Scavenger receptors in host defense: from functional aspects to mode of action

Scavenger receptors belong to a superfamily of proteins that are structurally heterogeneous and encompass the miscellaneous group of transmembrane proteins and soluble secretory extracellular domain. They are functionally diverse as they are involved in various disorders and biological pathways and their major function in innate immunity and homeostasis. Numerous scavenger receptors have been discovered so far and are apportioned in various classes (A-L). Scavenger receptors are documented as pattern recognition receptors and known to act in coordination with other co-receptors such as Toll-like receptors in generating the immune responses against a repertoire of ligands such as microbial pathogens, non-self, intracellular and modified self-molecules through various diverse mechanisms like adhesion, endocytosis and phagocytosis etc. Unlike, most of the scavenger receptors discussed below have both membrane and soluble forms that participate in scavenging; the role of a potential scavenging receptor Angiotensin-Converting Enzyme-2 has also been discussed whereby only its soluble form might participate in preventing the pathogen entry and replication, unlike its membrane-bound form. This review majorly gives an insight on the functional aspect of scavenger receptors in host defence and describes their mode of action extensively in various immune pathways involved with each receptor type.

The mechanisms of cell invasion in cnidarian-dinoflagellate symbiosis: Learning from parasitic strategies

<p>Cnidarians such as corals, anemones and hydroids commonly form an intracellular symbiosis with photosynthetic dinoflagellates of the genus Symbiodinium. Dinoflagellate symbionts are most often obtained anew from the environment during larval development, and, once acquired reside inside host-derived vacuoles within the cnidarian gastrodermal cells. In order to gain entry to host cells, the symbionts likely interact with innate immune receptors in the extracellular matrix, the first line of defense against microbial attack. While several innate immune pathways have been described in cnidarians, little is known about the specific receptor-ligand interactions that allow the symbiont to gain entry to host cells. Furthermore, it is unclear how these pathways are involved in enabling friendly microbes to reside within host cells while maintaining an immune response to harmful pathogens. The invasion strategies of vertebrate intracellular parasites are well studied, especially those used by members of the Apicomplexa. Apicomplexan parasites have evolved mechanisms to evade immune receptors in the extracellular matrix and exploit specific receptors to their own benefit, to gain entry to host cells. Apicomplexans are closely related to dinoflagellates, both belonging to the infrakingdom Alveolata. The malaria parasite Plasmodium spp. has evolved the thromobospondin-related anonymous protein, or TRAP, that uses a thrombospondin structural homology repeat (TSR) domain to bind to a scavenger receptor (SRB1) on the hepatocyte cell surface and gain entry to the cell. This is of particular interest, as class B scavenger receptors are upregulated in the symbiotic state of two anemone species. The aims of the research presented in this thesis were to: (1) characterize the scavenger receptor (SR) repertoire in cnidarians; (2) characterize the TSR-domain-containing protein repertoire of cnidarians and their symbiotic dinoflagellates; and (3) establish, through experimental manipulation, the potential role for SR-TSR domain interactions at the onset of symbiosis in the sea anemone Aiptasia