Enterovirus Infection Research Articles

Echovirus serotype 11 induced sepsis in a young female patient with multiple sclerosis treated with anti-CD20 monoclonal antibody ocrelizumab.

Enterovirus infection has been described as a cause of severe viral sepsis in humorally immunosuppressed patients. A 20-year-old female with a history of multiple sclerosis on ocrelizumab therapy with persistent agammaglobulinemia and autoimmune hepatitis treated with azathioprine/budesonide presented with subacute sensorineural hearing loss, hepatitis, pneumonia, enterocolitis and pancreatitis. Molecular pathological techniques detected enterovirus RNA in samples from the liver, blood, ascites fluid, and pleural effusions, confirming Echovirus serotype 11. The case was managed successfully with supportive care and high-dose intravenous immunoglobulins in addition to fluoxetine. This patient's unique presentation and clinical course presents important implications for the care of immunosuppressed patients with cryptic complaints.

High mortality rates and long-term complications in children with infectious brainstem encephalitis: A study of sixteen cases.

Brainstem encephalitis (BE) can cause sudden death in children. Fewer studies have been conducted on the incidence, clinical manifestations, pathogens and post-infectious sequelae of pediatric infectious BE. Pediatric patients diagnosed with BE in our Medical Center from 01 January 2015 to 31 July 2024 were retrospectively reviewed. The clinical data of these children were obtained from the hospital's medical database on 15 August 2024. The number of outpatient and inpatient patients at our Medical Center during that period were provided by the hospital data center. Data analysis was conducted using Excel 2019. A total of twenty-eight cases were diagnosed with BE in our National Children's Medical Center over the past decade. Among them, 57.1% (16/28) cases were diagnosed with infectious BE. The incidence of infectious BE was estimated to be 16 cases per 30 million outpatient visits and 13 cases per 500,000 hospitalized patients. Fever, consciousness disorders and seizures were observed in 75.0% (12/16), 68.8% (11/16) and 62.5% (10/16) of the cases, respectively. Among them, 31.3% (5/16) cases were diagnosed as human enterovirus infections, 12.5% (2/16) cases were confirmed to be influenza B virus infections, while one case each was diagnosed with herpes simplex virus 1 and human herpesvirus 6 infection. The mortality rate during hospitalization was 12.5% (2/16). Among the surviving patients, 50.0% (7/14) of them had follow-up records, 85.7% (6/7) of the survivors suffered from sequelae such as motor disorders. Fever, consciousness disorders and seizures were the major clinical manifestations in patients with infectious BE visited our Medical Center. These rare cases exhibited a notably high mortality rate and a significant frequency of long-term complications.

Hemophagocytic lymphohistiocytosis in a neonate with enterovirus infection: case report and literature review

Hemophagocytic lymphohistiocytosis in a neonate with enterovirus infection: case report and literature review

868 Severe neonatal enterovirus infection: a case study of complications and management

868 Severe neonatal enterovirus infection: a case study of complications and management

P-2354. Neonatal Enterovirus and Parechovirus Infections—National Enterovirus Surveillance System, United States, 2004–2022

Abstract Background Enteroviruses (EV)—a group of viruses including echoviruses (E) and coxsackieviruses (CV)—and parechoviruses (PeV) can cause a range of symptoms, including respiratory illness; hand, foot, and mouth disease; acute flaccid myelitis; meningitis; and sepsis. Neonates (persons < 1 month old) are at higher risk of severe EV or PeV disease. We analyzed data from the National Enterovirus Surveillance System (NESS) to assess types and outcomes of neonatal EV and PeV infections reported during 2004–2022. Methods NESS is a passive, laboratory-based surveillance system that collects reports of positive EV and PeV virus type results in the United States. We analyzed data on EV and PeV specimens collected during January 1, 2004–December 31, 2022. Outcome data (defined as whether the patient died) were reported to NESS during 2014–2022. Chi-squared tests were used to compare virus type frequencies by age, with differences considered significant if p < 0.05. Results Overall, 10,833 EV and PeV infections were reported during 2004–2022: 9,197 (85%) had reported age, of which 753 (8%) were among neonates. Among 631 neonatal EV or PeV infections with identified virus type (84%), Coxsackievirus type B5 (CVB5) (76; 12%), CVB3 (64; 10%), PeVA3 (61; 10%), E11 (54; 9%), and CVB4 (52; 8%) were detected most frequently. Compared with persons ≥ 1 month old, CVB types 1–5, PeVA3, and E11 were significantly more likely to be detected among neonates, whereas EV-D68 and E30 infections were less common. Among 483 neonates with EV or PeV infections during 2014–2022, 68 (14%) had known outcome, of whom 16 (24%) died. Conclusion EV and PeV infections can cause severe disease among neonates. The frequencies of EV and PeV virus types detected among neonates differ from those among persons ≥1 month old, although this may partially reflect testing differences by age. Assessing mortality among neonates with EV and PeV illness is limited by incomplete outcome data and lack of systematic EV and PeV testing and reporting, which may be biased toward including patients with more severe illness. Strengthening capacity for EV and PeV testing, typing, and surveillance would be beneficial for understanding the disease burden among neonates and informing treatment options and prevention measures. Disclosures All Authors: No reported disclosures

