T11TS immunotherapy augments microglial and lymphocyte protective immune responses against Cryptococcus neoformans in the brain

Abstract

Cryptococcus neoformans, the encapsulated yeast acquired through inhalation, remains localized in lungs, but harbours the CNS in immunocompromised individuals. Several treatment regimes have failed combating this disease totally, but long‐term usage of drugs leads to organ damage. As T11‐target structure (T11TS) has documented profound immune potentiation, we aimed to investigate the role of microglia, pivotal immune cells of brain in ameliorating cryptococcosis, with T11TS immunotherapy. Murine model with C neoformans infection was prepared by intraperitoneal injection and the brains of rats examined 7 days post‐infections for histopathology by PAS and Alcian blue staining corroborated with organ fungal burden evidencing restorative T11TS action on Cryptococcal meningitis. Immunotherapy with three doses of T11TS, a CD2 ligand, in C neoformans infected rats, upregulates toll‐like receptors 2, −4 and −9 of microglia, indicating increased phagocytosis of the fungus. Flowcytometric analysis revealed increased numbers of T11TS treated brain infiltrating CD4+ and CD8+ T‐lymphocytes along with increased MHC I and MHC II on microglia, activating the infiltrating lymphocytes aiding the killing mechanism. Present study also indicated that T11TS increased production of Th1 inflammatory cytokines conducive to fungal elimination while the inhibitory Th2 cytokines were dampened. This preclinical study is first of its kind to show that T11TS effected profound immune stimulation of microglial activity of C neoformans infected rats eradicating residual fungal burden from the brain and can be a useful therapeutic strategy in fighting against this deadly disease.

Establishing immune scoring model based on combination of the number, function, and phenotype of lymphocytes

“…Since different lymphocyte phenotypes are also correlated with different lymphocyte function, we first established an immune scoring model based on combination of the number, function and phenotype of lymphocytes to comprehensively assess host immunity. The imbalance of immunity leads to many immune-related diseases, such as autoimmune disease (hyperimmune status) [30] and opportunistic infection (hypoimmune status) [31][32][33][34][35][36]. The validation data from patients with different immune status showed that the model had high sensitivities in the determination of both hyperimmune and hypoimmune status.…”

T11TS immunotherapy potentiates the repressed calcineurin‐NFAT signalling pathway of T cells in Cryptococcus neoformans infected rats: a cue towards T‐cell activation for antifungal immunity

“…Our recent study showed that T11TS modulates the immunological synapse of T cells (data communicated). We have also shown that T11TS mediates the elimination of fungal burden in the rats' brains (Hazra et al 2019). 10 0 10 1 10 2 10 3 10 4 10 0 10 1 10 2 10 3 10 4 10 0 10 1 10 2 10 3 10 4 10 0 10 1 10 2 10 3 10 4 10 0 10 1 10 2 10 3 10 4 In our present study, we have attempted to dissect the role of major intracellular partners involved in the CaN-NFAT signalling pathway during C. neoformans infection and following T11TS immunotherapy.…”

“…One millilitre of T11TS (0Á4 mg kg À1 body weight) was administered to 7 days post-infected rats i.p., followed by a second, and a third booster dose, making a dosing schedule of 1, 2 and 3 ml to the CT1, CT2 and CT3 animals, respectively. For each dose, T11TS were injected at an interval of 6 days (Hazra et al 2019).…”

“…By stimulating T cell, T11TS has shown to be an effective and safer candidate to abrogate glioma (Sarkar et al 2002; Chaudhuri et al 2014; Chaudhuri et al 2015). Recently, our group has shown how T11TS activates microglial cells isolated from the brain and brain‐infiltrating lymphocytes, to eliminate C. neoformans burden in the brain (Hazra et al 2019). The current work is a further extension of our previous work published in the Hazra et al ’s (2019) paper, which was focused on the pathological findings in the brain.…”

“…Recently, our group has shown how T11TS activates microglial cells isolated from the brain and brain‐infiltrating lymphocytes, to eliminate C. neoformans burden in the brain (Hazra et al 2019). The current work is a further extension of our previous work published in the Hazra et al ’s (2019) paper, which was focused on the pathological findings in the brain. However, the current study reports the analysis of T lymphocytes isolated from the spleen of C. neoformans infected and T11TS‐administered animals.…”