The many faces of parasite calreticulin.

Calreticulin from parasites and its vertebrate hosts share ~50% identity and many of its functions are equally conserved. However, the existing amino acid differences can affect its biological performance. Calreticulin plays an important role in Ca2+ homeostasis and as a chaperone involved in the correct folding of proteins within the endoplasmic reticulum. Outside the endoplasmic reticulum, calreticulin is involved in several immunological functions such as complement inhibition, enhancement of efferocytosis, and immune upregulation or inhibition. Several parasite calreticulins have been shown to limit immune responses and promote infectivity, while others are strong immunogens and have been used for the development of potential vaccines that limit parasite growth. Furthermore, calreticulin is essential in the dialogue between parasites and hosts, inducing Th1, Th2 or regulatory responses in a species-specific manner. In addition, calreticulin participates as initiator of endoplasmic reticulum stress in tumor cells and promotion of immunogenic cell death and removal by macrophages. Direct anti-tumoral activity has also been reported. The highly immunogenic and pleiotropic nature of parasite calreticulins, either as positive or negative regulators of the immune response, render these proteins as valuable tools to modulate immunopathologies and autoimmune disorders, as well as a potential treatment of neoplasms. Moreover, the disparities in the amino acid composition of parasite calreticulins might provide subtle variations in the mechanisms of action that could provide advantages as therapeutic tools. Here, we review the immunological roles of parasite calreticulins and discuss possible beneficial applications.

Similarities and divergences in the metabolism of immune cells in cancer and helminthic infections.

Energetic and nutritional requirements play a crucial role in shaping the immune cells that infiltrate tumor and parasite infection sites. The dynamic interaction between immune cells and the microenvironment, whether in the context of tumor or helminth infection, is essential for understanding the mechanisms of immunological polarization and developing strategies to manipulate them in order to promote a functional and efficient immune response that could aid in the treatment of these conditions. In this review, we present an overview of the immune response triggered during tumorigenesis and establishment of helminth infections, highlighting the transition to chronicity in both cases. We discuss the energetic demands of immune cells under normal conditions and in the presence of tumors and helminths. Additionally, we compare the metabolic changes that occur in the tumor microenvironment and the infection site, emphasizing the alterations that are induced to redirect the immune response, thereby promoting the survival of cancer cells or helminths. This emerging discipline provides valuable insights into disease pathogenesis. We also provide examples of novel strategies to enhance immune activity by targeting metabolic pathways that shape immune phenotypes, with the aim of achieving positive outcomes in cancer and helminth infections.