The Toll-Like Receptor 2 agonist PEG-Pam2Cys as an immunochemoprophylactic and immunochemotherapeutic against the liver and transmission stages of malaria parasites

Abstract

Both vaccine and therapeutic approaches to malaria are based on conventional paradigms; whole organism or single antigen epitope-based vaccines administered with or without an adjuvant, and chemotherapeutics (anti-malaria drugs) that are toxic to the parasite. Two major problems that limit the effectiveness of these approaches are i) high levels of antigenic variation within parasite populations rendering vaccination efficacy against all variants difficult, and ii) the capacity of the parasite to quickly evolve resistance to drugs. We describe a new approach to both protection from and treatment of malaria parasites that involves the direct stimulation of the host innate immune response through the administration of a Toll-Like Receptor-2 (TLR2) agonist. The activity of PEG-Pam2Cys against the hepatocytic stages, erythrocytic stages and gametocytes of the rodent malaria parasite Plasmodium yoelii was investigated in laboratory mice. We show that administration of PEG-Pam2Cys, a soluble form of the TLR2 agonist S-[2,3-bis(palmitoyloxy)propyl] cysteine (Pam2Cys), significantly and dramatically reduces the numbers of malaria parasites that grow in the livers of mice following subsequent challenge with sporozoites. We also show that treatment can also clear parasites from the liver when administered subsequent to the establishment of infection. Finally, PEG-Pam2Cys can reduce the numbers of mosquitoes that are infected, and the intensity of their infection, following blood feeding on gametocytaemic mice. These results suggest that this compound could represent a novel liver stage anti-malarial that can be used both for the clearance of parasites following exposure and for the prevention of the establishment of infection.

A cutting-edge immunoinformatics approach for design of multi-epitope oral vaccine against dreadful human malaria

“…It is quite interesting to note that the PVs designed without adjuvants were also able to interact (dock) with TLR2 and TLR4 (having good energy scores) over control except PV3. Therefore, they might be capable to elicit innate immunity [98][99][100], which are in well agreement with earlier studies regarding the rapid production of IFN-γ [101,102]. Amongst 15 designed PVs, PV3, PV5A and PV4B were not able to dock by ClusPro tool with their respective receptors.…”

Modulation of the Innate Immune Response by Targeting Toll-like Receptors: A Perspective on Their Agonists and Antagonists

“…In order to provide an alternative approach for the development of an effective vaccine for malaria prevention, Chua and Culletton described a protocol that potentially grants protection from parasitic invasion and simultaneously stimulates the host immune system. 130 They investigated the activity of the TLR2 agonist PEG-Pam 2 Cys in mouse models of malaria induced by P. voelii, in both hepatocytic and erythrocytic stages. Results showed a significant decrease in the number of malaria parasites in mice liver, following sporozoites invasion.…”

“…Kalantari has recently reviewed the mechanisms by which Plasmodium components (especially glycosylphosphatidylinositol anchors, hemozoin and DNA) are recognized by the immune system, highlighting the role of TLRs in sensing these molecules. , The major issues that limited the development of an effective vaccine or chemotherapeutic agent for malaria treatment over the years are the high antigenic variability within parasite populations and the capacity of the latter to quickly develop a resistance to drugs. In order to provide an alternative approach for the development of an effective vaccine for malaria prevention, Chua and Culletton described a protocol that potentially grants protection from parasitic invasion and simultaneously stimulates the host immune system . They investigated the activity of the TLR2 agonist PEG-Pam 2 Cys in mouse models of malaria induced by P. voelii , in both hepatocytic and erythrocytic stages.…”

TLR2 Agonistic Small Molecules: Detailed Structure–Activity Relationship, Applications, and Future Prospects

“…Among the various TLR2 ligands, Pam 3 CSK 4 counteracted influenza A virus (IAV), 40 SMIP demonstrated a good response as vaccine adjuvant against tetanus and influenza, 45 whereas the pegylated Pam 2 Cys induced high antibody titers in a mice model against parasitic infection caused by Plasmodium voelii. 168 Pam 2 Cys and Pam 3 Cys were also employed in various vaccine formulations such as oil-in-water squalene emulsions and polymeric solid core particles targeting different stages of malaria. 169 Pam 2 CSK 4 also reduced the parasitic burden and provided Th1 polarizing protection against whole cell leishmania vaccine.…”