sp, a model system for the study of the cnidariandinoflagellate symbiosis. In Chapter 2, I characterized the large and diverse SR repertoire of six cnidarian species. Cnidarians lack the classic SR type-A collagen domain-containing proteins that are common in humans, however the cnidarian SR cysteine-rich domain-containing protein repertoire is expanded and diverse. Phylogenetic analysis of SR type-B proteins defines two or three distinct groups. Functional experimental data presented here show that blocking SR binding sites with fucoidan significantly reduces dinoflagellate uptake by the anemone Aiptasia sp. These data provide further evidence that SRs are important to symbiont recognition and uptake, and may be an essential component of symbiont acquisition. In Chapter 3, I investigated a SR ligand, the thrombospondin structural homology repeat, or TSR domain. In particular, I characterized the TSR-domain-containing protein repertoire of six cnidarian species and compared these proteins to vertebrate TSR proteins of known function. Searches revealed a large repertoire of TSR-domaincontaining proteins. Of particular interest is the large number of Adams metalloprotease-like proteins, a group that is common in both humans and cnidarians, suggesting that this is an ancestral TSR protein group. Phylogenetic analysis of TSR domains shows that binding motifs and 3-D folding sites are highly conserved. These data suggest that TSR domains are ancient and have changed very little in amino acid sequence from lower metazoans to vertebrates. In Chapter 4, I explored the role of TSR-domain-containing proteins at the onset of symbiosis in the model Aiptasia sp. system. In functional experiments, aposymbiotic anemones were challenged with proteins and antibodies to either block or stimulate TSR domain binding. Symbiont uptake was measured over several time-points to determine the effects on symbiont acquisition. Adding an excess of TSR-domaincontaining protein or TSR synthetic peptide increased symbiont uptake, while blocking TSR domains prevented symbiont uptake. Finally, the addition of exogenous TGFβ to TSR antibody-challenged anemones, reversed the blocking effect. These data suggest that the immune-suppressive TGFβ pathway is involved in early onset of the symbiosis. Since the TSR domain is implicated in the TGFβ pathway, these results support previous findings of the involvement of TGFβ in promoting tolerance of symbionts within the host. Apicomplexan parasites exploit scavenger receptor-TSR domain-binding to gain entry, and also use immune modulation to persist inside host cells. Data presented here suggest that dinoflagellates are utilizing the same mechanisms to form a mutualistic relationship with the cnidarian host. Overall, the work presented here provides new information about several cnidarian extracellular matrix proteins, with searches revealing large repertoires of both scavenger receptors and TSR-domain-containing proteins. Functional data suggest that both protein families are involved in the cnidarian-dinoflagellate symbiosis. Searches of the dinoflagellate genome did not find a clear dinoflagellate homologue to the apicomplexan TRAP proteins. However, this research provides further evidence that similar receptor-ligand interactions are involved in the entry of both beneficial and pathogenic microbes to host cells. These results add to growing knowledge about the complex molecular pathways that enable and support cnidarian-dinoflagellate symbiosis. An understanding of the mechanisms that support healthy symbiosis is essential when trying to predict the vitality and productivity of reef ecosystems in the face of climate change.</p>

