Innate Immunity Acts as the Major Regulator in Talaromyces marneffei Coinfected AIDS Patients: Cytokine Profile Surveillance During Initial 6-Month Antifungal Therapy

Abstract

Background: Talaromycosis caused by Talaromyces marneffei infection is a fatal systemic mycosis in immunosuppressed individuals, such as patients with AIDS. Cytokines and immunocytes play a central role against fungus infection. However, how the host immune system responds to infection and treatment has not been reported to date.

Methods: Forty-one Talaromyces marneffei coinfected AIDS patients were followed up, their immunocytes and cytokine profiles were obtained at different antifungal treatment stages, and data on clinical features and laboratory examinations were collected. Correlation analysis was used to identify factors associated with host immunity against Talaromyces marneffei infection in AIDS patients.

Results: Common diseases and conditions of these 41 patients were lymphadenopathy, hepatomegaly, and splenomegaly. CD4⁺ T cells were extremely low in all of them. Moreover, significant increases of proinflammatory cytokines (IL-12, IL-17A, TNF-α, IFN-γ, IL-18, and IL-1β), anti-inflammatory cytokines (IL-10), and chemokines (IP-10) were observed in talaromycosis before treatment (P < .05), comparing to both AIDS patients and healthy controls. The cytokines IL-6, IL-8, TNF-α, IL-18, IL-17A, IL-7, IP-10, and IL-1β reached peak levels 3 days after initial antifungal therapy, and then gradually decreased. The symptoms of the patients gradually decreased. Furthermore, patients who died showed the highest levels of IL-6, TNF-α, IL-8, IL-1β, and IP-10, which were 1.4- to 164-fold higher than in surviving patients.

Conclusions: Our findings indicate that innate immune-cell-derived cytokines are critical for host defense against AIDS-associated Talaromyces marneffei infection; furthermore, excessive inflammatory cytokines are associated with poor outcomes.

Keywords: AIDS; Talaromyces marneffei; antifungal therapy; cytokines; innate immunity.

Figure 1.

Cytokine profile during antifungal therapy in T. marneffei coinfected AIDS patients. (A) Levels of proinflammatory cytokines. TNF-α, IL-6, IL-8, IL-1β, IL-17A, IL-7, IL-18 at pretreatment were higher than those of healthy control and HIV-infected group. Besides IL-18, they continued to rise and reached the peak levels 3 days after treatment. The levels of IL-12 and IFN-γ reached peak levels at pretreatment compared to healthy controls and HIV-1-only group and then gradually decreased after treatment and returned to normal levels 7 days after treatment. (B) Levels of anti-inflammatory cytokines and chemokines. SDF-1α and IP-10 showed high levels at 3 days, and 7 days after treatment. Anti-inflammatory cytokines IL-10 quickly peaked 3 days after treatment and soon returned to almost baseline level 7 days after treatment. However, IL-4 reached peak levels at baseline and began to decrease gradually after treatment. IL indicates interleukin; IFN-γ, interferon γ; TNF-α, tumor necrosis factor-α; SDF-1α, stromal cell-derived factor-1α; IP-10, Interferon-induced protein 10.

Figure 2.

Plasma level of proinflammatory cytokines and chemokines in survivin and deceased patients. Pretreatment levels of TNF-α, IL-6, IL-8, IL-1β, and IP-10 in deceased patients were significantly higher than surviving patients (P < .05). HIV-1-only indicates the cytokine levels in patients with HIV-1 infection but without T. marneffei coinfection; surviving represents the cytokine levels at pretreatment stage in AIDS patients with T. marneffei coinfection; deceased indicates cytokine levels in the AIDS-patients with T. marneffei coinfection who died despite antifungal treatment.

Figure 3.

Correlation between levels of inflammatory cytokines and innate immunocytes. Positive correlations were found between percentage of neutrophil (%) and IFN-γ, IL-18, IL-17A, IP-10, and IL-6 (P < .05). IFN-γ had a significant positive correlation with IL-12 (P = .002).