Figure 12: Prevalence map (14)
Worldwide, Leishmania affects at least 12 million people each year, with nearly 350 million people at risk, primarily in developing countries (Figure 12). Its clinical symptoms can range anywhere from disfiguring ulcerations to an invasive infection with a lethal outcome. Knowledge of parasitic evasion of the host immune system is necessary to produce candidate vaccines or targets for antiparasitic drugs. Currently, there is no vaccine against any human parasitic infection. Looking at the sheer numbers of people suffering from parasitic diseases, it isunfortunate that more is not being done to develop safe and effective vaccines. One of the reasons for this is that parasitic diseases mainly afflict people in developing nations, precisely the subpopulation that would not be able to afford a new, expensive vaccine (20). Such a limitation has discouraged most research and development from occurring.
However, going back to the immunological basis of our discussion, it must also be noted that the inherent complexity of parasites makes vaccine development challenging;they have aremarkableability to adaptto immunologic pressure, and this is compounded by the spread of host resistance to drugs. As such, current treatment for leishmaniasis includes antimonials such as Pentostam and Glucantime, along with supplemental therapies such as the newer drugs Pentamidine, Amphotericin B and Miltefosine (20) (Figure 13). Unfortunately, like many other drugs, these treatments are no longer as effective dueto increasing host resistance. The current emerging resistance by parasites is most likely due to inadequate doses that stem from the inability to finance a complete regiment.
Fortunately, there are many projects currently in development that hope to further the progress of decreasing the burden of Leishmania (Figure 14). One such undertaking is from the Walter and Eliza Hall Institute of Medical Research in Australia. Dr. Emanuela Handman’s laboratory has been developing a prototype vaccine based on a Leishmania surface component (Parasite Surface Antigen Complex 2, or PSA-2). This antigen is present in all Leishmania species, so it seems ideal for protection against several forms of the disease. Dr. Diane McMahon Pratt in the United States has shown that this parasite protein can vaccinate and protect against the South American form of the disease. Through the Cooperative Research Center for Vaccine Technology, the Hall Institute and the Leishmania laboratory are at the forefront of this new area of vaccinology (21).
Figure 14: Several steps for drug development
Also of major importance is the Institute for OneWorld Health, which is a nonprofit pharmaceutical company that develops safe, effective, and affordable new medicines for people with infectious diseases in the developing world. It is active in rural, poor areas of India, Nepal, Bangaladesh, Sudan, and Brazil. On May 22, 2007, OneWorld Health’s first approved drug was added to the WHO Essential Medicines List. Paromomycin IM injection is a cost-effective, aminoglycoside antibiotic treatment for visceral leishmaniasis. It works by inhibiting protein synthesis by binding to ribosomal RNA. This is a huge step in drug development for parasitic diseases. Next, OneWorld Health is hoping to establish collaborations with government agencies and other global health organizations to distribute this drug to all patients who need treatment and seek regulatory approval in these and other affected countries (22).
It is important to realize that these projects depend on the knowledge of the evasive mechanisms used by the Leishmania parasites, for a deeper understanding of these immune reactions is integral in determining the best targets for drug treatment. We have shown that mechanistic details will differ, sometimes markedly, between Leishmania promastigotes and amastigotes and also between different species of Leishmania. These differences are likely to be of great importance in explaining the widely different clinical manifestations of leishmaniasis; however, it is clear that their common trait is the manipulation of the host cell signaling system. As signaling pathways can be pharmacologically manipulated, a better knowledge of their role in normal cellular functioning and the mechanisms whereby they regulate host immune cell functions and pathogen growth can allow for the development of new therapies to control such infectious agents as Leishmania. Only with the biological basis of parasitic infections under firm grasp can drug development and clinical trials go on to begin helping those afflicted.
During our study of parasites’ evasion of the host immune system, we have come across numerous mechanisms that are used by several different parasites. The fact that mechanisms such as complement lysis resistance and inhibition of MHC presentation have evolved over time and exist among a range of parasites highlights their roles as some of the most integral aspects of the immune response. In addition, it is important to keep in mind the fact that good parasites do not kill their hosts (23). The parasite’s goal is to simply maintain a healthy balance with the host’s immune system that allows the parasite to survive and reproduce. Just like humans living in the earth’s environment, they have adapted their surroundings in order to ensure their perpetuation. Put by the WEHI Institute, the host-parasite relationship is “a delicate balancing act between the ability of the parasite to create a safe environment for growth and developing in the host, and the efforts of the host to defend against the parasite, using the immune system for resistance” (21). In the case of Leishmaniasis, this balancing act often leads to effective immune system evasion. It can be said that Leishmania is a crafty parasite that utilizes all aspects of its life cycle in order to ensure its reproduction.