P-2363. Efficacy Of SARS–CoV-2 Specific Antiviral Therapy for Enteroviral Myalgic Encephalomyelitis/ChronicFatigue Syndrome

Abstract Background Etiology remains elusive for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), and no treatment exists. Antivirals had no efficacy in randomized clinical trials (RCT) for Epstein-Barr Virus and HHV-6. Enteroviruses (EV) have been implicated, but no antivirals are available. Many patients who received SARS–CoV-2-specific antiviral drugs for acute Covid-19 (COV19) infection experienced significant improvement of prior ME/CFS symptoms. This study summarizes their responses to antivirals for SARS-Cov-2. Methods Neutralizing Antibody (NA) for Coxsackievirus B (CVB)1-6 and Echovirus 6, 7, 9, 11, 30 were done by ARUP lab. Enterovirus Protein (EVP) of Peripheral Blood Leukocytes (PBL) was determined by Western Blot. ME/CFS patients fulfilled Canadian consensus criteria, and had either elevated NA for enteroviruses and/or positive EVP in PBL. ME/CFS patients hospitalized for acute COV19 infection and patients without COV19, were given 5-10 days of IV Remdesivir (Rem) +/- immune modulators. Controls: 20 ME/CFS patients seen concurrently without Remdesivir treatment. Other ME/CFS patients (non-COV19) were given Nirmaltrelvir/Ritonavir (PAX) daily for 10 days +/- one repeat. The energy index (EI) was monitored by the patients before, during and after treatment. Significant improvement was defined as > 30%. Results 15/20 (75%) ME/CFS patients – 10/12 hospitalized, 5/8 non-COV19 patients – responded to IV Rem 2-6 weeks after infusions; remission lasted 6-8 weeks to 6-9 months before relapse. Of Controls: 2/20 had mild improvement (< 0.001, X 2 ). 104/200 (52%) of PAX-treated ME/CFS patients improved, often within 2-3 days; all relapsed within days to weeks after treatment. 66%, 33% and 44% of CVB4+, CVB3+, non-CVB3,4+ patients responded to treatment, respectively. EVP decreased and increased with clinical response and relapse. Conclusion Rem and PAX demonstrated clinical efficacy in ME/CFS patients with chronic enterovirus infections. Placebo-controlled RCT will be needed to clarify the role of antivirals in ME/CFS. Disclosures All Authors: No reported disclosures

298. Host Response Profiling from Clinical Metagenomic Sequencing Data for Diagnosis of Central Nervous System Infections

