A novel role for CD5L in modulating the immune responses against protozoan parasites

CD5 antigen-like (CD5L) is a protein found circulating in the blood, belonging to the scavenger receptor cyteine-rich (SRCR) superfamily. SRCR members are being extensively studied in the context of infections, emerging as a unique group of pattern recognition receptors (PRRs) capable of detecting various bacteria and fungi. Traditionally, these receptors were viewed as playing roles in neutralizing these microorganisms and enhancing macrophage phagocytosis. However, recent research, including our own, is changing this understanding. The findings suggest that these proteins, particularly CD5L, possess an important anti-inflammatory function, which may be just as significant as their ability to sense microbes. Also recent investigations have unveiled that certain SRCR proteins, including CD5L, possess the ability to detect protozoan parasites, thus broadening their known spectrum of targets. These discoveries are profoundly reshaping our comprehension of SRCR proteins and their role in orchestrating immune responses.
In the past two decades, the focus has been on elucidating the molecular and cellular mechanisms regulated by SRCR proteins and, more recently, six knockout (KO) mouse models have been developed to analyze the susceptibility to diseases resulting from the absence of individual SRCR members. In experiments utilizing the cecal ligation and puncture (CLP) polymicrobial sepsis model and the LPS model of endotoxic shock, the absence of CD5L rendered mice highly vulnerable to attenuated procedures, in contrast to the near-complete survival observed in wild-type (WT) mice. Conversely, the administration of recombinant CD5L (rCD5L) significantly mitigated disease severity in immunocompetent WT mice amidst acute infection and inflammation induced by lethal CLP and LPS models. Remarkably, survival of mice treated with rCD5L exceeded 70%, whereas untreated mice exhibited a notably lower survival rate.
The vector-borne protozoan diseases Malaria and Human African Trypanosomiasis, caused by Plasmodium spp and Trypanosoma brucei parasites, respectively, collectively affected over 240 million people worldwide as of 2021. Initial investigations revealed elevated CD5L levels in the serum of mice infected with Trypanosoma brucei and Plasmodium berghei, with the protein demonstrating effective binding to the surface of these parasites. Interestingly, CD5L KO mice exhibited decreased survival rates after T. brucei infection. However, this increased susceptibility does not correlate with pathogen load, as initial data indicated comparable parasitemia between mutant and WT animals near the time of death.
The function of CD5L against parasites may vary due to several factors, including parasite characteristics and their interactions with the host immune system: i) For T. brucei , an extracellular bloodstream parasite, CD5L’s role may involve its anti-inflammatory properties, as indicated by elevated serum levels in infected mice. CD5L could regulate the immune response by mitigating excessive inflammation and tissue damage. Additionally, its binding to T. brucei surface suggests a direct interaction, affecting parasite survival or host immune recognition; ii) Plasmodium parasites, with their complex life cycle, pose varied challenges. CD5L may modulate the initial immune response during the liver stage, where sporozoites infect and multiply into red blood cells (RBCs)-infective forms inside hepatocytes, and influence inflammation and parasite clearance during the blood stage, where parasites undergo repetitive cycles of multiplication inside RBCs.
While the anti-inflammatory properties of CD5L may limit immune-mediated pathology in Trypanosoma brucei and Plasmodium spp infections, its specific mechanisms and effects on parasite survival may differ. In this project, we propose to further explore the role of CD5L in immune responses against vector-borne protozoan parasites using our in-house developed CD5L KO mice. Further research is needed to elucidate the precise role of CD5L in the context of these parasitic infections and its therapeutic potential. Given the limited therapeutic options for these diseases, in particular to the severe forms, exploring these models will provide essencial evidence for the involvement of CD5L in diseases imposing significant global health and economic burdens, potentially leading to the development of novel therapeutic interventions.

Basic Science
Immunology

Jan 2025 — Jun 2026

$53,996

Portugal