Mevalonate kinase deficiency is associated with lack of mature NK cells and a dysregulated response to viral infection — ASN Events
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Mevalonate kinase deficiency is associated with lack of mature NK cells and a dysregulated response to viral infection (#180)

Michael J Rogers 1 , Iona Schuster 2 , Etienne Masle-Farquhar 1 , James Cremasco 1 , Oliver P Skinner 1 , Ryan Chai 1 , Ariel Castro-Martinez 1 , Zoe Ingram 1 , Lisette van de Corput 3 , Flore Wouters 4 , Jeroen van der Hilst 4 , Cindy S Ma 1 , John J Zaunders 5 , Joost Frenkel 3 , Mariapia Degli-Esposti 2 , Marcia A Munoz 1
  1. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. Monash University, Melbourne, Victoria, Australia
  3. Utrecht University Medical Centre, Utrecht, The Netherlands
  4. Hasselt University, Hasselt, Belgium
  5. Centre for Applied Medical Research, St Vincent’s Hospital, Sydney, NSW, Australia

Mevalonate kinase deficiency (MKD) is a rare, autosomal recessive autoinflammatory disorder caused by variants in mevalonate kinase (MVK). Infection is a common trigger for systemic inflammatory flares in MKD, with some patients presenting with features of HLH/MAS. However, the mechanisms underpinning disease remain largely unknown.

In mice with a variety of bi-allelic mutations in Mvk, scRNA-seq analysis of PBMCs revealed negligible changes in immune cell types other than a decrease in circulating NK cells. Flow cytometry confirmed a decrease in the number and proportion of the most mature NK subset (NK1.1+CD27-CD11b+) in spleen and blood. This reduction was cell intrinsic and recapitulated in wildtype recipients of Mvk mutant bone marrow. Furthermore, Mvk mutant mature NK cells had substantially increased levels of mitochondrial superoxide, suggesting decreased cell fitness. Importantly, and consistent with our findings in Mvk mutant mice, we found a ~50% decrease in frequency of the most terminally-differentiated subset of circulating, memory-like CD57+CD56dimCD16+ NK cells in MKD patients compared to healthy controls.

Since infection is a common trigger of MKD flares, we examined the effect of cytomegalovirus (CMV) infection. Mvk mutant mice had significantly higher viral loads in liver, lung, spleen and salivary gland than infected controls. Mvk mutants also had exacerbated liver pathology with increased neutrophil and monocyte infiltration. The reduction in CD27-CD11b+ NK cells at baseline persisted in CMV-infected mutant mice, accompanied by lower numbers of Ly49H+ NK cells. Furthermore, 7 days post-infection, serum cytokines and chemokines were significantly elevated in infected Mvk mice, particularly IFNγ, whilst in infected controls their levels were back to baseline.

We propose a new paradigm in which the inflammatory flares in MKD are caused by a dysregulated anti-viral response and insufficient viral clearance, resulting in cytokine-mediated macrophage activation (particularly via IFNγ) and systemic inflammation, similar to HLH/MAS.