Effect of Coxsackievirus B4 Infection on the Thymus: Elucidating Its Role in the Pathogenesis of Type 1 Diabetes

Nekoua, Magloire Pandoua; Michaux, Hélène; Sané, Famara; Halouani, Aymen; Alidjinou, Enagnon Kazali; Martens, Henri; Jaïdane, Hela; Geenen, Vincent; Hober, Didier

doi:10.3390/microorganisms9061177

Cited by 17 publications

(13 citation statements)

References 84 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, deficient Igf2 expression in the thymus has been implicated in the development of autoimmune diabetes mellitus in BBDP rats 120 . Together, these findings support the hypothesis that CVB infections, through the inhibition of Igf2 , might play a part in the decrease of central tolerance to insulin due to defective negative selection of autoreactive T cells 121 .…”

Section: Experimental Evidence For Cvb Persistencesupporting

confidence: 80%

Persistent coxsackievirus B infection and pathogenesis of type 1 diabetes mellitus

2022

Self Cite

View full text Add to dashboard Cite

Enteroviruses are believed to trigger or accelerate islet autoimmunity in genetically susceptible individuals, thereby resulting in loss of functional insulin-producing β-cells and type 1 diabetes mellitus (T1DM). Although enteroviruses are primarily involved in acute and lytic infections in vitro and in vivo, they can also establish a persistent infection. Prospective epidemiological studies have strongly associated the persistence of enteroviruses, especially coxsackievirus B (CVB), with the appearance of islet autoantibodies and an increased risk of T1DM. CVB can persist in pancreatic ductal and β-cells, which leads to structural or functional alterations of these cells, and to a chronic inflammatory response that promotes recruitment and activation of pre-existing autoreactive T cells and β-cell autoimmune destruction. CVB persistence in other sites, such as the intestine, blood cells and thymus, has been described; these sites could serve as a reservoir for infection or reinfection of the pancreas, and this persistence could have a role in the disturbance of tolerance to β-cells. This Review addresses the involvement of persistent enterovirus infection in triggering islet autoimmunity and T1DM, as well as current strategies to control enterovirus infections for preventing or reducing the risk of T1DM onset.

show abstract

Section: Experimental Evidence For Cvb Persistencesupporting

confidence: 80%

Persistent coxsackievirus B infection and pathogenesis of type 1 diabetes mellitus

2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…To evaluate cross-protective immune responses generated by the vaccine virus, we considered two serotypes, CVB1 and CVB4. While CVB3 is generally implicated in the causation of myocarditis [4,30], CVB4 and CVB1 infections were shown to be associated with T1D [13,[31][32][33], and all three serotypes can induce pancreatitis [5,24,34]. We immunized groups of mice with or without vaccine virus and collected sera on days 0, 14, 21, and 35 post-vaccination (Figure 1a).…”

Section: Vaccine Virus Induces Nabs Against Both Cvb1 and Cvb4mentioning

confidence: 99%

“…Importantly, CVB3 is mainly implicated in the causation of myocarditis that can lead to dilated cardiomyopathy (DCM) [6][7][8]. Likewise, although multiple serotypes (CVB1, CVB3, and CVB4) can induce pancreatitis, CVB1 and CVB4 infections may trigger type I diabetes (T1D) as demonstrated in the non-obese diabetic (NOD) mouse model and humans [9][10][11][12][13]. Despite the negative impact of CVB infections, vaccines are not available to prevent them, in part because their disease outcomes are not as devastating as those noted with some newly emerged viruses, such as Ebola, Zika, and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) [14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Mt10-CVB3 Vaccine Virus Protects against CVB4 Infection by Inducing Cross-Reactive, Antigen-Specific Immune Responses

