with “Statsoft Statistica v. 10.0 for Windows” using the methods of variation and correlation statistics. Results. The obtained results analysis revealed changes in the system of cellular and humoral parts of the immune system and the diversity of the immune response in patients with IM. The progressive nature of changes in immune parameters indicated the formation of secondary cellular immune imbalance, activation of the humoral link, a change in the balance of immunoregulatory mediators towards Th2 cells. Significant changes in the cellular immune system were observed in the acute period and were characterized by the increase in the number of cells with killer activity, namely mature T-lymphocytes (CD3+), cytotoxic T-suppressor cells (CD8+), cells expressing the activation marker CD25+ (IL-2 receptor), and by the Th1/Th2 ratio increase. The appointment of combination therapy including ribonucleic acid was accompanied by immunomodulatory and antiviral effects, that was reflected in a more pronounced positive dynamics of immunological parameters, namely in strengthening the proliferative response, compared with the group of patients receiving only basic therapy. Conclusion. The expediency of the combination therapy application: the drug Nuclex (ribonucleic acid) (250 mg) 2 capsules 3 times a day for 14 days and valacyclovir (500 mg) at a dose of 1000 mg (2 tablets) 3 times a day for 14 days, is justified for the correction of immune disorders in patients with IM caused by EBV.