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Human IL-32 expression protects mice against a hypervirulent strain of Mycobacterium tuberculosis.

ABSTRACT: 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? gene is expressed using the surfactant protein C promoter (SPC-IL-32?Tg). Wild-type and SPC-IL-32?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?Tg mice, including tumor necrosis factor-alpha (TNF?) positive lung macrophages and dendritic cells, and IFN-gamma (IFN?) and TNF? 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? 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? enhances host immunity to MTB.

SUBMITTER: Bai X

PROVIDER: S-EPMC4413346 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Human IL-32 expression protects mice against a hypervirulent strain of Mycobacterium tuberculosis.

Bai Xiyuan X Shang Shaobin S Henao-Tamayo Marcela M Basaraba Randall J RJ Ovrutsky Alida R AR Matsuda Jennifer L JL Takeda Katsuyuki K Chan Mallory M MM Dakhama Azzeddine A Kinney William H WH Trostel Jessica J Bai An A Honda Jennifer R JR Achcar Rosane R Hartney John J Joosten Leo A B LA Kim Soo-Hyun SH Orme Ian I Dinarello Charles A CA Ordway Diane J DJ Chan Edward D ED

Proceedings of the National Academy of Sciences of the United States of America 20150327 16

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-32γ gene is expressed using the surfactant protein C promoter (SPC-IL-32γTg). Wild-type and SPC-IL-32γTg mice were infected with a low-dose aerosol of a hypervirulent strain of MTB (W-Beijing HN878). At 30 and ...[more]

PMID: 25820174

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Project description:Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), infects one third of the world's population. Among these infections, clinical isolates belonging to the W-Beijing appear to be emerging, representing about 50% of Mtb isolates in East Asia, and about 13% of all Mtb isolates worldwide. In animal models, infection with W-Beijing strain, Mtb HN878, is considered "hypervirulent" as it results in increased mortality and causes exacerbated immunopathology in infected animals. We had previously shown the Interleukin (IL) -17 pathway is dispensable for primary immunity against infection with the lab adapted Mtb H37Rv strain. However, it is not known whether IL-17 has any role to play in protective immunity against infection with clinical Mtb isolates. We report here that lab adapted Mtb strains, such as H37Rv, or less virulent Mtb clinical isolates, such as Mtb CDC1551, do not require IL-17 for protective immunity against infection while infection with Mtb HN878 requires IL-17 for early protective immunity. Unexpectedly, Mtb HN878 induces robust production of IL-1β through a TLR-2-dependent mechanism, which supports potent IL-17 responses. We also show that the role for IL-17 in mediating protective immunity against Mtb HN878 is through IL-17 Receptor signaling in non-hematopoietic cells, mediating the induction of the chemokine, CXCL-13, which is required for localization of T cells within lung lymphoid follicles. Correct T cell localization within lymphoid follicles in the lung is required for maximal macrophage activation and Mtb control. Since IL-17 has a critical role in vaccine-induced immunity against TB, our results have far reaching implications for the design of vaccines and therapies to prevent and treat emerging Mtb strains. In addition, our data changes the existing paradigm that IL-17 is dispensable for primary immunity against Mtb infection, and instead suggests a differential role for IL-17 in early protective immunity against emerging Mtb strains.

Dataset Information

Human IL-32 expression protects mice against a hypervirulent strain of Mycobacterium tuberculosis.

Publications

Human IL-32 expression protects mice against a hypervirulent strain of Mycobacterium tuberculosis.

Similar Datasets

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