Coxsackievirus B1 infections are associated with the initiation of insulin-driven autoimmunity that progresses to type 1 diabetes

Sioofy‐Khojine, Amir‐Babak; Lehtonen, Jussi; Nurminen, Noora; Laitinen, Olli H.; Oikarinen, Sami; Huhtala, Heini; Pakkanen, Outi; Ruokoranta, Tanja; Hankaniemi, Minna M.; Toppari, Jorma; Vähä-Mäkilä, Mari; Ilonen, Jorma; Veijola, Riitta; Knip, Mikael; Hyöty, Heikki

doi:10.1007/s00125-018-4561-y

Cited by 91 publications

(91 citation statements)

References 41 publications

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“…Hence, one might conceive that the impact of viral infection could significantly vary between these 2 phenotypes with distinct immunogenetic characteristics. It was disclosed by DIPP study that the effect of CVB1 was restricted to islet autoimmunity starting with insulin autoantibody (IAA) and was not related to GAD‐driven autoimmune process . Diverging from the findings of the TEDDY study and the DIPP study, the positivity of enterovirus RNA in blood was not predictive of the later appearance of islet autoantibodies among a cohort of children from The Norwegian Environmental Triggers of Type 1 Diabetes (MIDIA) study .…”

Section: Environmental Determinantsmentioning

confidence: 95%

“…It was disclosed by DIPP study that the effect of CVB1 was restricted to islet autoimmunity starting with insulin autoantibody (IAA) and was not related to GADdriven autoimmune process. 68 suggested that surrounding microbes can start to train infants' immunity during pregnancy. 73 It is speculated that hygienic measures intended for prevention of infectious diseases via eliminating microbes from residents' living environment can accordingly disturb the native gut microbiome and remove microbial communities fundamental for training the immune system.…”

Section: The Role Of Viral Infections and Gut Microbiomementioning

confidence: 99%

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Incidence and trend of type 1 diabetes and the underlying environmental determinants

Xia

Xie

Huang

et al. 2018

Diabetes Metabolism Res

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A wealth of epidemiological studies concerning the distribution of type 1 diabetes (T1D) around the world have pointed to the appreciable variation in the incidence of T1D among disparate age groups, ethnicities, and geographical locations. On the whole, the incidence of childhood T1D has been on the rise, and a plausible inverse relationship between the initial incidence rate and the following annual increase in incidence has been raised. Countries that used to exhibit lower incidences tend to have steep annual increase whereas those with already-established high incidences are more likely to show a modest increase or even stabilization in T1D incidence. Environmental agents considered responsible for the current evolving pattern of T1D incidence will be detailed, mainly including the increasing prevalence of childhood obesity, viral infections in a chronic manner, maternal-child interaction such as breastfeeding, and latitude-ultraviolet B-vitamin D pathway. Certain rationale has been put forward in an attempt to explain the potential association between environmental agents and development of T1D. For instance, accelerator hypothesis regards insulin resistance as the promoter of earlier disease onset in obese children whereas the negative correlation of microbial infections in background populations with incidence of T1D represents the basic component of the hygiene hypothesis. Further investigations are still warranted to verify these theories across multiple ethnic groups and to identify additional contributors to the variation in T1D incidence.

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Section: Environmental Determinantsmentioning

confidence: 95%

Section: The Role Of Viral Infections and Gut Microbiomementioning

confidence: 99%

Incidence and trend of type 1 diabetes and the underlying environmental determinants

Xia

Xie

Huang

et al. 2018

Diabetes Metabolism Res

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“…Enteroviruses cause diverse diseases in humans with symptoms varying from mild, such as common cold, to more severe such as meningitis, encephalitis, and myocarditis [1][2][3][4]. In addition to acute diseases, enteroviruses have been associated with chronic diseases like type I diabetes or asthma [5][6][7]. However, there is no antiviral on the market against enteroviruses.…”

Section: Introductionmentioning

confidence: 99%

Host Cell Calpains Can Cleave Structural Proteins from the Enterovirus Polyprotein

