Charline Miot’s research while affiliated with University of Angers and other places

Our study, including serum from 3678 hospital inpatients and outpatients sampled before, during and after the COVID-19 lockdown periods, showed a significant decrease in overall IgG levels during the periods of sanitary restriction, particularly in children 3–10 years of age. Few months after the lifting of COVID-19 restrictions, immunoglobulin levels normalized. COVID-19 lockdowns may have induced a transient humoral immune gap.

Background: X-Linked immunodeficiency with magnesium defect, Epstein-Barr virus infection and neoplasia (XMEN) disease is a primary immunodeficiency due to loss-of-function mutations in the gene encoding for the magnesium transporter 1 (MAGT1). Furthermore, as MAGT1 is involved in the N-glycosylation process, XMEN disease is classified as a Congenital Disorder of Glycosylation. Although XMEN-associated immunodeficiency is well described, the mechanisms underlying platelet dysfunction and responsible for life-threatening bleeding events have never been investigated. Objectives: To assess platelet functions in XMEN patients. Patients/methods: Two unrelated young boys, including one before and after hematopoietic stem-cell transplantation (HSCT), were investigated for their platelet functions, glycoprotein expression, and serum and platelet-derived N-glycans. Results: Platelet analysis highlighted abnormal elongated cells and unusual barbell-shaped proplatelets. Platelet aggregation, integrin αIIbβ3 activation, calcium mobilization and protein kinase C (PKC) activity were impaired in both patients. Strikingly, platelet responses to protease-activated receptor 1 activating peptide (PAR1-AP) were absent at both low and high concentrations. These defects were also associated with decreased molecular weight of glycoprotein (GP)Ibα, GPVI and integrin αIIb due to a partial impairment of N-glycosylation. All these defects were corrected after HSCT. Conclusions: Our results highlight prominent platelet dysfunction related to MAGT1 deficiency and a defective N-glycosylation in several platelet proteins, that could explain the hemorrhages reported in XMEN patients.

Zinc is an essential trace mineral. Dietary zinc deficiency results in stunted growth, skin lesions, hypogonadism, and frequent infections in humans. Mice genetically lacking Slc30a7 suffer from mild zinc deficiency and are prone to development of prostate cancer and insulin resistance. Disease-causing variants or mutations in the human SLC30A7 (ZNT7) gene have not been previously reported. Here we describe two-boy siblings from a French family with stunted growth, testicular hypoplasia, and bone marrow failure. Exome sequencing revealed compound heterozygous variants in ZNT7 consisting of NM_133496.5:c.21dup; p.Asp8ArgfsTer3 and c.842 + 15 T > C inherited from their unaffected mother and father, respectively. The c.21dup variant led to a premature stop codon generated in exon 1 of the ZNT7 coding sequence. RNA-seq analysis demonstrated that the c.842 + 15 T > C variant resulted in a leaky mRNA splicing event generating a premature stop codon right after the splicing donor site of exon 8. Moreover, the expression of ZNT7 protein was remarkably reduced by 80-96% in the affected brothers compared to the control cells. These findings strongly suggest that biallelic variants in SLC30A7 should be considered as a cause of growth retardation, testicular hypoplasia, and syndromic bone marrow failure.

Background & Aims Interleukin-26 (IL-26) is a proinflammatory cytokine involved in the pathophysiology of chronic inflammatory disorders. It has properties atypical for a cytokine, such as direct antibacterial activity and DNA-binding capacity. In a previous study, we observed an accumulation of IL-26 in fibrotic and inflammatory lesions in the livers of patients with chronic hepatitis C virus (HCV) infection and showed that infiltrating CD3⁺ lymphocytes were the principal source of IL-26. Surprisingly, immunohistochemical staining for IL-26 was also detected in the cytoplasm of hepatocytes from HCV-infected patients, even though these cells do not produce IL-26, even when infected with HCV. Based on this observation and possible interactions between IL-26 and nucleic acids, we investigated the possibility that IL-26 controlled HCV infection independently of the immune system. Methods We evaluated the ability of IL-26 to interfere with HCV replication in hepatocytes, and investigated the mechanisms by which IL-26 exerts its antiviral activity. Results We showed that IL-26 penetrated HCV-infected hepatocytes, where it interacted directly with HCV double-stranded RNA replication intermediates, thereby inhibiting viral replication. IL-26 interfered with viral RNA-dependent RNA polymerase activity, preventing the de novo synthesis of viral genomic single-stranded RNA. Conclusions These findings reveal a new role for IL-26 in direct protection against HCV infection, independently of the immune system, and increase our understanding of the antiviral defense mechanisms controlling HCV infection. Future studies should evaluate the possible use of IL-26 for treating other chronic disorders caused by RNA viruses, for which few treatments are currently available, or emerging RNA viruses. Lay summary This study sheds new light on the body’s arsenal for controlling HCV infection and identifies IL-26 as an antiviral molecule capable of blocking HCV replication. IL-26, which has unique biochemical and structural characteristics, penetrates infected hepatocytes and interacts directly with viral RNA, thereby blocking viral replication. IL-26 is, therefore, a new player in antiviral defenses, operating independently of the immune system. It is of considerable potential interest for treating HCV infection and other chronic disorders caused by RNA viruses for which few treatments are currently available, and for combating emerging RNA viruses.

Epstein-Barr virus (EBV) preferentially infects epithelial cells and B lymphocytes and sometimes T and NK lymphocytes. Persistence of EBV-infected cells results in severe lymphoproliferative disorders (LPDs). Diagnosis of EBV-driven T or NK cell LPD and chronic active EBV diseases (CAEBV) is difficult, often requiring biopsies. Herein, we report a flow-FISH cytometry assay that detects cells expressing EBV-encoded small RNAs (EBERs), allowing rapid identification of EBV-infected cells among PBMCs. EBV-infected B, T, and/or NK cells were detectable in various LPD conditions. Diagnosis of CAEBV in 22 patients of Caucasian and African origins was established. All exhibited circulating EBV-infected T and/or NK cells, highlighting that CAEBV is not restricted to native American and Asian populations. Proportions of EBV-infected cells correlated with blood EBV loads. We showed that EBV-infected T cells had an effector memory activated phenotype, whereas EBV-infected B cells expressed plasma cell differentiation markers. Thus, this method achieves accurate and unambiguous diagnoses of different forms of EBV-driven LPD and represents a powerful tool to study their pathophysiological mechanisms.