Signal transducer and activator of transcription 1 (STAT1) has an important role in the signaling for types I and II interferon (IFN) and their associated genes. STAT1 loss of function (LOF) mutations are associated with disseminated severe mycobacterial infections. STAT1 gain of function (GOF) mutations were initially described with chronic mucocutaneous candidiasis (CMC), and to lesser extent with recurrent bacterial, herpes viruses and endemic fungi infections.
We looked at the frequency, clinical features and characteristics of tuberculous and nontuberculous mycobacterial infections in a cohort of 35 STAT1 GOF patients followed at the US National Institutes of Health.
Seven (20%) patients with 6 different STAT1 mutations (figure 1) were found to have had 8 different episodes of mycobacterial infections. The mutations were characterized as GOF by functional assays showing high phosphorylation of STAT1 after IFN-gamma stimulation of peripheral mononuclear cells (3/6 mutations) (figure 2) or U3A and U3C cells transfected with the mutant expression vectors (4/6 mutations). GAS luciferase assays was abnormal in 4 mutations that were tested. All patients had a history of Candida infection prior to the mycobacterial infection (acute or chronic episodes). M. avium complex (MAC) was the most frequent species found in 3 cases. Two patients had M. fortuitum, 1 had M. abscessus, 1 had BCG and 1 had M. tuberculosis (TB) infection. Two of the infections were disseminated (MAC) and the rest were localized. In all cases but one (disseminated MAC infection), the infections were well controlled with antimycobacterial treatment. Two patients died during the follow up period; in both cases the cause of the death was not the mycobacterial infection (progressive multifocal leukoencephalopathy in one case, disseminated invasive aspergillosis infection in the other).
STAT1 GOF mutations are associated with increased risk of both localized as well as disseminated mycobacterial infection. STAT1 GOF mutations should be strongly considered in patients with mycobacterial infection and a history of candidiasis.
A. F. Freeman, None
C. Zerbe, None
G. Uzel, None
S. Rosenzweig, None
E. Sampaio, None
P. Chandrasekaran, None
A. Hsu, None
S. Holland, None