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[79]
mediates the adhesion of mononuclear cells to the endothelial cells . Both human and animal leishmanial
infections lead to increased levels of vascular endothelial growth factor-A (VEGF-A) and its receptor
(VEGF-R) in the skin [80,81] . Recently, Weinkopff et al. [133] showed that CL infection by L. major induces
VEGF-A in macrophages in an ARNT/HIF dependent manner, leading to the limitation of inflammation
and lymphangiogenesis. The expansion of the lymphatic network promotes lesion resolution, and inhibition
of this process enhances the lesion development. In the VL model, L. donovani-infected mice aberrantly
express neurotrophic tyrosine kinase receptor type-2 (Ntrk2) on splenic endothelial cells, which plays a role
[82]
in pathologic remodeling of the spleen .
Role of exosomes in leishmaniasis
The role of exosomes in Leishmania infection is well studied, revealing that they serve as a key mode
of delivery of Leishmania virulence factors and effector proteins to host cells during infection [136] . Both
pathogen and host-derived exosomes have been identified in this process. Leishmania-derived exosomes
can transport virulence factors into the host macrophages and induce secretion of IL-8 instead of
TNF-β [105] . Proteomic analysis has revealed that one such virulence factor contained in L. major exosomes
is the metalloprotease glycoprotein GP63, which regulates protein tyrosine phosphatases (PTPs) and
transcription factors (TFs), such as NF-kB, in target macrophages [108] . PTPs prevent macrophage activation
by inhibiting the secretion of pro-inflammatory IFN-g, IL-12, and NO [137,138] , which are important in host
control of parasite infection. These act to modulate the immune response, diminishing inflammation in
favor of parasite growth and survival. Exosomes released from L. donovani-infected macrophages contain
GP63, which proteolyzes Dicer1 in hepatocytes to block miRNA-122, production leading to disease
progression [109] . Exosomes released from L. donovani promastigotes can effectively alter the cytokine
response of monocytes through the upregulation of IL-10 and inhibition of TNF-a production. Similarly, it
has been observed that monocyte-derived DCs that have been exposed to parasite exosomes have inhibited
levels of IL-12p70, TNF-a, and IL-10. Exosome-exposed DCs cannot induce naïve T cell differentiation
into mature Th1 cells [106] . In contrast, Schnitzer et al. [110] showed that that vaccination with L. major antigens
present in DC-derived exosomes can induce immune-protection against the infection.
Leishmania is also able to modify the production and content of exosomes in response to environmental
stress (heat shock and pH) that mimic infection. Silverman et al. [105] showed that vesicle release from
parasites can be increased by three-fold in response to heat shock. Interestingly, Atayde et al. [107] showed
that Leishmania release exosomes within the lumen of the sand-fly midgut, which are ejected in the
egested inoculum during by the sand-fly bite. These exosomes lead to exacerbated lesions in L. major
and L. infantum models, possibly due to increased production of inflammatory cytokine IL-17a, and
overproduction of IL-4 and IL-10, which are both known to suppress the Th1 responses and play a role in
disease susceptibility.
TOXOPLASMOSIS
Toxoplasmosis is caused by the obligate intracellular protozoan parasite, Toxoplasma gondii, which
infects healthy and immunocompromised individuals worldwide. It is estimated that more than 11% of
the population in the US and 60% of the population throughout the world are infected [139] (https://www.
cdc.gov/parasites/toxoplasmosis/epi.html). The transmission of toxoplasmosis mainly occurs through
ingesting raw meat containing T. gondii cysts (foodborne) or water containing oocysts from feline feces
(waterborne). The parasite can also be transmitted congenitally when a woman acquires the infection
during pregnancy [139] , or very rarely through transplantation of organs [140] . Although felines act as definitive
hosts for T. gondii, it can infect almost all nucleated mammalian and avian cells. The life cycle of T. gondii
mainly involves an asexual phase within nucleated cells and a sexual phase, which occurs in felines.
Ingested oocysts released in feline feces serve as the infectious stage for humans. Toxoplasmosis can
cause miscarriage, stillborn infants, or severe central nervous system (CNS) disease; in adults, it can lead