Characteristics of Mycobacterial, COVID-19, and Talaromyces Marneffei Infections in Patients with IL12RB1 and IFNGR1 Mutations in Western China.

BACKGROUND: Mendelian susceptibility to mycobacterial disease (MSMD) is a rare immunodeficiency characterized by increased vulnerability to weakly virulent mycobacteria. However, its clinical and molecular spectrum, as well as its susceptibility to infections beyond mycobacteria, remains incompletely understood. OBJECTIVE: To evaluate the clinical and genetic characteristics of MSMD patients, focusing on their susceptibility to mycobacteria, SARS-CoV-2 and endemic fungal infections. METHODS: Thirteen MSMD patients underwent genetic analyses, immunological assays, and clinical evaluations. COVID-19 outcomes were documented. Pathological findings and mNGS confirmed Talaromyces marneffei infections. RESULTS: Following BCG vaccination, 92.3% (12/13) developed regional or disseminated infections. Additional infections included severe tuberculosis and Mycobacterium avium. All patients experienced SARS-CoV-2 infections and present mild symptoms. One IL12RB1-deficient patient presented with isolated disseminated Talaromyces marneffei infection but otherwise healthy. Another AR IFNGR1-deficient patient with concurrent mycobacterial and fungal infections. Genetic analysis identified five novel mutations (c.155G > C, p.C52S, c. 617 A > C, p.Q206P, c.923 A > G; p.Y308C, c.1282_1301deIACCTTGTGGTCTACGGTCCTinsC; p.T428fs* in IL12RB1 and c.811 A > T, p.K271X in IFNGR1). Functional assays confirmed impaired IL12-IFNγ axis signaling. Patients with partial IFNGR1 defects showed complete clinical remission with higher doses IFN-γ therapy basing on STAT1 phosphorylation dynamics analysis under IFN-γ activation in vitro. CONCLUSION: The patient experienced significant diagnostic delays. Adverse reactions to BCG vaccination, NTM infection or severe mycobacteria tuberculosis infections in other wise healthy children strongly suggest MSMD. MSMD patients are susceptible to SARS-CoV-2 but do not exhibit severe COVID-19. Talaromyces marneffei could be an initial manifestation of MSMD in endemic regions. Early diagnosis and targeted therapy, including IFNγ and anti-tuberculosis treatments, are critical to improving outcomes.