The mechanisms of cell invasion in cnidarian-dinoflagellate symbiosis: Learning from parasitic strategies

<p>Cnidarians such as corals, anemones and hydroids commonly form an intracellular symbiosis with photosynthetic dinoflagellates of the genus Symbiodinium. Dinoflagellate symbionts are most often obtained anew from the environment during larval development, and, once acquired reside inside host-derived vacuoles within the cnidarian gastrodermal cells. In order to gain entry to host cells, the symbionts likely interact with innate immune receptors in the extracellular matrix, the first line of defense against microbial attack. While several innate immune pathways have been described in cnidarians, little is known about the specific receptor-ligand interactions that allow the symbiont to gain entry to host cells. Furthermore, it is unclear how these pathways are involved in enabling friendly microbes to reside within host cells while maintaining an immune response to harmful pathogens. The invasion strategies of vertebrate intracellular parasites are well studied, especially those used by members of the Apicomplexa. Apicomplexan parasites have evolved mechanisms to evade immune receptors in the extracellular matrix and exploit specific receptors to their own benefit, to gain entry to host cells. Apicomplexans are closely related to dinoflagellates, both belonging to the infrakingdom Alveolata. The malaria parasite Plasmodium spp. has evolved the thromobospondin-related anonymous protein, or TRAP, that uses a thrombospondin structural homology repeat (TSR) domain to bind to a scavenger receptor (SRB1) on the hepatocyte cell surface and gain entry to the cell. This is of particular interest, as class B scavenger receptors are upregulated in the symbiotic state of two anemone species. The aims of the research presented in this thesis were to: (1) characterize the scavenger receptor (SR) repertoire in cnidarians; (2) characterize the TSR-domain-containing protein repertoire of cnidarians and their symbiotic dinoflagellates; and (3) establish, through experimental manipulation, the potential role for SR-TSR domain interactions at the onset of symbiosis in the sea anemone Aiptasia sp, a model system for the study of the cnidariandinoflagellate symbiosis. In Chapter 2, I characterized the large and diverse SR repertoire of six cnidarian species. Cnidarians lack the classic SR type-A collagen domain-containing proteins that are common in humans, however the cnidarian SR cysteine-rich domain-containing protein repertoire is expanded and diverse. Phylogenetic analysis of SR type-B proteins defines two or three distinct groups. Functional experimental data presented here show that blocking SR binding sites with fucoidan significantly reduces dinoflagellate uptake by the anemone Aiptasia sp. These data provide further evidence that SRs are important to symbiont recognition and uptake, and may be an essential component of symbiont acquisition. In Chapter 3, I investigated a SR ligand, the thrombospondin structural homology repeat, or TSR domain. In particular, I characterized the TSR-domain-containing protein repertoire of six cnidarian species and compared these proteins to vertebrate TSR proteins of known function. Searches revealed a large repertoire of TSR-domaincontaining proteins. Of particular interest is the large number of Adams metalloprotease-like proteins, a group that is common in both humans and cnidarians, suggesting that this is an ancestral TSR protein group. Phylogenetic analysis of TSR domains shows that binding motifs and 3-D folding sites are highly conserved. These data suggest that TSR domains are ancient and have changed very little in amino acid sequence from lower metazoans to vertebrates. In Chapter 4, I explored the role of TSR-domain-containing proteins at the onset of symbiosis in the model Aiptasia sp. system. In functional experiments, aposymbiotic anemones were challenged with proteins and antibodies to either block or stimulate TSR domain binding. Symbiont uptake was measured over several time-points to determine the effects on symbiont acquisition. Adding an excess of TSR-domaincontaining protein or TSR synthetic peptide increased symbiont uptake, while blocking TSR domains prevented symbiont uptake. Finally, the addition of exogenous TGFβ to TSR antibody-challenged anemones, reversed the blocking effect. These data suggest that the immune-suppressive TGFβ pathway is involved in early onset of the symbiosis. Since the TSR domain is implicated in the TGFβ pathway, these results support previous findings of the involvement of TGFβ in promoting tolerance of symbionts within the host. Apicomplexan parasites exploit scavenger receptor-TSR domain-binding to gain entry, and also use immune modulation to persist inside host cells. Data presented here suggest that dinoflagellates are utilizing the same mechanisms to form a mutualistic relationship with the cnidarian host. Overall, the work presented here provides new information about several cnidarian extracellular matrix proteins, with searches revealing large repertoires of both scavenger receptors and TSR-domain-containing proteins. Functional data suggest that both protein families are involved in the cnidarian-dinoflagellate symbiosis. Searches of the dinoflagellate genome did not find a clear dinoflagellate homologue to the apicomplexan TRAP proteins. However, this research provides further evidence that similar receptor-ligand interactions are involved in the entry of both beneficial and pathogenic microbes to host cells. These results add to growing knowledge about the complex molecular pathways that enable and support cnidarian-dinoflagellate symbiosis. An understanding of the mechanisms that support healthy symbiosis is essential when trying to predict the vitality and productivity of reef ecosystems in the face of climate change.</p>

