Treatment of mice with S4B6 IL‑2 complex prevents lethal toxoplasmosis via IL‑12‑ and IL‑18‑dependent interferon‑gamma production by non‑CD4 immune cells

Kupz, Andreas, Pai, Saparna, Giacomin, Paul R., Whan, Jennifer A., Walker, Robert A., Hammoudi, Pierre-Mehdi, Smith, Nicholas C., and Miller, Catherine M. (2020) Treatment of mice with S4B6 IL‑2 complex prevents lethal toxoplasmosis via IL‑12‑ and IL‑18‑dependent interferon‑gamma production by non‑CD4 immune cells. Scientific Reports, 10. 13115.

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Abstract

Toxoplasmic encephalitis is an AIDS-defining condition. The decline of IFN-γ-producing CD4⁺ T cells in AIDS is a major contributing factor in reactivation of quiescent Toxoplasma gondii to an actively replicating stage of infection. Hence, it is important to characterize CD4-independent mechanisms that constrain acute T. gondii infection. We investigated the in vivo regulation of IFN-γ production by CD8⁺ T cells, DN T cells and NK cells in response to acute T. gondii infection. Our data show that processing of IFN-γ by these non-CD4 cells is dependent on both IL-12 and IL-18 and the secretion of bioactive IL-18 in response to T. gondii requires the sensing of viable parasites by multiple redundant inflammasome sensors in multiple hematopoietic cell types. Importantly, our results show that expansion of CD8+ T cells, DN T cells and NK cell by S4B6 IL-2 complex pre-treatment increases survival rates of mice infected with T. gondii and this is dependent on IL-12, IL-18 and IFN-γ. Increased survival is accompanied by reduced pathology but is independent of expansion of TReg cells or parasite burden. This provides evidence for a protective role of IL2C-mediated expansion of non-CD4 cells and may represent a promising lead to adjunct therapy for acute toxoplasmosis.

Item ID: 64075
Item Type: Article (Research - C1)
ISSN: 2045-2322
Copyright Information: © The Author(s) 2020.
Funders: National Health and Medical Research Council of Australia (NHMRC), Australian Institute of Tropical Health and Medicine (AITHM)
Projects and Grants: NHMRC CJ Martin Biomedical Early Career Fellowship (APP1052764), NHMRC Career Development Level 1 Fellowship (APP1140709), AITHM Capacity Building Grant (15031)
Date Deposited: 08 Sep 2020 19:26
FoR Codes: 06 BIOLOGICAL SCIENCES > 0605 Microbiology > 060502 Infectious Agents @ 40%
11 MEDICAL AND HEALTH SCIENCES > 1103 Clinical Sciences > 110309 Infectious Diseases @ 40%
11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110707 Innate Immunity @ 20%
SEO Codes: 97 EXPANDING KNOWLEDGE > 970106 Expanding Knowledge in the Biological Sciences @ 65%
92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920109 Infectious Diseases @ 35%
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