Coxsackievirus-B4E2 can infect monocytes and macrophages in vitro and in vivo.

Viral RNA (vRNA) is found in mice inoculated with coxsackievirus-B4E2 (CV-B4E2). The CV-B4E2 infection of murine spleen cells in vitro is enhanced with CV-B4E2-infected mouse serum. It has been investigated whether monocyte/macrophages were targets of CV-B4E2 in mice. vRNA has been detected in spleen and bone marrow of infected animals. The levels of vRNA were higher in CD14+ cells than in CD14- spleen cells and in F4/80- cells than in F4/80+ spleen cells. Meanwhile, CD14+ cells and F4/80- cells were more permissive to CV-B4E2 in vitro and the infection was enhanced when the virus was mixed with immune serum. While CV-B4E2 infected BMDM cultures (98% F4/80+); however, the immune serum did not enhance the infection. In conclusion, CV-B4E2 infects monocytes (CD14+, F4/80-) and macrophages (CD14+, F4/80+) in vivo and immune serum can enhance the in vitro infection of these cells arising out of the spleen.

In-utero coxsackievirus B4 infection of the mouse thymus.

Type B coxsackievirus (CV-B) infections are involved frequently in the triggering of several autoimmune diseases such as myocarditis, dilated cardiomyopathy, pericarditis, pancreatitis, type 1 diabetes, encephalitis, thyroiditis or Sjögren's syndrome. Serological and virological evidence suggests that maternal infections during pregnancy can play a role in the appearance of these diseases in offspring. The current study aims to explore the effect of an in-utero CV-B infection on the fetal thymus, the central site for programming immunological self-tolerance. In this perspective, female Swiss albino mice were inoculated intraperitoneally or orally with the diabetogenic CV-B4 E2 strain at gestational days 10 or 17. Offspring were killed at different post-inoculation times, and their thymuses were analysed for evidence of infection and alterations in thymic T cell subsets. In-utero CV-B infection of the thymus was demonstrated during the course of vertical transmission, as attested by viral RNA and infectious virus detection in most analysed samples. No histopathological changes were evident. Thymic T cells were not depleted, despite being positive for viral RNA. As evidenced by flow cytometry analysis, CV-B infection of the fetal thymus induced significant changes of thymic T cell populations, particularly with maternal inoculation at gestational day 10. Altogether, these findings suggest that CV-B infection of the fetal thymus may play an important role in the genesis of autoimmune diseases.

Immunology in the clinic review series; focus on type 1 diabetes and viruses: enterovirus, thymus and type 1 diabetes pathogenesis.

Thymus dysfunction, especially immune suppression, is frequently associated with various virus infections. Whether viruses may disturb the thymus function and play a role in the pathogenesis of autoimmune diseases is an open issue. Enteroviruses, especially Coxsackievirus B4 (CV-B4), have been largely suggested as potential inducers or aggravating factors of type 1 diabetes (T1D) pathogenesis in genetically predisposed individuals. Several pathogenic mechanisms of enterovirus-induced T1D have been suggested. One of these mechanisms is the impairment of central self-tolerance due to viral infections. Coxsackievirus-B4 is able to infect murine thymus in vitro and in vivo and to infect human thymus in vitro. Thymic epithelial cells and thymocytes are targets of infection with this virus, and several abnormalities, especially disturbance of maturation/differentiation processes, were observed. Altogether, these data suggest that CV-B infection of thymus may be involved in the pathogenesis of T1D. Further investigations are needed to explore this hypothesis.

Immunology in the clinic review series; focus on type 1 diabetes and viruses: role of antibodies enhancing the infection with Coxsackievirus-B in the pathogenesis of type 1 diabetes.

