Limits...
Mechanisms of Beta Cell Dysfunction Associated With Viral Infection.

Petzold A, Solimena M, Knoch KP - Curr. Diab. Rep. (2015)

Bottom Line: Recently, a rapid increase in the incidence of childhood T1D has been observed worldwide; this is too fast to be explained by genetic factors alone, pointing to the spreading of environmental factors linked to the disease.While several studies point to the likelihood of such correlation, epidemiological evidence in its support is inconclusive or in some instances even against it.Hence, it is still unknown if and how EVs are involved in the development of T1D.

View Article: PubMed Central - PubMed

Affiliation: Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital Carl Gustav Carus and Faculty of Medicine, Technische Universität Dresden, Fetscherstr.74, 01307, Dresden, Germany, antje.petzold@mailbox.tu-dresden.de.

ABSTRACT
Type 1 diabetes (T1D) results from genetic predisposition and environmental factors leading to the autoimmune destruction of pancreatic beta cells. Recently, a rapid increase in the incidence of childhood T1D has been observed worldwide; this is too fast to be explained by genetic factors alone, pointing to the spreading of environmental factors linked to the disease. Enteroviruses (EVs) are perhaps the most investigated environmental agents in relationship to the pathogenesis of T1D. While several studies point to the likelihood of such correlation, epidemiological evidence in its support is inconclusive or in some instances even against it. Hence, it is still unknown if and how EVs are involved in the development of T1D. Here we review recent findings concerning the biology of EV in beta cells and the potential implications of this knowledge for the understanding of beta cell dysfunction and autoimmune destruction in T1D.

No MeSH data available.


Related in: MedlinePlus

Impact of CVB infection on beta cell function and survival. CVB binds to CAR, PVR, and/or integrin αvβ3 at the plasma membrane of the beta cell. Upon entry and translocation into the cytoplasm, the sense-stranded CVB RNA is translated in a PTBP1-mediated, IRES-dependent fashion by the host machinery. Cap-dependent translation of host cell proteins is inhibited through cleavage of eIF4G and PABP. Glucose-stimulated translation of insulin secretory granule (SG) cargoes is, however, unaffected being itself cap-independent and reliant on PTBP1, which in CVB-infected cells undergoes a massive nucleo-cytoplasmic translocation. Insulin secretion is nevertheless impaired and granule stores are depleted due to the targeting of their cargo proteins to intracellular disposal. Recognition of viral dsRNA by dsRNA sensors activates the antiviral response with production and secretion of pro-inflammatory cytokines and upregulation of MHC class I molecules. Additionally, dsRNA activates PKR with inhibition of the antiapoptotic Mcl-1 and thereby release of pro-apoptotic Bim and activation of the mitochondrial caspase cascade leading to apoptosis. Apoptosis can be further induced by pro-inflammatory cytokines and switch to necrosis in case of concomitant ATP depletion
© Copyright Policy - OpenAccess
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4539350&req=5

Fig1: Impact of CVB infection on beta cell function and survival. CVB binds to CAR, PVR, and/or integrin αvβ3 at the plasma membrane of the beta cell. Upon entry and translocation into the cytoplasm, the sense-stranded CVB RNA is translated in a PTBP1-mediated, IRES-dependent fashion by the host machinery. Cap-dependent translation of host cell proteins is inhibited through cleavage of eIF4G and PABP. Glucose-stimulated translation of insulin secretory granule (SG) cargoes is, however, unaffected being itself cap-independent and reliant on PTBP1, which in CVB-infected cells undergoes a massive nucleo-cytoplasmic translocation. Insulin secretion is nevertheless impaired and granule stores are depleted due to the targeting of their cargo proteins to intracellular disposal. Recognition of viral dsRNA by dsRNA sensors activates the antiviral response with production and secretion of pro-inflammatory cytokines and upregulation of MHC class I molecules. Additionally, dsRNA activates PKR with inhibition of the antiapoptotic Mcl-1 and thereby release of pro-apoptotic Bim and activation of the mitochondrial caspase cascade leading to apoptosis. Apoptosis can be further induced by pro-inflammatory cytokines and switch to necrosis in case of concomitant ATP depletion

Mentions: CVBs are small, non-enveloped, positive-stranded RNA viruses containing an icosahedral capsid of ∼30 nm in diameter that consist of four viral proteins (VP1-VP4) [40]. To invade the host cell, they primarily use the coxsackievirus and adenovirus receptor (CAR) [45] but also the decay-accelerating factor (DAF) [46] (Table 1). CAR is expressed in both alpha and beta cells of human pancreatic islets [47] while DAF has not been detected in human islets [28]. Poliovirus receptor (PVR) and integrin αvβ3 can also mediate CVB entry, as antibodies against them protected human beta cells from CVB4 and CVB5 infection [28] (Fig. 1).Table 1


Mechanisms of Beta Cell Dysfunction Associated With Viral Infection.

