The many faces of parasite calreticulin

Abstract

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.

Crystal structure of Trichinella spiralis calreticulin and the structural basis of its complement evasion mechanism involving C1q

“…It has been shown that CRTs are highly conserved in several parasite species, from protozoa ( Trypanosoma , Amoeba , and Leishmania ) to helminths ( Echinococcus , Opisthorchis viverrini , Brugia malayi and Necator americanus ), and play important roles in the adaptation of parasites to the hostile environments and escape from host immune responses ( 4 , 7 , 21 , 45 , 46 ). Our previous studies have determined that TsCRT can bind to human complement C1q and inhibit C1q-initiated classical complement activation to enable the parasite to evade host first-line immune attack ( 15 , 16 ).…”

“…Protozoa and helminths have both developed sophisticated strategies to evade immune attack by manipulating the host immune system during the long revolutionary process of parasite-host interplay. One of these strategies is to secrete proteins that target complement components to inhibit MAC formation ( 2 – 4 ). Calreticulin (CRT), for instance, is a key protein in immune evasion against complement attack.…”

“…Within their immune evasion role, CRT proteins derived from different parasites may adopt different C1q-binding modes. Protozoal T. cruzi -produced CRT (TcCRT) was reported to interfere with the activation of the complement classical pathway through binding to C1q collagen-like fragment (C1q-CLF) ( 4 , 11 , 24 ). Meanwhile, nematode B. malayi –produced calreticulin (BmCRT) and TsCRT were predicted to interact with C1q-GR to interfere with the initiation of complement activation ( 16 , 20 ).…”

The Molecular Mechanisms Employed by the Parasite Myxobolus bejeranoi (Cnidaria: Myxozoa) from Invasion through Sporulation for Successful Proliferation in Its Fish Host

“…Calreticulin was suggested to be a key molecule in host–parasite interaction. In T. cruzi , helminths, and arthropod parasites, calreticulin interferes with C1q binding and complement system activation, and modulates the host cellular or humoral immune response (reviewed by [ 28 , 67 ]). Calreticulin is likely to play a prominent role in myxozoan virulence, as it does in other parasites [ 68 ].…”

Advancing Cancer Therapy: A Review of Recent Progress in Monoclonal Antibodies

“…Lastly, mAbs that can be employed in combination with conventional chemotherapy therapies to attack tumors by complementary modes of action. These mechanisms may include the production of antibodies by cytons of chemotherapeutic medical products that express anti-tumor immune responses [35] that may have been had diminished.…”