Type I interferon exacerbates Mycobacterium tuberculosis induced human macrophage death

Area of Science:

• Immunology
• Infectious Diseases
• Cell Biology

Background:

• Type I interferons (IFN-I) are linked to tuberculosis (TB) exacerbation, but the underlying mechanisms remain unclear.
• Previous studies in mice indicated that IFN-I produced by Mycobacterium tuberculosis (Mtb)-infected macrophages contributes to cell death.

Purpose of the Study:

• To investigate whether Mtb-infected human monocyte-derived macrophages (MDM) also produce IFN-I and if it contributes to their death.
• To elucidate the role of IFN-I signaling in the response of human MDM to Mtb infection.

Main Methods:

• Human MDM were infected with Mtb, and the expression of interferon-stimulated genes (ISGs) was analyzed.
• Antibodies inhibiting IFN-I signaling were used to assess their impact on ISG induction and MDM death.
• Quantification of secreted IFN-I and assessment of MDM response to exogenous IFN-I were performed.

Main Results:

• Mtb-infected human MDM markedly upregulated ISGs, particularly when prepared conventionally.
• IFN-I signaling inhibition prevented ISG induction but did not reduce Mtb-infected MDM death.
• Secreted IFN-I was undetectable until late stages, despite early ISG induction.
• Exogenous IFN-I induced ISG expression and increased MDM death.

Conclusions:

• Mtb-infected human MDM produce and respond to low levels of IFN-I, contributing to ISG induction and cell death.
• The observed IFN-I signaling is complex, with only partial susceptibility to neutralizing antibodies.
• IFN-I likely promotes infected macrophage death in TB patients, potentially involving various cell types.