Anti–IFN-γ autoantibodies underlie disseminatedTalaromyces marneffeiinfections

Abstract

Talaromyces marneffei causes life-threatening opportunistic infections, mainly in Southeast Asia and South China. T. marneffei mainly infects patients with human immunodeficiency virus (HIV) but also infects individuals without known immunosuppression. Here we investigated the involvement of anti–IFN-γ autoantibodies in severe T. marneffei infections in HIV-negative patients. We enrolled 58 HIV-negative adults with severe T. marneffei infections who were otherwise healthy. We found a high prevalence of neutralizing anti–IFN-γ autoantibodies (94.8%) in this cohort. The presence of anti–IFN-γ autoantibodies was strongly associated with HLA-DRB1*16:02 and -DQB1*05:02 alleles in these patients. We demonstrated that adult-onset acquired immunodeficiency due to autoantibodies against IFN-γ is the major cause of severe T. marneffei infections in HIV-negative patients in regions where this fungus is endemic. The high prevalence of anti–IFN-γ autoantibody–associated HLA class II DRB1*16:02 and DQB1*05:02 alleles may account for severe T. marneffei infections in Southeast Asia. Our findings clarify the pathogenesis of T. marneffei infection and pave the way for developing novel treatments.

Clinical findings of Talaromyces marneffei infection among patients with anti-interferon-γ immunodeficiency: a prospective cohort study

“…Immune deficiency, which is caused by anti-interferon-γ autoantibodies (anti-IFN-γ autoAbs), is an adult immune deficiency syndrome that was first described among patients with mycobacterial infection [ 1 ]. Patients have high titers of serum anti-IFN-γ autoAbs, which can inhibit signal transducer and activator of transcription 1 (STAT1) phosphorylation and interleukin-12 production, resulting in severe dysfunction of the Th1 response [ 2 – 4 ] and increased risk of infection by multiple intracellular pathogens, including nontuberculous Mycobacterium (NTM), Talaromyces marneffei ( T. marneffei ), Cryptococcus neoformans , and other intracellular pathogens [ 1 – 12 ]. Talaromycosis is a severe deep mycosis that mainly involves organs rich in monocyte-macrophages (i.e., the lungs, liver, and lymph nodes) and can be categorized into localized and disseminated disease.…”

“…In some regions, such as southern China, T. marneffei infection has historically been the major opportunistic infection associated with acquired immunodeficiency syndrome [ 15 ]. However, T. marneffei infection has been increasingly reported among non-HIV-infected patients with impaired cell-mediated immunity [ 16 ], and immune deficiency syndrome caused by anti-IFN-γ autoAbs is an important risk factor [ 11 , 12 ]. However, the impact of anti-IFN-γ autoAbs on talaromycosis progression has not been clearly described.…”

Serum Sphingolipids Aiding the Diagnosis of Adult HIV-Negative Patients with Talaromyces marneffei Infection

“…Talaromyces marneffei ( T. marneffei ) is a dimorphic fungus causing life-threatening opportunistic infections that is endemic in southern China, southeastern Asia, and northeastern India, and it was previously considered the agent of a common infectious disease complication of HIV patients ( Le et al., 2017 ; Guo et al., 2020 ). However, it was found in recent reviews that the morbidity due to T. marneffei infection in HIV-negative patients has been increasing ( Hu et al., 2013 ; Chan et al., 2016 ), which is associated with changes in susceptibility factors.…”

Clinical findings of Talaromyces marneffei infection among patients with anti-interferon-γ immunodeficiency: a prospective cohort study

“…Patients have high titers of serum anti-IFN-γ autoAbs, which can inhibit signal transducer and activator of transcription 1 (STAT1) phosphorylation and interleukin-12 production, resulting in severe dysfunction of the Th1 response [1] and increased risk of infection by multiple intracellular pathogens, including nontuberculous Mycobacterium (NTM), Talaromyces marneffei (T. marneffei), Cryptococcus neoformans, and other intracellular pathogens [1][2][3][4][5][6][7][8][9][10][11][12]. Talaromycosis is a severe deep mycosis that mainly involves organs rich in monocyte-macrophages (i.e., the lungs, liver, and lymph nodes) and can be categorized into localized and disseminated disease.…”

“…In some regions, such as southern China, T. marneffei infection has historically been the major opportunistic infection associated with acquired immunode ciency syndrome [15]. However, T. marneffei infection has been increasingly reported among non-HIV-infected patients with impaired cell-mediated immunity [16], and immune de ciency syndrome caused by anti-IFN-γ autoAbs is an important risk factor [11,12]. However, the impact of anti-IFN-γ autoAbs on talaromycosis progression has not been clearly described.…”