Research Article: IFN-γ immune priming of macrophages in vivo induces prolonged STAT1 binding and protection against Cryptococcus neoformans

Date Published: October 10, 2018

Publisher: Public Library of Science

Author(s): Chrissy M. Leopold Wager, Camaron R. Hole, Althea Campuzano, Natalia Castro-Lopez, Hong Cai, Marley C. Caballero Van Dyke, Karen L. Wozniak, Yufeng Wang, Floyd L. Wormley, Mairi C. Noverr.


Development of vaccines against opportunistic infections is difficult as patients most at risk of developing disease are deficient in aspects of the adaptive immune system. Here, we utilized an experimental immunization strategy to induce innate memory in macrophages in vivo. Unlike current trained immunity models, we present an innate memory-like phenotype in macrophages that is maintained for at least 70 days post-immunization and results in complete protection against secondary challenge in the absence of adaptive immune cells. RNA-seq analysis of in vivo IFN-γ primed macrophages revealed a rapid up-regulation of IFN-γ and STAT1 signaling pathways following secondary challenge. The enhanced cytokine recall responses appeared to be pathogen-specific, dependent on changes in histone methylation and acetylation, and correlated with increased STAT1 binding to promoter regions of genes associated with protective anti-fungal immunity. Thus, we demonstrate an alternative mechanism to induce macrophage innate memory in vivo that facilitates pathogen-specific vaccine-mediated immune responses.

Partial Text

Vaccines in clinical use today were designed from the onset to generate antigen-specific memory T and/or B cell (antibody) immune responses (reviewed in [1–3]). However, vaccines designed to elicit T cell and/or antibody-mediated immune responses are predicted to be ineffective in patients rendered immune compromised due to diseases such as HIV/AIDS or immunosuppressive therapies to prevent solid organ transplant rejection or ameliorate various autoimmune diseases. Novel approaches in vaccine design are needed to induce protective immunity in the increasing population of immunocompromised individuals.

In the present study, we demonstrate that macrophages from mice immunized with an IFN-γ producing strain of C. neoformans are primed to rapidly respond to a subsequent exposure to this pathogen. The effect appears to be STAT1-dependent, as demonstrated by expedited transcription of genes that are directly and indirectly associated with the STAT1 pathway as well as increased binding of STAT1 at promotor regions of select genes. Activation of STAT1 in macrophages results in their polarization toward an M1 phenotype which has been widely demonstrated as anti-cryptococcal and necessary for protective immunity against C. neoformans [16, 17, 19–22, 26]. To date, myelofibrosis treatment of two patients with Ruxolitinib, which inhibits JAK1,2 and likely STAT1, is hypothesized to have contributed to the development of cryptococcosis in these individuals [27, 28].




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