Abstract Background Clinical metagenomic next-generation sequencing (mNGS) testing of cerebrospinal fluid (CSF) increases diagnostic yield for suspected central nervous system (CNS) infections. Nevertheless, up to 45% of cases remain unknown despite extensive testing and 6 months of follow-up. We developed artificial intelligence-machine learning (AI-ML) classification models (classifiers) based on RNA gene expression / host response data from CSF mNGS testing to enhance diagnostic performance.Figure 1.An artificial intelligence machine learning classifier. (A) Schematic illustration of the different steps to generate the sub-classifiers then integrated into a consensus classifier. (B) The parasitic sub-classifier was generated using the "leave-one-out" algorithm due to the low sample numbers. (C) Performance metrics of the main classifiers. Methods From June 2016 and April 2023, 464 CSF mNGS results from UCSF patients with a confirmed viral (n=175), bacterial (n=91), fungal (n=44), or non-infectious (n=155) diagnosis were randomly divided into training and test subsets in an 80:20 ratio (Figure 1A). Clinicians adjudicated their confidence in the final diagnosis based on blinded medical chart review and laboratory test results. Gene (feature) selection was carried out using high-confidence samples, followed by 50-fold cross-validation. All possible pairwise comparisons were performed to generate sub-classifiers which were then integrated into a consensus classifier. Performance metrics were obtained by running the consensus classifier on the independent test subset. A separate classifier was developed for parasitic infections (n=24) using a “leave-one-out” algorithm to assess performance (Figure 1B). Classifier results were displayed as a score ranging from 0 to 10, corresponding to specificities of ≤70% to ≥99%.Figure 2.Differentially expressed gene analysis with pair-wise comparison between sub-classifiers. Left panel shows genes selected by the LASSO (least absolute shrinkage and selection operator) algorithm, and right panel the pathway/function these genes. Results Classifier accuracy based on the test set was 83%, with individual area under the curve (AUC) scores ranging from 0.88-0.93 for each category (Figure 1C). The function of the selected genes corresponded well with the category (Figure 2). Classifier examples include patients with (i) culture-negative CNS tuberculosis, (ii) persistent Toxoplasma gondii infection despite 19 days of treatment, (iii) a rare autoimmune syndrome, and (iv) a chronic enterovirus infection misclassified as an atypical bacterial infection, suggesting that acute and chronic host response profiles differ (Figure 3).Figure 3.Classifier examples. (i) culture-negative CNS tuberculosis, (ii) persistent Toxoplasma gondii infection despite 19 days of treatment, (iii) a rare autoimmune syndrome, and (iv) a chronic enterovirus infection misclassified as an atypical bacterial infection. Conclusion Host response profiling with AI-ML classifiers complements mNGS testing and can enhance diagnostic yield for unexplained CNS syndromes. Disclosures Charles Chiu, MD, PhD, Abbott Laboratories, Inc: Grant/Research Support|Biomeme: Advisor/Consultant|Biomeme: Board Member|BiomeSense: Advisor/Consultant|BiomeSense: Board Member|Delve Bio: Advisor/Consultant|Delve Bio: Board Member|Delve Bio: Grant/Research Support|Flightpath Biosciences: Advisor/Consultant|Flightpath Biosciences: Board Member|Mammoth Biosciences: Advisor/Consultant|Mammoth Biosciences: Board Member|Pathogen detection using next generation sequencing: US patent 11380421|Poppy Health: Advisor/Consultant|Poppy Health: Board Member

ILC3 Function as a Double-Edged Sword in EV71 Infection

Enterovirus 71 (EV71) is a common pathogen responsible for hand, foot, and mouth disease (HFMD), leading to severe neurological complications and even death. However, the mechanisms underlying severe EV71-induced disease remain unclear, and no effective specific treatments are available. In this study, we successfully infected mice of different ages using a mouse-adapted EV71 strain, resulting in disease and mortality. We compared immune system responses between infected and uninfected mice of different ages to identify key pathogenic targets during EV71 infection. Our findings revealed that the level of Group 3 Innate Lymphoid Cells (ILC3s) in mice negatively correlated with the severity of disease induced by EV71 infection. We conducted anti-ILC3 cytokine injections and cytokine neutralizing antibody experiments on 14-day-old EV71-infected mice. The results showed that the cytokine IL-17 secreted by ILC3 cells had a mild protective effect, while IL-22 promoted inflammatory responses. Our research demonstrates that ILC3 cells play a dual role in EV71 infection. These findings not only clarify key immune factors in the progression of EV71-induced disease but also provide a promising approach for the early diagnosis and treatment of severe EV71 infections.

A serosurvey study of hand, foot and mouth disease in healthy children aged 6 to 71 months old in West Bandung and Bandung Region, Indonesia

BackgroundHand, foot, and mouth disease (HFMD) is an infectious disease that often affects children under 5 years of age. Over the past 20 years, enterovirus 71 (EV71) has become a major concern among children, especially in the Asia-Pacific region. Currently, there are no data showing the seroprevalence of HMFDs in Indonesia. This study aimed to determine the seroprevalence of antibodies to EV71 infection in rural and urban areas.MethodsThis study was an observational analysis and cross-sectional seroprevalence survey of HFMD in children aged 6 to 71 months. The sampling locations were the Padalarang health centre, which is rural, and the Garuda health centre, which is urban. The total sample included 600 children aged 6–71 months from these two locations. Blood sample testing uses enzyme-linked immunosorbent assays (ELISAs) to identify subjects who are positive for IgG EV71 and the risk factors that may influence it.ResultsIn total, 596 subjects (99.3%) were positive for the seroprevalence of EV71 IgG in rural and urban areas. Child age, sex, nutritional status, height/age, immunisation status, parental income, and father’s and mother’s educations were not statistically related in rural and urban areas (p > 0.05) because the rate of IgG EV71 seropositivity was very high.ConclusionThis study revealed that the rate of IgG EV71 HFMD seropositivity in Indonesia, especially in the Padalarang health centre and Garuda health centre, was very high. Further research is needed to investigate HFMD cases because of the lack of attention given to this disease and the need to consider whether immunisation is necessary to prevent HFMD.Trial registrationThis study is registered at clinicaltrials.gov, National Clinical Trial (NCT) No. NCT05637229.

