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Varikuti et al. Vessel Plus 2020;4:28 I http://dx.doi.org/10.20517/2574-1209.2020.27 Page 5 of 20
[38]
regulatory T (Treg) cells . Treg cells promote an immunosuppressive environment by secreting exosomes
containing anti-inflammatory molecules that inhibit IFN-g secretion and CD4+ Th1 cell proliferation, as
well as signal other T cells to differentiate into Treg cells. It has also been found that CD4+ T cells and
certain B cells whose exosomes contain FasL can induce apoptosis in recipient T cells. Furthermore, ECs
transfer anti-inflammatory miRNA through exosomes to mediate T cell responses and prevent chronic
[62]
inflammation .

HUMAN PROTOZOAN PARASITIC DISEASES
In humans, protozoan parasitic infections represent a substantial threat causing more than one million
[63]
deaths annually . According to the World Health Organization (WHO), it is estimated that protozoan
parasitic infections occur in billions of people worldwide and are associated with significant mortality
[64]
and morbidity and negatively impact many countries economically (WHO.org and ). The three most
important protozoan diseases in humans are malaria, leishmaniasis, and African trypanosomiasis that
cause disability-adjusted life years in millions of patients (WHO.org 2008 and 2010).

Many protozoan infections cause non-self-limiting chronic infections and neglected diseases. There are
20 diseases that affect more than one billion people in almost 149 tropical and subtropical countries
and are responsible for approximately 12% of the total global health burden, which are categorized as
Neglected Tropical Diseases (NTDs) (https://www.who.int/neglected_diseases/diseases/en/). Due to
[65]
the disease burdens, limited available effective treatments, and lack of vaccines, the WHO has classified
NTDs such as leishmaniasis, Chagas disease, and Human African trypanosomiasis under the specialized
[66]
program “Innovative and Intensified Disease Management” . While most of these infections occur in
[67]
developing countries, it is evident that developed countries are also affected . In addition, the emergence
of anti-microbial resistant strains, toxicity, and low effectiveness of the currently available treatments
pose a substantial problem . Globalization and socioeconomic conditions also play a major role in the
[68]
[69]
emergence and spreading of specific protozoan parasitic infections . Furthermore, while many protozoan
infections remain asymptomatic, they can lead to death, especially among children. It is important to
note that, unlike bacterial and viral infections, many protozoan parasitic infections do not have readily
[70]
available vaccines . The lack of reliable drugs, difficulties in vector control, and limited knowledge about
these infections are also major barriers to preventing, controlling, and treating these protozoan parasitic
infections. Understanding the host immune response to protozoan parasites is very important to develop
vaccines and new drugs with low toxicity and high efficacy.

The most severe protozoan infections, such as malaria, leishmaniasis, Chagas diseases, Human African
trypanosomiasis (HAT), and toxoplasmosis are transmitted through blood, although Chagas disease
[71]
and Toxoplasmosis can also be transmitted through the consumption of infected meat and liquid .
Hematophagous arthropod vectors serve as intermediate hosts and transmit the parasites (Leishmania,
Trypanosomes, and Plasmodium) between successive vertebrate hosts. Thus, these bloodborne and vector-
transmitted infections involve complex interactions between the parasite and insect and mammalian hosts.

Below, we discuss the role of VE and exosomes in malaria, leishmaniasis, toxoplasmosis, Chagas disease,
and HAT, as well as their effects on the innate and adaptive immune responses in these infections. The roles
of VE and exosomes in these infections are summarized in Tables 1 and 2, respectively.

MALARIA
Malaria is the most prevalent tropical disease, which annually infects 300-500 million individuals
worldwide (CDC.org). It is estimated that 2-3 million people are at risk every year, most of whom are
children who die from the infection without the proper treatment along with the development of other