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Page 8 of 20 Varikuti et al. Vessel Plus 2020;4:28 I http://dx.doi.org/10.20517/2574-1209.2020.27

Role of exosomes in malaria
Production of exosomes from infected-host cells and Plasmodium species during infection correlates with
higher malarial disease severity [39,132] . Supporting this idea, a study of P. falciparum revealed that exosome-
like particles released from infected RBCs facilitate cell-to-cell communication among parasites through
gene delivery. The P. falciparum protein PfPTP2 has been identified as a critical player in this mechanism.
This cellular communication pathway promotes the multiplication of sexual forms (gametocytes), which is
a key process to maintain malaria infection and increase transmission probability [104] . Furthermore, it has
been hypothesized that blocking the synthesis of these exosome-like vesicles as a therapeutic target may
lead to decreased parasite transmissibility [104] .

Exosome production may serve as a means of host protection during malaria infection. In a study of
P. yoelii-infected mice, parasite protein-containing exosomes were released from reticulocytes, which
could induce antigen presentation and elicit a long-term antibody protective immune response when
administered as a vaccine in naive mice. The production of IgG antibodies and recognition of the parasite-
infected RBCs in response to the vaccination with released exosomes reduces the parasite load and leads
to increased survival as well as reticulocytosis [102] . Vaccination of mice in vivo, as well as in vitro in human
spleen cells, with CpG adjuvanted P. yoelii-infected reticulocyte-derived exosomes (rexPy) induces a spleen-
dependent memory response against the parasite infection. This memory response is associated with the
activation of spleen cells through rexPy uptake, leading to changes in the distribution of T cell subsets and,
more specifically, an increase in memory CD4+ and CD8+ T cells [103] . Due to the immunoregulatory action,
[39]
Plasmodium exosome particles are viable candidates in the development of future malaria vaccines .

LEISHMANIASIS
Leishmaniases are a group of neglected tropical diseases caused by infection with parasites belonging to the
genus Leishmania, which are transmitted by the bite of infected sand flies. It is estimated that one billion
people are at risk of infection and about 1.7 million new cases of leishmaniasis occur each year in 102
countries (https://www.who.int/leishmaniasis/resources/who_wer9122/en/). Due to the lack of efficient
treatment options or a vaccine, leishmaniasis has become the second largest cause of death among parasitic
infections after malaria. Leishmaniasis consists of a spectrum of clinical syndromes and is dependent on
the species of infecting parasite. There are three main forms of the disease: localized or disseminated skin
lesions [cutaneous leishmaniasis (CL) or diffuse cutaneous leishmaniasis caused by L. major and L. tropica],
mucocutaneous disease (mucocutaneous leishmaniasis caused by L. Mexicana, L. braziliensis, and L.
amazonensis), and systemic disease [visceral leishmaniasis (VL) caused by L. donovani and L. infantum].
Infection is initiated when infected female phlebotomine sand flies take a blood meal, leading to
inoculation with infective promastigotes. Promastigotes are phagocytized by macrophages and neutrophils,
which transform into and multiply as intracellular amastigotes, which can metastasize to distant organs.
The lifecycle is complete when the infected macrophages are ingested by uninfected sandflies, which
transform and replicate as promastigotes in the insect gut (https://www.cdc.gov/parasites/leishmaniasis/
biology.html).

Role of the VE in leishmaniasis
The VE is critical for the initiation of inflammatory processes and vascular remodeling, including
angiogenesis and lymphangiogenesis, which occur in the inflammatory microenvironments of both VL and
CL infections [133,134] . Intra- and extracellular parasites attached to the wall of dermal blood vessels and the
capillary lumen lead to the development of secondary infections and the spread of the disease, especially
in endemic areas [135] . During CL, it has been shown that endothelial cells release NO, which counteracts
the recruitment of granulocytes and limits the spreading of infection [135] . In CL infections, the venous
endothelium of skin lesions expresses ICAM-1, which helps in the migration of lymphocytes to the site of
[78]
inflammation . CL infection with L. major has been shown to increase the expression of VCAM-1, which