Synergistic combination of orally available safe-in-man pleconaril, AG7404, and mindeudesivir inhibits enterovirus infections in human cell and organoid cultures

Enteroviruses can infect various human organs, causing diseases such as meningitis, the common cold, hand-foot-and-mouth disease, myocarditis, pancreatitis, hepatitis, poliomyelitis, sepsis, and type 1 diabetes. Currently, there are no approved treatments for enterovirus infections. In this study, we identified a synergistic combination of orally available, safe-in-man pleconaril, AG7404, and mindeudesivir, that at non-toxic concentrations effectively inhibited enterovirus replication in human cell and organoid cultures. Importantly, the cocktail did not alter glucose and insulin levels in the culture medium of pancreatic β-cells and preserved the contraction rhythm of infected heart organoids. These findings highlight a promising drug cocktail for further preclinical studies and clinical trials targeting a broad range of enterovirus-mediated diseases.

Opportunistic enteroviral infections in MS patients treated with anti-CD20 therapies.

Opportunistic enteroviral infections in MS patients treated with anti-CD20 therapies.

In Vivo and In Vitro Studies Assessing the Antiviral Efficacy of Double Combinations Against Coxsackievirus B Infection.

Coxsackievirus B (CVB) infections, ranging from mild to severe diseases, lack specific antiviral treatments, underscoring the need for novel therapeutic strategies. Drug therapy is an important tool for controlling enterovirus infections, but clinically effective drugs do not currently exist, mainly due to the development of drug resistance. Combination therapy with two or more drugs has the potential to successfully inhibit viral infection more effectively than either drug alone as well as delay the development of resistance. This study explores the consecutive alternating administration (CAA) scheme in mice with CVB1 infection, utilizing double antiviral combinations consisting of pleconaril and MDL-860, with guanidine hydrochloride and oxoglaucine. The CAA combinations of pleconaril achieved a survival rate, in infected mice, of up to 59%, while the combinations of MDL-860 showed no significant effects. CAA reduced mortality, prolonged mean survival time (up to 5 days), and mitigated drug resistance compared to monotherapy or simultaneous administration. Monotherapeutic courses and daily administration of double combinations had no effect. Phenotypic characterization using the IC50 marker of virus isolates from brain tissue of infected and treated mice was of particular importance for the evaluation of the CAA treatment scheme. The results show increased susceptibility of the virus isolates to the partner compounds in double CAA combinations. In contrast, virus isolates from the monotherapeutic groups manifested a diminished susceptibility to their respective compound, which signals the development of drug resistance. All data obtained prove the potential of the CAA scheme for the development of effective chemotherapy of enterovirus infections.

Completely conserved VP2 residue K140 of KREMEN1-dependent enteroviruses is critical for virus-receptor interactions and viral infection.

Hand, foot, and mouth disease (HFMD) annually affects millions of children worldwide. HFMD is caused by various enteroviruses, such as coxsackieviruses CVA6, CVA16, CVA10, and enterovirus 71 (EV-A71). Licensed inactivated EV-A71 vaccines do not provide cross-protection against other enteroviruses. There are no drugs specifically for HFMD. KREMEN1 (KRM1) serves as the cellular receptor for many HFMD-related enteroviruses, including CVA2-CVA6, CVA10, and CVA12. However, the molecular basis for broad recognition of these enteroviruses by the KRM1 receptor remains elusive. Here, we report that VP2 residue K140 (K2140) is completely conserved among all KRM1-dependent enteroviruses and is essential for virus-receptor binding and viral infection by interacting with residue D90 of KRM1. Overall, our findings provide a deeper understanding of the molecular basis of KRM1-dependent enterovirus infection in vitro and in vivo and may contribute to the development of broad-spectrum anti-enterovirus vaccines and treatments.

Neonatal acute liver failure cases with echovirus 11 infections, Japan, August to November 2024.

