Vemurafenib inhibits the replication of diabetogenic enteroviruses in intestinal epithelial and pancreatic beta cells.

Enteroviruses, which infect via the gut, have been implicated in type 1 diabetes (T1D) development. Prolonged faecal shedding of enterovirus has been associated with islet autoimmunity. Additionally, enteroviral proteins and viral RNA have been detected in the pancreatic islets of individuals with recent-onset T1D, implicating their possible role in beta cell destruction.

Production, analysis, and safety assessment of a soil and plant-based natural material with microbiome- and immune-modulatory effects.

It has been suggested that reduced contact with microbiota from the natural environment contributes to the rising incidence of immune-mediated inflammatory disorders (IMIDs) in western, highly urbanized societies. In line with this, we have previously shown that exposure to environmental microbiota in the form of a blend comprising of soil and plant-based material (biodiversity blend; BDB) enhances the diversity of human commensal microbiota and promotes immunoregulation that may be associated with a reduced risk for IMIDs. To provide a framework for future preclinical studies and clinical trials, this study describes how the preparation of BDB was standardized, its microbial content analysed and safety assessments performed.

Enteroviruses: epidemic potential, challenges and opportunities with vaccines.

Enteroviruses (EVs) are the most prevalent viruses in humans. EVs can cause a range of acute symptoms, from mild common colds to severe systemic infections such as meningitis, myocarditis, and flaccid paralysis. They can also lead to chronic diseases such as cardiomyopathy.

Coxsackievirus infection induces direct pancreatic β cell killing but poor antiviral CD8 T cell responses.

Coxsackievirus B (CVB) infection of pancreatic β cells is associated with β cell autoimmunity and type 1 diabetes. We investigated how CVB affects human β cells and anti-CVB T cell responses. β cells were efficiently infected by CVB in vitro, down-regulated human leukocyte antigen (HLA) class I, and presented few, selected HLA-bound viral peptides.

Coxsackievirus infection induces direct pancreatic β-cell killing but poor anti-viral CD8+ T-cell responses.

Coxsackievirus B (CVB) infection of pancreatic β cells is associated with β-cell autoimmunity. We investigated how CVB impacts human β cells and anti-CVB T-cell responses. β cells were efficiently infected by CVB , downregulated HLA Class I and presented few, selected HLA-bound viral peptides.

Coxsackievirus and Type 1 Diabetes: Diabetogenic Mechanisms and Implications for Prevention.

The evidence for an association between coxsackievirus B (CVB) infection, pancreatic islet autoimmunity, and clinical type 1 diabetes is increasing. Results from prospective cohorts and pancreas histopathology studies have provided a compelling case. However, the demonstration of a causal relationship is missing, and is likely to remain elusive until tested in humans by avoiding exposure to this candidate viral trigger.

Targeted plasma proteomics reveals signatures discriminating COVID-19 from sepsis with pneumonia.

Background: COVID-19 remains a major public health challenge, requiring the development of tools to improve diagnosis and inform therapeutic decisions. As dysregulated inflammation and coagulation responses have been implicated in the pathophysiology of COVID-19 and sepsis, we studied their plasma proteome profiles to delineate similarities from specific features.

Methods: We measured 276 plasma proteins involved in Inflammation, organ damage, immune response and coagulation in healthy controls, COVID-19 patients during acute and convalescence phase, and sepsis patients; the latter included (i) community-acquired pneumonia (CAP) caused by Influenza, (ii) bacterial CAP, (iii) non-pneumonia sepsis, and (iv) septic shock patients.

Coxsackievirus B infections are common in Cystic Fibrosis and experimental evidence supports protection by vaccination.

Viral respiratory tract infections exacerbate airway disease and facilitate life-threatening bacterial colonization in cystic fibrosis (CF). Annual influenza vaccination is recommended and vaccines against other common respiratory viruses may further reduce pulmonary morbidity risk. Enteroviruses have been found in nasopharyngeal samples from CF patients experiencing pulmonary exacerbations.

The Karolinska KI/K COVID-19 Immune Atlas: An open resource for immunological research and educational purposes.

The Karolinska KI/K COVID-19 Immune Atlas project was conceptualized in March 2020 as a part of the academic research response to the developing SARS-CoV-2 pandemic. The aim was to rapidly provide a curated dataset covering the acute immune response towards SARS-CoV-2 infection in humans, as it occurred during the first wave. The Immune Atlas was built as an open resource for broad research and educational purposes.

High-dimensional profiling reveals phenotypic heterogeneity and disease-specific alterations of granulocytes in COVID-19.

Since the outset of the COVID-19 pandemic, increasing evidence suggests that the innate immune responses play an important role in the disease development. A dysregulated inflammatory state has been proposed as a key driver of clinical complications in COVID-19, with a potential detrimental role of granulocytes. However, a comprehensive phenotypic description of circulating granulocytes in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients is lacking.

Coxsackievirus B Vaccines Prevent Infection-Accelerated Diabetes in NOD Mice and Have No Disease-Inducing Effect.