Petzold A, Solimena M, Knoch KP - Curr. Diab. Rep. (2015)

Impact of CVB infection on beta cell function and survival. CVB binds to CAR, PVR, and/or integrin αvβ3 at the plasma membrane of the beta cell. Upon entry and translocation into the cytoplasm, the sense-stranded CVB RNA is translated in a PTBP1-mediated, IRES-dependent fashion by the host machinery. Cap-dependent translation of host cell proteins is inhibited through cleavage of eIF4G and PABP. Glucose-stimulated translation of insulin secretory granule (SG) cargoes is, however, unaffected being itself cap-independent and reliant on PTBP1, which in CVB-infected cells undergoes a massive nucleo-cytoplasmic translocation. Insulin secretion is nevertheless impaired and granule stores are depleted due to the targeting of their cargo proteins to intracellular disposal. Recognition of viral dsRNA by dsRNA sensors activates the antiviral response with production and secretion of pro-inflammatory cytokines and upregulation of MHC class I molecules. Additionally, dsRNA activates PKR with inhibition of the antiapoptotic Mcl-1 and thereby release of pro-apoptotic Bim and activation of the mitochondrial caspase cascade leading to apoptosis. Apoptosis can be further induced by pro-inflammatory cytokines and switch to necrosis in case of concomitant ATP depletion
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4539350&req=5

Fig1: Impact of CVB infection on beta cell function and survival. CVB binds to CAR, PVR, and/or integrin αvβ3 at the plasma membrane of the beta cell. Upon entry and translocation into the cytoplasm, the sense-stranded CVB RNA is translated in a PTBP1-mediated, IRES-dependent fashion by the host machinery. Cap-dependent translation of host cell proteins is inhibited through cleavage of eIF4G and PABP. Glucose-stimulated translation of insulin secretory granule (SG) cargoes is, however, unaffected being itself cap-independent and reliant on PTBP1, which in CVB-infected cells undergoes a massive nucleo-cytoplasmic translocation. Insulin secretion is nevertheless impaired and granule stores are depleted due to the targeting of their cargo proteins to intracellular disposal. Recognition of viral dsRNA by dsRNA sensors activates the antiviral response with production and secretion of pro-inflammatory cytokines and upregulation of MHC class I molecules. Additionally, dsRNA activates PKR with inhibition of the antiapoptotic Mcl-1 and thereby release of pro-apoptotic Bim and activation of the mitochondrial caspase cascade leading to apoptosis. Apoptosis can be further induced by pro-inflammatory cytokines and switch to necrosis in case of concomitant ATP depletion
Mentions: CVBs are small, non-enveloped, positive-stranded RNA viruses containing an icosahedral capsid of ∼30 nm in diameter that consist of four viral proteins (VP1-VP4) [40]. To invade the host cell, they primarily use the coxsackievirus and adenovirus receptor (CAR) [45] but also the decay-accelerating factor (DAF) [46] (Table 1). CAR is expressed in both alpha and beta cells of human pancreatic islets [47] while DAF has not been detected in human islets [28]. Poliovirus receptor (PVR) and integrin αvβ3 can also mediate CVB entry, as antibodies against them protected human beta cells from CVB4 and CVB5 infection [28] (Fig. 1).Table 1

Bottom Line: Recently, a rapid increase in the incidence of childhood T1D has been observed worldwide; this is too fast to be explained by genetic factors alone, pointing to the spreading of environmental factors linked to the disease.While several studies point to the likelihood of such correlation, epidemiological evidence in its support is inconclusive or in some instances even against it.Hence, it is still unknown if and how EVs are involved in the development of T1D.

View Article: PubMed Central - PubMed

Affiliation: Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital Carl Gustav Carus and Faculty of Medicine, Technische Universität Dresden, Fetscherstr.74, 01307, Dresden, Germany, antje.petzold@mailbox.tu-dresden.de.

ABSTRACT
Type 1 diabetes (T1D) results from genetic predisposition and environmental factors leading to the autoimmune destruction of pancreatic beta cells. Recently, a rapid increase in the incidence of childhood T1D has been observed worldwide; this is too fast to be explained by genetic factors alone, pointing to the spreading of environmental factors linked to the disease. Enteroviruses (EVs) are perhaps the most investigated environmental agents in relationship to the pathogenesis of T1D. While several studies point to the likelihood of such correlation, epidemiological evidence in its support is inconclusive or in some instances even against it. Hence, it is still unknown if and how EVs are involved in the development of T1D. Here we review recent findings concerning the biology of EV in beta cells and the potential implications of this knowledge for the understanding of beta cell dysfunction and autoimmune destruction in T1D.

No MeSH data available.


Related in: MedlinePlus