In 2022-23, several European countries reported paediatric acute liver failure (ALF) with enterovirus infection. In August-November 2024, three neonatal cases of ALF with echovirus 11 (E11) were reported in Tokyo, Japan. All neonates developed irreversible multiple-organ failure and died. The E11 strain belonged to the new lineage 1, which was the same as strains isolated from neonatal ALF cases in Europe in 2022-23.

Enterovirus and Parechovirus Neurologic Infections in Children: Clinical Presentations and Neuropathogenesis.

Enteroviruses (EVs) and parechoviruses (PeVs) are common pathogens of childhood. Enteroviral infections cause a range of clinical syndromes from mild illness to neurologic manifestations of meningitis, encephalitis, and acute flaccid myelitis. Disease manifestations are driven by a combination of viral replication and host immune response. Despite ubiquitousness and clinical importance, there are no approved targeted therapies for these viruses and most are without an available vaccine. Studies of EV neuropathogenesis began with poliovirus and are ongoing for other nonpolio EVs and PeVs. Many unanswered questions remain with regard to cellular tropism, mechanisms of dissemination, receptor usage, immunologic control, and cellular death. This review describes what is known about epidemiology, clinical presentations, and neuropathogenesis of these important pathogens.

Understanding the Genetic and Environmental Factors Contributing to Type 1 Diabetes

Introduction: Complex autoimmune illness type 1 diabetes (T1D) is affected by epigenetic, environmental, and hereditary elements. Good preventative and treatment plans depend on an awareness of these connections. The relationships among epigenetic changes in T1D development, environmental exposures, and genetic predispositions are examined in this work. Methodology: From June 2022 until June 2024, Lady Reading Hospital (LRH) in Peshawar carried out a case-control study there were 88 individuals in all, 44 healthy controls and 44 diagnosed T1D patients. Data on demographic and clinical traits, family history, and environmental exposures as well as on With an eye toward non-HLA loci (PTPN22, INS) and HLA class II alleles (DR3-DQ2, DR4-DQ8), genetic study Examined were particular gene DNA methylation patterns (PTPN2, FOXP3). Chi-square tests, t-tests, odds ratios, and logistic regression comprised the statistical analyses. Results: T1D patients had significantly higher frequencies of DR3-DQ2 (63.6%) and DR4-DQ8 (59.1%) compared to controls (22.7% and 27.3%, p < 0.001). T1D patients (45.5% and 40.9%) also more often had non-HLA loci PTPN22 and INS than controls (18.2% and 13.6%, p = 0.01). T1D was substantially correlated with environmental elements including enteroviral infections (50.0% vs. 18.2%, p = 0.002), early exposure to cow's milk (59.1% vs. 31.8%, p = 0.01), gluten (54.5% vs. 27.3%, p = 0.01), and changed gut microbiota (68.2% vs. 31.8%, p In T1D patients, epigenetic analysis identified hypermethylation of PTPN2 (60.0% vs. 20.0%, p = 0.01) and hypomethylation of FOXP3 (50.0% vs. 10.0%, p = 0.02). Conclusion: This work validates in T1D the functions of epigenetic changes, environmental triggers, and genetic predisposition. The interactions among these elements underline the multifaceted character of T1D and imply that thorough interventions should target environmental as well as genetic elements.

Human enteroviruses and the long road to acute flacid paralysis eradication.

Enteroviruses (EVs) are a highly diverse group of viruses multiplying primarily in the gastrointestinal tract and/or the upper respiratory tract, initially distributed in two separate genera: Enterovirus and Rhinovirus, respectively. According to the similarities in genome organization and particle structure, rhinovirus species were later reclassified as also belonging to genus Enterovirus. Human EV infections are usually asymptomatic or causing mild clinical manifestations. Nevertheless, some EV infections may derive in severe neural complications, including acute flaccid paralysis (AFP) such as poliomyelitis, whose etiological agent is poliovirus, a member of the Enterovirus C species. The inactivated polio vaccine (IPV) and particularly the oral attenuated polio vaccine (OPV) have contributed to the virtual eradication of the disease. However, sustained global circulation of vaccine-derived poliovirus 2 (cVDPV2), originated from the genetic instability of OPV strain 2 and intertypic recombination between Sabin OPV strains and members of the Enterovirus C species, still causes outbreaks of AFP worldwide. In addition, humanitarian crises, in particular armed conflicts, hamper polio vaccination campaigns and facilitate the occurrence of cases. Additionally, besides poliovirus, other EV may also cause AFP, among them EV A71 or EV D68, and it is highly advisable to implement wastewater surveillance to elucidate the occurrence of not only polioviruses, but also of other EV susceptible to derive in serious neural complications, since the screening of viral RNA in cerebrospinal fluid samples in patients suffering from AFP is not a reliable diagnostic tool.

