Human Il-32 Expression Protects Mice Against A Hypervirulent Strain Of Mycobacterium Tuberculosis

Silencing of interleukin-32 (IL-32) in a differentiated human promonocytic cell line impairs killing of Mycobacterium tuberculosis (MTB) but the role of IL-32 in vivo against MTB remains unknown. To study the effects of IL-32 in vivo, a transgenic mouse was generated in which the human IL-32 gamma gene is expressed using the surfactant protein C promoter (SPC-IL-32 gamma Tg). Wild-type and SPC-IL-32 gamma Tg mice were infected with a low-dose aerosol of a hypervirulent strain of MTB (W-Beijing HN878). At 30 and 60 d after infection, the transgenic mice had 66% and 85% fewer MTB in the lungs and 49% and 68% fewer MTB in the spleens, respectively; the transgenic mice also exhibited greater survival. Increased numbers of host-protective innate and adaptive immune cells were present in SPC-IL-32 gamma Tg mice, including tumor necrosis factor-alpha (TNF alpha) positive lung macrophages and dendritic cells, and IFN-gamma (IFN gamma) and TNF alpha positive CD4(+) and CD8(+) T cells in the lungs and mediastinal lymph nodes. Alveolar macrophages from transgenic mice infected with MTB ex vivo had reduced bacterial burden and increased colocalization of green fluorescent protein-labeled MTB with lysosomes. Furthermore, mouse macrophages made to express IL-32. but not the splice variant IL-32 beta were better able to limit MTB growth than macrophages capable of producing both. The lungs of patients with tuberculosis showed increased IL-32 expression, particularly in macrophages of granulomas and airway epithelial cells but also B cells and T cells. We conclude that IL-32 gamma enhances host immunity to MTB.