Observational study on the use of subcutaneous recombinant IFN-γ as adjunctive personalized treatment for patients with life-threatening non-tuberculous mycobacteriosis

Non-tuberculous mycobacteria (NTM) can lead to life-threatening diseases. Interferon-gamma (INF-γ) is crucial role in innate and acquired immune responses against pathogenic mycobacteria. Defects in IFN-γ pathway increase NTM disease risk (1). Based on the encouraging results of a previously published study(2), four life-threatening disseminated refractory NTM were treated with subcutaneous recombinant INF-g. In parallel, exome sequencing was performed for all four patients. Three out four patients, that witnessed complete eradication of mycobacteria infection, carried the homozygous C221G missense mutation in the CCL4L2 (C-C motif chemokine ligand 4 like 2)gene. CCL4L2 is a chemokine mediating immune cell migration via the CCR5 chemokine receptor, and sensing of cytosolic DNA during innate immune response (3). This genetic finding may suggest a positive response to IFN-γ therapy and a preliminary proof for a personalized treatment of critically ill patients with severe mycobacterial infections. Further studies are required to validate these genetic findings on a larger cohort of patients, aiming at enhancing the predictability of IFN-γ response. <bold>1</bold>. Rosain, J., et al., Human IRF1 governs macrophagic IFN-gamma immunity to mycobacteria. Cell, 2023. 186(3): p. 621-645 e33. <bold>2</bold>. Holland, S.M., et al., Treatment of refractory disseminated nontuberculous mycobacterial infection with interferon gamma. A preliminary report. N Engl J Med, 1994. 330(19): p. 1348-55. <bold>3</bold>. Collins, A.C., et al., Cyclic GMP-AMP Synthase Is an Innate Immune DNA Sensor for Mycobacterium tuberculosis. Cell Host Microbe, 2015. 17(6): p. 820-8.