Laajala

Hankaniemi

Määttä

et al. 2019

Viruses

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Enteroviruses are small RNA viruses that cause diseases with various symptoms ranging from mild to severe. Enterovirus proteins are translated as a single polyprotein, which is cleaved by viral proteases to release capsid and nonstructural proteins. Here, we show that also cellular calpains have a potential role in the processing of the enteroviral polyprotein. Using purified calpains 1 and 2 in an in vitro assay, we show that addition of calpains leads to an increase in the release of VP1 and VP3 capsid proteins from P1 of enterovirus B species, detected by western blotting. This was prevented with a calpain inhibitor and was dependent on optimal calcium concentration, especially for calpain 2. In addition, calpain cleavage at the VP3-VP1 interface was supported by a competition assay using a peptide containing the VP3-VP1 cleavage site. Moreover, a mass spectrometry analysis showed that calpains can cleave this same peptide at the VP3-VP1 interface, the cutting site being two amino acids aside from 3C’s cutting site. Furthermore, we show that calpains cannot cleave between P1 and 2A. In conclusion, we show that cellular proteases, calpains, can cleave structural proteins from enterovirus polyprotein in vitro. Whether they assist polyprotein processing in infected cells remains to be shown.

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“…T he Enterovirus B species consists of tens of clinically relevant viruses, including over 30 serotypes of echoviruses and coxsackievirus B1 to B6 and A9. They can cause a wide variety of mild and severe infections, and many of them are also associated with the onset of type I diabetes and coeliac disease (1)(2)(3)(4). These viruses infect primarily gut epithelial cells and are naturally stabile in an acidic environment.…”

mentioning

confidence: 99%

Extracellular Albumin and Endosomal Ions Prime Enterovirus Particles for Uncoating That Can Be Prevented by Fatty Acid Saturation

Ruokolainen

Domanska

Laajala

et al. 2019

J Virol

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There is limited information about the molecular triggers leading to the uncoating of enteroviruses under physiological conditions. Using real-time spectroscopy and sucrose gradients with radioactively labeled virus, we show at 37°C, the formation of albumin-triggered, metastable uncoating intermediate of echovirus 1 without receptor engagement. This conversion was blocked by saturating the albumin with fatty acids. High potassium but low sodium and calcium concentrations, mimicking the endosomal environment, also induced the formation of a metastable uncoating intermediate of echovirus 1. Together, these factors boosted the formation of the uncoating intermediate, and the infectivity of this intermediate was retained, as judged by end-point titration. Cryo-electron microscopy reconstruction of the virions treated with albumin and high potassium, low sodium, and low calcium concentrations resulted in a 3.6-Å resolution model revealing a fenestrated capsid showing 4% expansion and loss of the pocket factor, similarly to altered (A) particles described for other enteroviruses. The dimer interface between VP2 molecules was opened, the VP1 N termini disordered and most likely externalized. The RNA was clearly visible, anchored to the capsid. The results presented here suggest that extracellular albumin, partially saturated with fatty acids, likely leads to the formation of the infectious uncoating intermediate prior to the engagement with the cellular receptor. In addition, changes in mono- and divalent cations, likely occurring in endosomes, promote capsid opening and genome release. IMPORTANCE There is limited information about the uncoating of enteroviruses under physiological conditions. Here, we focused on physiologically relevant factors that likely contribute to opening of echovirus 1 and other B-group enteroviruses. By combining biochemical and structural data, we show that, before entering cells, extracellular albumin is capable of priming the virus into a metastable yet infectious intermediate state. The ionic changes that are suggested to occur in endosomes can further contribute to uncoating and promote genome release, once the viral particle is endocytosed. Importantly, we provide a detailed high-resolution structure of a virion after treatment with albumin and a preset ion composition, showing pocket factor release, capsid expansion, and fenestration and the clearly visible genome still anchored to the capsid. This study provides valuable information about the physiological factors that contribute to the opening of B group enteroviruses.

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Coxsackievirus B1 infections are associated with the initiation of insulin-driven autoimmunity that progresses to type 1 diabetes

Abstract: CVB1 infections may contribute to the initiation of islet autoimmunity being particularly important in the insulin-driven autoimmune process.

Cited by 91 publications

References 41 publications

Incidence and trend of type 1 diabetes and the underlying environmental determinants

Incidence and trend of type 1 diabetes and the underlying environmental determinants

Host Cell Calpains Can Cleave Structural Proteins from the Enterovirus Polyprotein

Extracellular Albumin and Endosomal Ions Prime Enterovirus Particles for Uncoating That Can Be Prevented by Fatty Acid Saturation

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