et al. 2021

View full text Add to dashboard Cite

Group B coxsackieviruses (CVB) containing six serotypes, B1–B6, affect various organs, and multiple serotypes can induce similar diseases such as myocarditis and pancreatitis. Yet, no vaccines are currently available to prevent these infections. Translationally, the derivation of vaccines that offer protection against multiple serotypes is highly desired. In that direction, we recently reported the generation of an attenuated strain of CVB3, termed Mt10, which completely protects against both myocarditis and pancreatitis induced by the homologous wild-type CVB3 strain. Here, we report that the Mt10 vaccine can induce cross-protection against multiple CVB serotypes as demonstrated with CVB4. We note that the Mt10 vaccine could induce cross-reactive neutralizing antibodies (nABs) against both CVB1 and CVB4. In challenge studies with CVB4, the efficacy of the Mt10 vaccine was found to be 92%, as determined by histological evaluation of the heart and pancreas. Antibody responses induced in Mt10/CVB4 challenged animals indicated the persistence of cross-reactive nABs against CVB1, CVB3, and CVB4. Evaluation of antigen-specific immune responses revealed viral protein 1 (VP1)-reactive antibodies, predominantly IgG2a, IgG2b, IgG3, and IgG1. Similarly, by using major histocompatibility complex class II tetramers, we noted induction of VP1-specific CD4 T cells capable of producing multiple T cell cytokines, with interferon-γ being predominant. Finally, none of the vaccine recipients challenged with CVB4 revealed the presence of viral nucleic acid in the heart or pancreas. Taken together, our data suggest that the Mt10 vaccine can prevent infections caused by multiple CVB serotypes, paving the way for the development of monovalent CVB vaccines to prevent heart and pancreatic diseases of enteroviral origin.

show abstract

“…Six CVB serotypes, CVB1 to CVB6 that infect various organs such as the heart, pancreas, liver, central nervous, and gastrointestinal systems have been identified [ 19 , 20 , 21 ]. While all serotypes can cause pancreatitis, CVB3 is generally implicated in myocarditis [ 22 , 23 , 24 ], and CVB1 and CVB4 are known to be associated with insulitis, thus acting as cofactors for the development of T1D [ 25 , 26 , 27 ]. The reason for such differential disease phenotypes remains obscure since CVBs require Coxsackievirus-Adenovirus Receptor (CAR) to enter the target cells [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

A Monovalent Mt10-CVB3 Vaccine Prevents CVB4-Accelerated Type 1 Diabetes in NOD Mice

et al. 2022

View full text Add to dashboard Cite

Enteroviruses, which include Coxsackieviruses, are a common cause of virus infections in humans, and multiple serotypes of the group B Coxsackievirus (CVB) can induce similar diseases. No vaccines are currently available to prevent CVB infections because developing serotype-specific vaccines is not practical. Thus, developing a vaccine that induces protective immune responses for multiple serotypes is desired. In that direction, we created a live-attenuated CVB3 vaccine virus, designated mutant (Mt)10, that offers protection against myocarditis and pancreatitis induced by CVB3 and CVB4 in disease-susceptible A/J mice. Here, we report that the Mt10 vaccine protected against CVB4-triggered type 1 diabetes (T1D) in non-obese diabetic (NOD) mice but the expected subsequent development of spontaneous T1D in these genetically predisposed NOD mice was not altered. We noted that Mt10 vaccine induced significant amounts of neutralizing antibodies, predominantly of the IgG2c isotype, and the virus was not detected in vaccine-challenged animals. Furthermore, monitoring blood glucose levels—and to a lesser extent, insulin antibodies—was found to be helpful in predicting vaccine responses. Taken together, our data suggest that the monovalent Mt10 vaccine has the potential to prevent infections caused by multiple CVB serotypes, as we have demonstrated in various pre-clinical models.

show abstract

Effect of Coxsackievirus B4 Infection on the Thymus: Elucidating Its Role in the Pathogenesis of Type 1 Diabetes

Cited by 17 publications

References 84 publications

Persistent coxsackievirus B infection and pathogenesis of type 1 diabetes mellitus

Persistent coxsackievirus B infection and pathogenesis of type 1 diabetes mellitus

Mt10-CVB3 Vaccine Virus Protects against CVB4 Infection by Inducing Cross-Reactive, Antigen-Specific Immune Responses

A Monovalent Mt10-CVB3 Vaccine Prevents CVB4-Accelerated Type 1 Diabetes in NOD Mice

Contact Info

Product

Resources

About