The neurological damage caused by enterovirus 71 infection is associated with hsa_circ_0069335/miR-29b/PMP22 pathway.

Enterovirus 71 (EV71) infection is usually accompanied by neurological damage, which is the leading cause of death in children with hand-foot-mouth disease. In this study, we demonstrated that EV71 infection can cause pathological damage in the nervous system, such as neuronal vacuolar degeneration, shrinkage of some neurons, edema of brain tissues in the hippocampus, and a decreased number of Nissl bodies in the infarction area. Also, EV71 infection caused apparent structural damage to Schwann cells, including a decreased number of cytoplasmic organelles and severe damage of rough endoplasmic reticulum and mitochondria. However, the pathological damage was alleviated with the decrease of EV71 viral load. The cell experiment in vitro showed that EV71 infection significantly reduced ATP levels and promoted Schwann cell apoptosis, thus inhibiting cell growth. The extended infection time and the decreased viral load resulted in the gradual improvement of cell growth status. Meanwhile, EV71 inhibited the expression of miR-29b and promoted the expression of PMP22 in a time-dependent manner at both mRNA and protein levels, with the most significant change at 36 h of infection. Subsequently, the expression of miR-29b and PMP22 was gradually restored with the reduction of EV71 viral load. In addition, EV71 regulated the expression of hsa_circ_0069335, which could bind and co-localize with miR-29b. Therefore, EV71 infection can cause significant damage to the nervous system and may be related to hsa_circ_0069335/miR-29b/PMP22 pathway. The present study provides a new therapeutic target for neurological damage induced by EV71 infection.IMPORTANCEEV71 can cause severe neurological damage and even death, but the mechanism remains unclear. In this study, we exhibited the pathological changes of nervous system in EV71 infection and revealed that the damage degree was consistent with the EV71 viral load. From the molecular perspective, EV71 infection up-regulated the PMP22 expression in Schwann cells, which is accompanied by apparent structural damage of Schwann cells and myelin sheaths. Furthermore, EV71 promoted the expression of PMP22 and inhibited the expression of miR-29b in a time-dependent manner, with the most significant change at 36 h of infection. Otherwise, the hsa_circ_0069335, which binds and co-localizes with miR-29b, was also regulated by EV71 infection. The hsa_circ_0069335/miR-29b/PMP22 axis may be a potential molecular mechanism involved in EV71 infection-induced fatal neuronal damage. Drug development targeting this pathway may bring clinical improvement of EV71-infected patients.

Coxsackievirus and adenovirus receptor expression facilitates enteroviral infections to drive the development of pancreatic cancer

The development of pancreatic cancer requires both, acquisition of an oncogenic mutation in KRAS as well as an inflammatory insult. However, the physiological causes for pancreatic inflammation are less defined. We show here that oncogenic KRas-expressing pre-neoplastic lesion cells upregulate coxsackievirus (CVB) and adenovirus receptor (CAR). This facilitates infections from enteroviruses such as CVB3, which can be detected in approximately 50% of pancreatic cancer patients. Moreover, using an animal model we show that a one-time pancreatic infection with CVB3 in control mice is transient, but in the presence of oncogenic KRas drives chronic inflammation and rapid development of pancreatic cancer. We further demonstrate that a knockout of CAR in pancreatic lesion cells blocks these CVB3-induced effects. Our data demonstrate that KRas-caused lesions promote the development of pancreatic cancer by enabling certain viral infections.

Environmental Factors in Type 1 Diabetes.

The contribution of environmental factors to the pathogenesis of type 1 diabetes is considered substantial, but their identification has turned out to be challenging. Large prospective studies are crucial for reliable identification of environmental risk and protective factors. However, only few large prospective birth cohort studies have been carried out. Enterovirus infections have shown quite consistent risk association with the initiation of islet autoimmunity (IA) across these studies. Also, certain dietary factors have been consistently associated with IA risk, omega-3 fatty acids inversely, and childhood cow's milk intake directly. However, the mechanisms of these associations are not fully understood, and possible causality has not been confirmed. Clinical trial programs with enterovirus vaccines and antiviral drugs are in progress to evaluate the causality of enterovirus association. The only nutritional primary prevention randomized trial, TRIGR, did not find a difference between weaning to extensively hydrolyzed versus conventional cow's milk-based infant formula.