Phenotypic complementation of genetic immunodeficiency by chronic herpesvirus infection

Variation in the presentation of hereditary immunodeficiencies may be explained by genetic or environmental factors. Patients with mutations in HOIL1 (RBCK1) present with amylopectinosis-associated myopathy with or without hyper-inflammation and immunodeficiency. We report that barrier-raised HOIL-1-deficient mice exhibit amylopectin-like deposits in the myocardium but show minimal signs of hyper-inflammation. However, they show immunodeficiency upon acute infection with Listeria monocytogenes, Toxoplasma gondii or Citrobacter rodentium. Increased susceptibility to Listeria was due to HOIL-1 function in hematopoietic cells and macrophages in production of protective cytokines. In contrast, HOIL-1-deficient mice showed enhanced control of chronic Mycobacterium tuberculosis or murine γ-herpesvirus 68 (MHV68), and these infections conferred a hyper-inflammatory phenotype. Surprisingly, chronic infection with MHV68 complemented the immunodeficiency of HOIL-1, IL-6, Caspase-1 and Caspase-1;Caspase-11-deficient mice following Listeria infection. Thus chronic herpesvirus infection generates signs of auto-inflammation and complements genetic immunodeficiency in mutant mice, highlighting the importance of accounting for the virome in genotype-phenotype studies

Uric Acid in Sugar Cane Workers in Nicaragua

Background: A significant increase in Chronic Kidney Disease of unknown etiology in persons 20-40 persists in Nicaragua and El Salvador despite 15 years of research. The disease is known as Mesoamerican Nephropathy (MeN). Men and women have early morbidity and mortality from this disease, however this study focuses on males, as it disproportionately affects them. One possible etiology that is lacking in studies is elevated uric acid among field workers on sugarcane farms. Objective: Characterize prevalence of hyperuricemia and changes in uric acid among field workers. Methods: Measured biomarkers of uric acid were used to create dichotomous uric acid variables. Unconditional logistic regression was used to estimate prevalence odds ratios for field work, dichotomous hyperuricemia and dichotomous years worked at ISA. Results: In this population the CKD prevalence was 33% with low hematuria and low proteinuria, which is similar to other MeN studies.. There was an increased odds of hyperuricemia of 1.3 for those that ever worked in the field as a cane cutter and/or irrigator versus those who had not. There was an increased odds of having multiple episodes of hyperuricemia of 7.9 for those who worked in a field vs those who did not. Conclusion: There appears to be an association between field workers and hyperuricemia and incidents of hyperuricemia, which could be a precursor to MeN

Phenotypic complementation of genetic immunodeficiency by chronic herpesvirus infection.

Variation in the presentation of hereditary immunodeficiencies may be explained by genetic or environmental factors. Patients with mutations in HOIL1 (RBCK1) present with amylopectinosis-associated myopathy with or without hyper-inflammation and immunodeficiency. We report that barrier-raised HOIL-1-deficient mice exhibit amylopectin-like deposits in the myocardium but show minimal signs of hyper-inflammation. However, they show immunodeficiency upon acute infection with Listeria monocytogenes, Toxoplasma gondii or Citrobacter rodentium. Increased susceptibility to Listeria was due to HOIL-1 function in hematopoietic cells and macrophages in production of protective cytokines. In contrast, HOIL-1-deficient mice showed enhanced control of chronic Mycobacterium tuberculosis or murine γ-herpesvirus 68 (MHV68), and these infections conferred a hyper-inflammatory phenotype. Surprisingly, chronic infection with MHV68 complemented the immunodeficiency of HOIL-1, IL-6, Caspase-1 and Caspase-1;Caspase-11-deficient mice following Listeria infection. Thus chronic herpesvirus infection generates signs of auto-inflammation and complements genetic immunodeficiency in mutant mice, highlighting the importance of accounting for the virome in genotype-phenotype studies