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to multi-organ involvement including encephalitis, retino-uveitis, and pulmonary disease, especially in
immunosuppressed hosts cerebral toxoplasmosis.

Role of the VE in toxoplasmosis
It is believed that T. gondii can modulate the gene expression of brain ECs and promote dissemination
through the BBB. T. gondii transforms into motile extracellular forms (tachyzoites) that use transcellular or
paracellular migration to cross the BBB and infect host cells. In this context, the ECs serves as a replicative
[83]
niche for the entry of T. gondii to the CNS . The most common clinical manifestation of toxoplasmosis is
retinal infection. Recently, Furtado et al. [141] demonstrated that tachyzoites can cross the retinal endothelium
to establish infection and that blocking this entrance leads to reduced diseased burdens. It has also been
[84]
observed that T. gondii infection leads to induction and activation of cerebral blood vessel ECs .

Role of exosomes in toxoplasmosis
[38]
T. gondii was the first non-viral protozoan pathogen for which exosomes were identified . Although
T. gondii exosomes are continuously released during infection by tachyzoites, the bulk of released
molecules are non-exosome associated excretory/secretory antigens constitute during the acute phase of
infection [114] . An earlier study conducted by Aline et al. [111] revealed exosomes are important in generating
protective immunity against T. gondii infection; T. gondii-pulsed DCs can effectively induce a spleen-
derived Th1 immune response that is protective against acute and chronic infection It has also been shown
that exosomes secreted by SRDCs induce a protective humoral immune response against the infection in
syngeneic and allogeneic mice associated with high levels of IgA antibodies [112] . Furthermore, vaccination
of mice before pregnancy with exosomes secreted by T. gondii-pulsed DCs protects pups from congenital
infection due to a robust T cell response [142] .

Li et al. [113] characterized T. gondii-derived exosomes as ~50 nm in size and containing HSP70, CD63,
and T. gondii surface marker P30. These exosomes were shown to modulate macrophage activation
through increased production of IL-12, TNF-a, and IFN-g and a decrease in IL-10. Mice immunized
with these exosomes exhibited cellular and humoral immune responses and were protected against acute
infection [39,113] . Li et al. [143] also reported that T. gondii exosomes activate JNK signaling to elicit this innate
immune response. Macrophages infected with T. gondii release exosomes containing PAMPs, which
activate inflammatory responses in adjacent macrophages in a TLR- and myeloid differentiation factor 88
[53]
(MyD88)-dependent manner . Some T. gondii exosomes contain miRNA that may interact and modulate
the host cells through gene regulation [114] . Taken together, T. gondii-derived exosomes displayed significant
immunogenic properties that make them viable candidates for vaccine production.

CHAGAS DISEASE
The hemoflagellate Trypanosoma cruzi is the etiologic agent of Chagas disease, also termed American
trypanosomiasis. Chronic infection by this parasite is characterized by chronic myocarditis,
cardiomyopathy, and vasculopathy, as well as mega-organ syndromes [144-147] . It is estimated that ~8 million
people are currently infected worldwide and that 20%-30% of those individuals develop sequelae of chronic
infection. Chagas disease is the leading cause of heart failure in Latin America [148-151] . The parasite exists in
four morphological forms: epimastigotes, insect metacyclic trypomastigotes, human trypomastigotes, and
intracellular amastigotes [151] . Insect stage trypomastigotes (also termed metacyclic trypomastigotes) are the
infective stage of the parasite, which are present in the feces of hematophagous triatomine insects, which
contaminate wounded skin or mucous membranes [148,152] . Metacyclic trypomastigotes invade nucleated
host cells to establish the infection. Inside the host cells, they transform and replicate as intracellular
amastigotes, eventually differentiating into blood-stage trypomastigotes and exit the host cells to
disseminate to multiple organs, including the heart and gastrointestinal tract of the mammalian hosts [148] .