Type 1 diabetes results from an interaction between genetic and environmental factors. Coxsackieviruses B (CV-B) are major environmental candidates, as suggested by epidemiological and experimental studies. The mechanisms leading to the disease involve interactions between the virus, host target tissue (pancreas) and the immune system. The infection of target cells with viruses can be prevented by antibodies. Conversely, the infection can be enhanced by antibodies. The antibody-dependent enhancement (ADE) of infection has been described with various viruses, especially Picornaviruses. In mice infected with CV-B3 this phenomenon resulted in an extended inflammatory reaction and myocarditis. In the human system non-neutralizing antibodies can increase the infection of monocytes with CV-B4 and stimulate the production of interferon (IFN)-α by these cells in vitro. CV-B4/immunoglobulin (Ig)G immune complexes interacted with a specific viral receptor [Coxsackievirus and adenovirus receptor (CAR)] and with IgG Fc fraction receptors (FcγRII and FcγRIII) at the surface of monocytes. The virus-antibody complexes are internalized (CAR) and receptors for the Fc of IgG (FcγRII and FcγRIII). Such antibodies have been detected in patients with type 1 diabetes and they could be responsible for the presence of enteroviral RNA and IFN-α in peripheral blood mononuclear cells (PBMC) of these individuals. The target of enhancing antibodies has been identified as the VP4 protein, which allowed the detection of these antibodies by enzyme-linked immunosorbent assay (ELISA). It cannot be excluded that antibodies enhancing the infection with CV-B may play a role in the pathogenesis of type 1 diabetes, induced or aggravated by these viruses. They can cause a viral escape from the immune response and may participate in the spreading of viruses to ß cells. Whether enhancing antibodies raised against VP4 can play a role in iterative homologous and/or heterologous CV-B infections and in the persistence of viruses within the host deserves further study.

Coxsackievirus B4 and type 1 diabetes pathogenesis: contribution of animal models.

The role of enteroviruses, in particular type B coxsackieviruses (CV-B), in type 1 diabetes (T1D) pathogenesis is supported by epidemiological, clinical and experimental observations.The investigation of T1D pathogenesis benefits from the contribution of animal models called spontaneously diabetic. Among these animals the non-obese diabetic (NOD) mouse and the bio-breeding diabetes-prone (BBDP) rat present a genetic susceptibility manifested by the expression of an autoimmune diabetes similar to the pathology observed in human beings. Other models whose genetic predisposition is less known are of considerable contribution as well. Numerous major observations relative to several aspects of T1D pathogenesis in the context of CV-B infections, such as susceptibility, diabetogenicity, pancreatotropism, mechanisms of beta cells destruction and others, have been deduced thanks to investigations with animal models. Despite their limits, these models are necessary in improving our knowledge of the role of enteroviruses, like CV-B4, in the pathogenesis of T1D, and the recent advances ensuing from their contribution may have important therapeutic and preventive spin-offs.

Role of coxsackievirus B4 in the pathogenesis of type 1 diabetes.

Environmental factors, especially viruses, are thought to play an important role in the initiation or acceleration of the pathogenesis of type 1 diabetes (T1D). Data from retrospective and prospective epidemiological studies strongly suggest that enteroviruses, such as coxsackievirus B4 (CV-B4), may be associated with the development of T1D. It has also been shown that enterovirus infections are significantly more prevalent in at-risk individuals such as the siblings of diabetic patients, when they develop anti-beta-cell autoantibodies or T1D, and in recently diagnosed diabetic patients, compared with control subjects. The isolation of CV-B4 from the pancreas of diabetic patients supports the hypothesis of a relationship between the virus and the disease. Furthermore, studies performed in vitro and in vivo in animal models have increased our knowledge of the role of CV-B4 in T1D by helping to clarify the pathogenic mechanisms of the infection that can lead to beta-cell destruction, including direct virus-induced beta-cell lysis, molecular mimicry, 'bystander activation' and viral persistence. The role of enteroviruses as the sole agents in T1D, and a causal link between these agents and T1D, have not yet been established, although arguments that support such a role for these viruses in the pathogenesis of the disease cannot be ignored.

[Relationship between enteroviruses and diabetes]. / Vers une meilleure compréhension de la relation entre entérovirus et diabète de type 1.

