Phenotypic complementation of genetic immunodeficiency by chronic herpesvirus infection

Abstract

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.DOI: http://dx.doi.org/10.7554/eLife.04494.001

Intestinal virome changes precede autoimmunity in type I diabetes-susceptible children

“…This suggests the hypothesis that the balance between protective and disease causing changes in the virome may modulate human autoimmune disease in genetically susceptible individuals. This would be consistent with the finding that viruses can interact with host disease risk genes to modulate diseases in mice (22,58,59). Taken together, these findings in a single cohort suggest a model in which the risk for human autoimmunity (in this case T1D) is related to a combination of protective vs. disease riskconferring effects of the virome.…”

Role of Linear Ubiquitination in Health and Disease

“…However, HOIL-1L-deficient BMDMs respond to TNF-a stimulation in a similar manner to their WT counterparts (51). These phenotypic differences support the reasoning that HOIL-1L and SHARPIN may differentially contribute to complex formation and have distinct functions independent of the complex that may vary by cell type (69).…”

“…Conversely, naive HOIL-1L 2/2 mice are viable and show no overt phenotype compared with their wild-type (WT) counterparts (68). Interestingly, HOIL-1L knockout mice presented immunodeficiency on infection with Listeria monocytogenes, Citrobacter rodentium, or Toxoplasma gondii, whereas exposure to murine C-herpesvirus 68 or Mycobacterium tuberculosis was met with hyperinflammation (69). In addition, studies done in BMDM derived from mice lacking SHARPIN exhibit NF-kB defects classically associated with a loss of LUBAC function (70).…”

“…Although SHARPIN lacks a catalytic domain, it has been shown to interact with other proteins to affect physiological responses (69). In addition to binding to HOIP, the UBL domain of SHARPIN has been shown to bind cellular integrins (71).…”

Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease

“…The importance of the linear ubiquitin pathway in the regulation of innate immune responses has been demonstrated in murine models. Mice deficient in LUBAC subunits have variable degrees of inflammation, from a mild phenotype in HOIL-1-deficient mice (16) to more severe inflammation and dermatitis in SHARPIN KO (2,17) to defective vascularization and embryonic lethality in HOIP KO (18). Consistent with the essential function of OTULIN in regulation of multiple signaling pathways, OTULINdeficient mice (gumby/gumby) are embryonic lethal due to vascular and neuronal defects caused by dysregulation in canonical Wnt signaling (8).…”