During the last 100 years, cell signaling has evolved into a common mechanism for most physiological processes across systems. Although the majority of cell signaling principles were initially derived from hormonal studies, its exponential growth has been supported by interdisciplinary inputs, e.g., from physics, chemistry, mathematics, statistics, and computational fields. As a result, cell signaling has grown out of scope for any general review. Here, we review how the messages are transferred from the first messenger (the ligand) to the receptor, and then decoded with the help of cascades of second messengers (kinases, phosphatases, GTPases, ions, and small molecules such as cAMP, cGMP, diacylglycerol, etc.). The message is thus relayed from the membrane to the nucleus where gene expression ns, subsequent translations, and protein targeting to the cell membrane and other organelles are triggered. Although there are limited numbers of intracellular messengers, the specificity of the response profiles to the ligands is generated by the involvement of a combination of selected intracellular signaling intermediates. Other crucial parameters in cell signaling are its directionality and distribution of signaling strengths in different pathways that may crosstalk to adjust the amplitude and quality of the final effector output. Finally, we have reflected upon its possible developments during the coming years.

Leishmaniasis is a neglected protozoan parasitic disease that occurs in 88 countries but a vaccine is unavailable. Vaccination with live, killed, attenuated (physically or genetically) Leishmania have met with limited success, while peptide-, protein-, or DNA-based vaccines showed promise only in animal models. Here, we critically assess several technical issues in vaccination and expectation of a host-protective immune response. Several studies showed that antigen presentation during priming and triggering of the same cells in infected condition are not comparable. Altered proteolytic processing, antigen presentation, protease-susceptible sites, and intracellular expression of pathogenic proteins during Leishmania infection may vary dominant epitope selection, MHC-II/peptide affinity, and may deter the reactivation of desired antigen-specific T cells generated during priming. The robustness of the memory T cells and their functions remains a concern. Presentation of the antigens by Leishmania-infected macrophages to antigen-specific memory T cells may lead to change in the T cells’ functional phenotype or anergy or apoptosis. Although cells may be activated, the peptides generated during infection may be different and cross-reactive to the priming peptides. Such altered peptide ligands may lead to suppression of otherwise active antigen-specific T cells. We critically assess these different immunological issues that led to the non-availability of a vaccine for human use.