Environmental factors, especially viruses, are involved in the initiation or the acceleration of type 1 diabetes (T1D) pathogenesis. Epidemiological data strongly suggest that enteroviruses, like coxsackievirus B4 (CV-B4), can be associated with T1D. It has been demonstrated that enterovirus infections were significantly more prevalent in at risk individuals, such as siblings of diabetic patients, when they developed anti-b cells autoantibodies or T1D, and in recently diagnosed diabetic patients, compared with control subjects. The isolation of CV-B4 from the pancreas of diabetic patients strengthened the hypothesis of a relationship between the virus and the disease. Studies performed in vitro and in vivo in animal models helped in discovering mechanisms of the infection of pancreas and other tissues, able to play a role in the pathogenesis of T1D. Interestingly, it cannot be excluded that enteroviruses behave as half-devil half-angel since experimental studies suggest that, in certain conditions, these agents would be able to protect individuals against the disease.

[Neuromeningeal enterovirus infections in Tunisia: epidemiology, clinical presentation, and outcome of 26 pediatric cases]. / Entéroviroses neuroméningées en Tunisie: profil épidémiologique, clinique et évolutif. A propos de 26 cas pédiatriques.

UNLABELLED: Non-polio enteroviruses are the most common identified cause of viral neuromeningeal infections following the introduction of the mumps and polio vaccines. OBJECTIVE: The aim of this study was to describe the epidemiology, clinical presentation, and the outcome of enteroviral infections of the CNS. METHOD AND PATIENTS: We performed a prospective study on 41 children admitted for viral neuromeningeal infections in the pediatric department of Monastir between December 2001 and November 2002. Enteroviruses were detected from cerebrospinal fluid by RT-PCR. RESULTS: This study showed that enteroviruses were responsible for 63.4% of the infections. The mean age of patients was 6.1 years. Aseptic meningitis was diagnosed in 14 cases and encephalitis in 10. The most frequent symptom was fever (61.5%), followed by seizures (42.3%), and confusion (23%). On follow-up, all patients with meningitis had recovered without sequels. Neurological complications in patients with encephalitis were epilepsy (3 cases), cerebral palsy (2 cases), and mental retardation (1 case). CONCLUSION: This study confirmed that enteroviruses were the most common cause of viral infections of the CNS. Common use of RT-PCR can have a significant impact on the outcome of patients with enterovirus infections.

[Value of mass dosage of the MB isoenzyme of creatinine phosphokinase in the diagnosis of recent myocardial infarction]. / Intérêt du dosage pondéral de l'iso-enzyme MB de la créatine phosphokinase pour le diagnostic de l'infarctus du myocarde récent.

In 391 patients admitted 3.7 hours (h) (median) after experiencing infarct-like pain, kinetic monitoring of CK-MB "mass" (threshold: 7 micrograms/l), myoglobin (threshold: 90 micrograms/l) and total CK (threshold: 290 micrograms/l) was carried out at the time of admission and after 1.5, 3, 6, 9, 12, 24 and 48 h. When myocardial infarction (MI) was treated conventionally (102 patients). CK-MB peaked 11 h (median) after the onset of pain, later than myoglobin (9 h), but before total CK (12 h). The peak of the markers was higher in Q+ than in Q-MI (p < 0.05). When MI was treated by thrombolytic medications (44 patients), the increases in CK-MB, myoglobin and total CK were larger, and occurred sooner (peaks 9, 6 and 6 h, after the onset of pain respectively), but did not last as long. In 245 patients who had not had MI (including 123 with spontaneous angina), the levels of the three markers remained stable and well below the decision thresholds. The sensitivities of CK-MB, myoglobin and total CK were respectively 47.1, 51.8 and 34.8% at the time of admission, 67.3, 82.7 and 57.1% after 3 h and 83.1, 76.9 and 88.9% after 6 h. The combined determination of CK-MB and of myoglobin had a higher sensitivity (67.7% at the time of admission, 84.9% after 1.5% and 88.2% after 3 h: but most of this gain was due to myoglobin. The specificity of the three markers and their diagnostic accuracy are comparable. In the course of recent MI, the kinetics of CK-MB mass are thus slower than those of myoglobin, but a little faster than those of total CK. The choice of the most effective biochemical marker depends upon the interval between onset of chest pain and hospitalization of the patient. Repetition of the determinations improves the diagnostic situation.