Malaria Parasites Hijack Host Receptors From Exosomes to Capture Lipoproteins

Malaria parasites cannot multiply in host erythrocytes without cholesterol because they lack complete sterol biosynthesis systems. This suggests parasitized red blood cells (pRBCs) need to capture host sterols, but its mechanism remains unknown. Here we identified a novel high-density lipoprotein (HDL)-delivery pathway operating in blood-stage Plasmodium. In parasitized mouse plasma, exosomes positive for scavenger receptor CD36 and platelet-specific CD41 increased. These CDs were detected in pRBCs and internal parasites. A low molecular antagonist for scavenger receptors, BLT-1, blocked HDL uptake to pRBCs and suppressed Plasmodium growth in vitro. Furthermore, platelet-derived exosomes were internalized in pRBCs. Thus, we presume CD36 is delivered to malaria parasites from platelets by exosomes, which enables parasites to steal HDL for cholesterol supply. Cholesterol needs to cross three membranes (RBC, parasitophorous vacuole and parasite’s plasma membranes) to reach parasite, but our findings can explain the first step of sterol uptake by intracellular parasites.

Scavenger Receptors: Novel Roles in the Pathogenesis of Liver Inflammation and Cancer

The scavenger receptor superfamily represents a highly diverse collection of evolutionarily-conserved receptors which are known to play key roles in host homeostasis, the most prominent of which is the clearance of unwanted endogenous macromolecules, such as oxidized low-density lipoproteins, from the systemic circulation. Members of this family have also been well characterized in their binding and internalization of a vast range of exogenous antigens and, consequently, are generally considered to be pattern recognition receptors, thus contributing to innate immunity. Several studies have implicated scavenger receptors in the pathophysiology of several inflammatory diseases, such as Alzheimer's and atherosclerosis. Hepatic resident cellular populations express a diverse complement of scavenger receptors in keeping with the liver's homeostatic functions, but there is gathering interest in the contribution of these receptors to hepatic inflammation and its complications. Here, we review the expression of scavenger receptors in the liver, their functionality in liver homeostasis, and their role in inflammatory liver disease and cancer.

Single-cell transcriptome analysis reveals mesenchymal stem cells in cavernous hemangioma

A cavernous hemangioma, well-known as vascular malformation, is present at birth, grows proportionately with the child, and does not undergo regression. Although a cavernous hemangioma has well-defined histopathological characteristics, its origin and formation remain unknown. In the present study, we characterized the cellular heterogeneity of cavernous hemangioma using single-cell RNA sequencing (scRNA-seq). The main contribution of this study is the discovery of mesenchymal stem cells (MSCs) that cause tumour formation in cavernous hemangioma and we propose that these MSCs may be abnormally differentiated or incompletely differentiated from epiblast stem cells.Other new findings include the responsive ACKR1 positive endothelial cell (ACKR1+EC) and BTNL9 positive endothelial cell (BTNL9+EC) and the BTNL9-caused checkpoint blockade enhanced by the CXCL12-CXCR4 signalling. The activated CD8+T and NK cells may highly express CCL5 for their infiltration in cavernous hemangiomas, independent on the tumor cell-derived CCL5-IFNG-CXCL9 pathway. The highly co-expression of CXCR4 and GZMB suggested that plasmacytoid dendritic cells (pDCs) function for anti-tumour as CD8+T cells in cavernous hemangiomas. The oxidised low-density lipoprotein (oxLDL) in the TME of cavernous hemangiomas may play an important role as a signalling molecular in the immune responses. Notably, we propose that oxLDL induces the oxLDL-OLR1-NLRP3 pathway by over-expression of OLR1 in M1-like macrophages, whereas oxLDL induces the oxLDL-SRs-C1q (SRs are genes encoding scavenger receptors of oxLDL except OLR1) pathway by over-expression of other scavenger receptors in M2-like macrophages.The present study revealed the origin of cavernous hemangiomas and discovered marker genes, cell types and molecular mechanisms associated with the origin, formation, progression, diagnosis or therapy of cavernous hemangiomas. The information from the present study makes important contributions to the understanding of cavernous hemangioma formation and progression and facilitates the development of gold standard for molecular diagnosis and effective drugs for treatment.