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.
Highlights
HOIL-1, HOIP (RNF31) and SHARPIN form the linear ubiquitin chain assembly complex (LUBAC), which linearly ubiquitinates receptor signaling complex components such as NEMO to enhance NF-κB activation after engagement of immune receptors including TNF-R1, IL-1R, MacDuff et al eLife 2015;4:e04494
We report that HOIL-1 is essential during infection with Listeria, T. gondii and C. rodentium, but not with murine γ-herpesvirus 68 (MHV68) or M. tuberculosis in mice
The requirement of HOIL-1 for the induction of protective inflammatory cytokines, TNFα, interleukin 6 (IL-6) and IL-12, following infection of macrophages with Listeria in vitro is consistent with reports that LUBAC is required for efficient NF-κB activation following TLR engagement (Zak et al, 2011; Boisson et al, 2012), but not with a recent report that NF-κB activation following stimulation of TLR4 and TNF-R1 on macrophages by LPS and TNFα, respectively, is unaffected by HOIL-1 deficiency (Rodgers et al, 2014)
Summary
HOIL-1 (encoded by the RBCK1 gene), HOIP (RNF31) and SHARPIN form the linear ubiquitin chain assembly complex (LUBAC), which linearly ubiquitinates receptor signaling complex components such as NEMO to enhance NF-κB activation after engagement of immune receptors including TNF-R1, IL-1R, MacDuff et al eLife 2015;4:e04494. Immunology | Microbiology and infectious disease eLife digest The immune system protects an individual from invading bacteria, viruses and parasites, as well as malfunctioning or cancerous host cells. Some people inherit genetic defects that cause part of the immune system to be missing or to not work properly. This is called a genetic immunodeficiency, and puts individuals at a higher risk of infection and disease. Only some of the individuals who have defects in both of their copies of a gene called HOIL-1—which has been linked to several roles in the body's immune response—are reported to suffer from an altered susceptibility to bacterial infections and chronic (persistent) inflammation. Gaining a clear understanding of the possible factors that influence such variations in the symptoms of genetic immune deficiencies could help to speed up their diagnosis, as well as helping to develop more effective treatments
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