Enteroviruses, including the Coxsackievirus Bs (CVB), have been implicated as causal agents in human type 1 diabetes. Immunization of at-risk individuals with a CVB vaccine provides an attractive strategy for elucidating the role of CVBs in the disease etiology. Previously, we have shown that an inactivated whole-virus vaccine covering all CVB serotypes (CVB1-6) is safe to administer and highly immunogenic in preclinical models, including nonhuman primates.

Inhibition of Type III Interferon Expression in Intestinal Epithelial Cells-A Strategy Used by Coxsackie B Virus to Evade the Host's Innate Immune Response at the Primary Site of Infection?

Increasing evidence highlights the importance of the antiviral activities of the type III interferons (IFNλs; IL-28A, IL-28B, IL29, and IFNλ4) in the intestine. However, many viruses have developed strategies to counteract these defense mechanisms by preventing the production of IFNs. Here we use infection models, a clinical virus isolate, and several molecular biology techniques to demonstrate that both type I and III IFNs induce an antiviral state and attenuate Coxsackievirus group B (CVB) replication in human intestinal epithelial cells (IECs).

Defining the proteolytic landscape during enterovirus infection.

Viruses cleave cellular proteins to remodel the host proteome. The study of these cleavages has revealed mechanisms of immune evasion, resource exploitation, and pathogenesis. However, the full extent of virus-induced proteolysis in infected cells is unknown, mainly because until recently the technology for a global view of proteolysis within cells was lacking.

Structural Insight into CVB3-VLP Non-Adjuvanted Vaccine.

Coxsackievirus B (CVB) enteroviruses are common pathogens that can cause acute and chronic myocarditis, dilated cardiomyopathy, aseptic meningitis, and they are hypothesized to be a causal factor in type 1 diabetes. The licensed enterovirus vaccines and those currently in clinical development are traditional inactivated or live attenuated vaccines. Even though these vaccines work well in the prevention of enterovirus diseases, new vaccine technologies, like virus-like particles (VLPs), can offer important advantages in the manufacturing and epitope engineering.

Mouse Models of Virus-Induced Type 1 Diabetes.

Virus infections have been linked to the induction of autoimmunity and disease development in human type 1 diabetes. Experimental models have been instrumental in deciphering processes leading to break of immunological tolerance and type 1 diabetes development. Animal models have also been useful for proof-of-concept studies and for preclinical testing of new therapeutic interventions.

Antibody Responses against Enterovirus Proteases are Potential Markers for an Acute Infection.

Background: Enteroviruses are a group of common non-enveloped RNA viruses that cause symptoms ranging from mild respiratory infections to paralysis. Due to the abundance of enterovirus infections it is hard to distinguish between on-going and previous infections using immunological assays unless the IgM fraction is studied.

Methods: In this study we show using Indirect ELISA and capture IgM ELISA that an IgG antibody response against the nonstructural enteroviral proteins 2A and 3C can be used to distinguish between IgM positive ( = 22) and IgM negative ( = 20) human patients with 83% accuracy and a diagnostic odds ratio of 30.

Human Enterovirus Group B Viruses Rely on Vimentin Dynamics for Efficient Processing of Viral Nonstructural Proteins.

We report that several viruses from the human enterovirus group B cause massive vimentin rearrangements during lytic infection. Comprehensive studies suggested that viral protein synthesis was triggering the vimentin rearrangements. Blocking the host cell vimentin dynamics with β, β'-iminodipropionitrile (IDPN) did not significantly affect the production of progeny viruses and only moderately lowered the synthesis of structural proteins such as VP1.

Formalin treatment increases the stability and immunogenicity of coxsackievirus B1 VLP vaccine.

Type B Coxsackieviruses (CVBs) are a common cause of acute and chronic myocarditis, dilated cardiomyopathy and aseptic meningitis. However, no CVB-vaccines are available for human use. We have previously produced virus-like particles (VLPs) for CVB3 with a baculovirus-insect cell production system.

A comparative study of the effect of UV and formalin inactivation on the stability and immunogenicity of a Coxsackievirus B1 vaccine.

Type B Coxsackieviruses (CVBs) belong to the enterovirus genus, and they cause both acute and chronic diseases in humans. CVB infections usually lead to flu-like symptoms but can also result in more serious diseases such as myocarditis, aseptic meningitis and life-threatening multi-organ infections in young infants. Thus, CVBs have long been considered as important targets of future vaccines.

Coxsackievirus B Persistence Modifies the Proteome and the Secretome of Pancreatic Ductal Cells.

The group B Coxsackieviruses (CVB), belonging to the Enterovirus genus, can establish persistent infections in human cells. These persistent infections have been linked to chronic diseases including type 1 diabetes. Still, the outcomes of persistent CVB infections in human pancreas are largely unknown.

Genetic and Environmental Interaction in Type 1 Diabetes: a Relationship Between Genetic Risk Alleles and Molecular Traits of Enterovirus Infection?

Purpose Of Review: We provide an overview of the current knowledge regarding the natural history of human type 1 diabetes (T1D) and the documented associations between virus infections (in particular the enteroviruses) and disease development. We review studies that examine whether T1D-specific risk alleles in genes involved in the function of the immune system can alter susceptibility to virus infections or affect the magnitude of the host antiviral response. We also highlight where the major gaps in our knowledge exist and consider possible implications that new insights gained from the discussed gene-environment interaction studies may bring.