Background/Purpose: Type I IFN (IFN-I) signaling is a potent inflammatory pathway fundamental to antiviral immunity. In humans, loss of IFN-I activity underlies severe viral disease, while excess IFN-I activity leads to autoinflammation. Canonically, these phenotypes are considered opposing, mutually-exclusive phenomena. Here, we aim to uncover the molecular underpinnings of a family of three siblings presenting with recurrent respiratory failure in the setting of viral infections, each of whom were ultimately diagnosed with pulmonary alveolar proteinosis.

Methods: We performed whole exome sequencing and various immunologic analyses on peripheral blood, patient-derived cells and transduced cell-lines.

Results: Genetic analysis uncovered a novel homozygous variant (R223Q) in STAT2, a mediator of IFN-I signaling that acts directly in signal transduction and indirectly in negative regulation via interaction with the inhibitor USP18. Despite the apparent viral-associated disease in vivo, R223Q STAT2 conferred normal transcription-complex activity and viral control in vitro. However, cells homozygous for the R223Q variant failed to terminate the IFN-I response, owing to impaired localization of USP18. The ensuing inflammation proved variably lethal: the two older siblings, who encountered more frequent or early infections, died in infancy, while the youngest sibling with less infectious stimuli survived. Informed by these studies, the youngest sibling was subsequently started on JAK inhibitors with marked clinical improvement.

Conclusion: We demonstrate that STAT2-Associated Type-I Interferonopathy (STATi) can mimic severe viral susceptibility via overexuberant antiviral responses. In turn, clinical severity in STATi may be regulated by the frequency of immune stimulation. Paradoxically, pharmacologic immune suppression improves infection-associated disease, while maintaining sufficient viral control.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/stat2-associated-type-i-interferonopathy-a-masquerade-of-infectious-susceptibility/