Cryptococcus lungs in individuals with depressed CMI.Lung being

Cryptococcus
neoformans is an encapsulated, opportunistic, hetero-basidiomycetousfungus
producing infections in severely immunosuppressed host like inHIV infection,
organ transplantation, hematologicalmalignancy or patients receiving high doses
of corticosteroids. It is acquired through inhalation of basidiospore
or yeast cells and remains localized in lungs but due to its neurotropic
nature, disseminates to the central nervous system (CNS) by escaping from lungs
in individuals with depressed CMI.Lung being the port of entry of Cryptococcus; local pulmonary defensemechanism
is believed to play an important role in the control of infection, whereas, extrapulmonary
dissemination causing meningoencephalitis and meningitis are the most
common clinical manifestations of cryptococcosis progression causing mortality
in immunosuppressed individuals.Immune responses in the CNS are limited by the
presence of unique effector cells, such as microglia, astrocytes and the blood
brain barrier (BBB). BBB is a layer of tightly packed capillary endothelial
cells which restricts the normal migration of cells and soluble factors to the
brain and protects the brain from chemical and infectious damage (5-6). Several
in vivo studies have depicted that
the fungus crosses the blood-brain barrier (BBB) either (i) directly
interacting with brain endothelial cells, leading to endocytosis and subsequent
transcytosis of free fungi; (ii) disruption of BBB endothelial cell junctions,
allowing paracellular passage of free fungi and (iii) as a passenger inside
host phagocytes either transcellularly or paracellularly using “Trojan Horse”
mechanism (7). However, the detail mechanism of entry of this route is yet to
be clarified. Microglia, the resident immune cells and the obligatory antigen
presenting cells of the central nervous system (CNS), plays an important role
in maintaining the CNS homeostasis. Within the CNS, these resident phagocytes
become activated upon interaction with the pathogen and up-regulate the
expression of activation markers like CD11b, CD25, MHC II (8-9) and CD45 (10) as
well as other stimulatory molecules.  The
inflammatory response is mediated by the activated microglia, respond to the
neuronal damages and remove them by phagocytic mechanism. So, activation of brain
microglia is a hallmark of brain pathology.

To combat
against this disease, several treatment regimeshave been introduced with the
goal of eradicating the Cryptococcus and
prevention of death, which includes a combination of antibiotic amphotericinB and
oral flucytosine, followed by fluconazole (11).But continuous usages of these
drugs have side effects of nephrotoxicity, gastric irritation and elevations of
hepatic enzymes respectively. As anti-fungal drugs fail to resolve the
management of systemic mycoses, the need for introducing vaccination or
boosting of the immune system with immune stimulator(s) as adjunct to specific
antifungal therapy became more pronounced (12).Despite the great potential,
there are several drawbacks of immunotherapies and due to the immuno-privilege
induced by the blood brain barrier; there is always a search for a therapeutic
agent to overcome these drawbacks to eradicate the minimal burden of C. neoformans.

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T11TS,
a novel immunomodulator with documented immunostimulatory (13-14) and non-toxic
efficacy (15-16), has been isolated from SRBC membrane andcharacterized in our
lab and have proposed it to possess potent antineoplastic action against glioma
(17). T11TS acts as a ligand of CD2 receptors on several immunocytes (17-19).T11TS-mediated
actions have direct consequences in rejuvenating the immune defense, with
increased immune cell phenotypic expressions, antigen presentation and cytokine
regulation in the brain compartment to overcome the immune suppression status (8,
12, 20, 21). T11TS causes activation of important components of the T-cell-
antigen presenting cell (APC) immunological synapse and trigger the activation
of T-cell (22). Previous publications with TIITS have proposed that in
glioma-bearing rats, T11TS promotes proliferation of the T-cells and also favors
the T-cell survival by apoptotic inhibition of T-cells through both the
extrinsic and intrinsic apoptotic pathways (23). Further studies have also
highlighted that immunotherapy with T11TS caused activation of T-cell CD2
mediated calcineurin-NFAT pathway (24) and also modulates PI3K-AKT survival
pathway favoring T-cell survival and proliferation by immunotherapy with T11TS
in T-cells (25). T11TS not only stimulates the peripheral immune system but
also rejuvenates the haematopoietic stemcells, the mother of all immune cells (26).
Previous studies with T11TS in different models like generalized demidicosisin
dogs (27), canine pyoderma (28), arsenic-induced carcinogenesis (29) have
showed that potent immune suppression was reversed to total immune restoration
and potentiation. This molecule differentially regulates the population of
microglia and lymphocytes in brain to regain homeostasis by modulation of
intrinsic cellular protein levels.

In the present study,
we propose that immunotherapy with glycopeptideT11TS induces an immune response
that is capable of significantly extending survival of rat infected with C. neoformans. To determine the effector
mechanisms associated with this CNS protection, we monitored the role of
microglia in combating the disease in brain. Resident microglia encountering
the pathogen, become activated and up-regulates the activation markers and participates
in defense mechanism. Thence they also up-regulates the major
histocompatibility complex I and II and act as antigen presenting cells and
their immune cross-talk with brain-infiltrating lymphocytes also is our subject
of interest. The fungal infection causes inflammation that leads to the
secretion of pro-inflammatory cytokines, which is dampened by immunotherapy
with T11TS. The aim of the present study isalso to understand the roles of TLRs
on resident microglia stimulation by respective PAMPs will provide insights
into how the immune response to fungal infection can be tailored to achieve
effective pathogen destruction without inducing excessive damage of surrounding
brain parenchyma, thereby protecting the brain during meningitis.