Mycobacterial Disease and Impaired IFN-γ Immunity in Humans with Inherited ISG15 Deficiency

Abstract

ISG15 is an interferon (IFN)-α/β-inducible, ubiquitin-like intracellular protein. Its conjugation to various proteins (ISGylation) contributes to antiviral immunity in mice. We describe human patients with inherited ISG15 deficiency and mycobacterial, but not viral diseases. The lack of intracellular ISG15 production and protein ISGylation was not associated with cellular susceptibility to any viruses tested, consistent with the lack of viral diseases in these patients. By contrast, the lack of mycobacterium-induced ISG15 secretion by leukocytes — granulocytes in particular — reduced the production of IFN-γ by lymphocytes, including natural killer cells, probably accounting for the enhanced susceptibility to mycobacterial disease. This experiment of Nature shows that human ISGylation is largely redundant for antiviral immunity, but that ISG15 plays an essential role as an IFN-γ-inducing secreted molecule for optimal antimycobacterial immunity.

Severe infectious diseases of childhood as monogenic inborn errors of immunity

“…In 1996, we jointly reported the first genetic etiology of MSMD: autosomal recessive complete IFN-γ receptor 1 (IFN-γR1) deficiency (17,18). Over the next 20 y, we and others pursued this forward genetic approach and discovered a group of 17 inborn errors of IFN-γ immunity involving nine genes (19)(20)(21)(22)(23). Some MSMD-causing genes control the production of IFN-γ; others govern its action.…”

ISG15 regulates IFN-γ immunity in human mycobacterial disease

“…Most recently, Bogunovic and colleagues published one critical paper in Science, providing new evidence to confirm that ISG15 acts as an extracellular cytokine and promotes IFN-γ production. More importantly, this paper shows an essential role of ISG15-regulated IFN-γ immunity against mycobacterial disease in human [9].…”

Fighting mycobacteria through ISGylation

“…As has been shown in ISG15 -/-and Ube1L -/-mice, Bogunovic et al found that cells from MSMD patients lack ISG15 expression after IFNα/β stimulation, but other ISGs are induced normally, confirming that ISG15 is not essential to elicit an IFN response [2]. Furthermore, patient cell lines are not more susceptible to infection by viruses such as herpes simplex virus, Sindbis virus and vesicular stomatitis virus.…”

“…Considering the limited number of viral infections common to both mice and man, it has been difficult to extrapolate what the in vivo functions of ISGylation might be in humans. The Bogunovic et al [2] study is a clear step forward in our understanding of ISG15 function in infection biology. By analysing patients with the rare paediatric syndrome, Mendelian susceptibility to mycobacterial disease (MSMD), they identified mutations in ISG15 that lead to its loss of expression and suggest that these mutations cause the disease.…”

“…It has been proposed that ISGylation is antiviral in mice, but its effects on human virus infection or other functional roles have been a long-standing question in the field. A study by the Casanova group provides important new insights into the role of ISG15 in humans, showing it is essential in the defence against mycobacterial disease but dispensable for other types of infection [2].…”