4.7 Article

Toxoplasma gondii Matrix Antigen 1 Is a Secreted Immunomodulatory Effector

期刊

MBIO
卷 12, 期 3, 页码 -

出版社

AMER SOC MICROBIOLOGY
DOI: 10.1128/mBio.00603-21

关键词

Toxoplasma gondii; dense granule protein; inflammasome

资金

  1. NIH [AI080621, AI134753]
  2. American Heart Association Postdoctoral fellowship [18POST34030036]

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The study reveals that the cyst matrix protein MAG1 functions as a secreted immunomodulatory effector, regulating parasite virulence and dissemination by suppressing inflammasome activation. The balance between GRA15-induced inflammasome activation and MAG1-mediated suppression plays a crucial role in host-parasite interactions and the establishment of chronic infection.
Our studies on novel cyst wall proteins serendipitously led us to the discovery that cyst wall and vacuolar matrix protein MAG1, first identified a quarter of a century ago, functions as a secreted immunomodulatory effector. MAG1 is a dense granular protein that is found in the parasitophorous vacuolar matrix in tachyzoite vacuoles and the cyst wall and matrix in bradyzoite vacuoles. In the current study, we demonstrated that MAG1 is secreted beyond the parasitophorous vacuole into the host cytosol in both tachyzoites and bradyzoites. Secretion of MAG1 gradually decreases as the parasitophorous vacuole matures, but prominent MAG1 puncta are present inside host cells even at 4 and 6 days following infection. During acute murine infection, Delta mag1 parasites displayed significantly reduced virulence and dissemination. In the chronic stage of infection, Delta mag1 parasites generated almost no brain cysts. To identify the mechanism behind the attenuated pathology seen with Delta mag1 parasites, various immune responses were screened in vitro using bone marrow-derived macrophages (BMDM). Infection of BMDM with Delta mag1 parasites induced a significant increase in interleukin 1 beta (IL-1 beta) secretion, which is a hallmark of inflammasome activation. Heterologous complementation of MAG1 in BMDM cells prevented this Delta mag1 parasite-induced IL-1 beta release, indicating that secreted MAG1 in host cytosol dampens inflammasome activation. Furthermore, knocking out GRA15 (an inducer of IL-1 beta release) in Delta mag1 parasites completely inhibited all IL-1 beta release by host cells following infection. These data suggest that MAG1 has a role as an immunomodulatory molecule and that by suppressing inflammasome activation, it would favor survival of the parasite and the establishment of latent infection. IMPORTANCE Toxoplasma gondii is an Apicomplexan that infects a third of humans, causing encephalitis in AIDS patients and intellectual disabilities in congenitally infected patients. We determined that one of the cyst matrix proteins, MAG1, which had been thought to be an innate structural protein, can be secreted into the host cell and suppress the host immune reaction. This particular immune reaction is initiated by another parasite-secreted protein, GRA15. The intricate balance of inflammasome activation by GRA15 and suppression by MAG1 protects mice from acute death while enabling parasites to disseminate and establish chronic cysts. Our finding contributes to our understanding of how parasites persist in the host and how T. gondii modulates the host immune system.

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