The CC Chemokine Receptor 5 Is Important in Control of Parasite Replication and Acute Cardiac Inflammation following Infection with Trypanosoma cruzi

ABSTRACT Infection of susceptible mice with the Colombiana strain of Trypanosoma cruzi results in an orchestrated expression of chemokines and chemokine receptors within the heart that coincides with parasite burden and cellular infiltration. CC chemokine receptor 5 (CCR5) is prominently expressed during both acute and chronic disease, suggesting a role in regulating leukocyte trafficking and accumulation within the heart following T. cruzi infection. To better understand the functional role of CCR5 and its ligands with regard to both host defense and/or disease, CCR5−/− mice were infected with T. cruzi, and the disease severity was evaluated. Infected CCR5−/− mice develop significantly higher levels of parasitemia (P ≤ 0.05) and cardiac parasitism (P ≤ 0.01) during acute infection that correlated with reduced survival. Further, we show that CCR5 is essential for directing the migration of macrophages and T cells to the heart early in acute infection with T. cruzi. In addition, data are provided demonstrating that CCR5 does not play an essential role in maintaining inflammation in the heart during chronic infection. Collectively, these studies clearly demonstrate that CCR5 contributes to the control of parasite replication and the development of a protective immune response during acute infection but does not ultimately participate in maintaining a chronic inflammatory response within the heart.

Download Full-text

Structural basis of the activation of the CC chemokine receptor 5 by a chemokine agonist

10.1101/2020.11.27.401117 ◽

2020 ◽

Author(s):

Polina Isaikina ◽

Ching-Ju Tsai ◽

Nikolaus Dietz ◽

Filip Pamula ◽

Anne Grahl ◽

...

Keyword(s):

Chemokine Receptor ◽

Chemokine Receptors ◽

Binding Mode ◽

Activation Mechanism ◽

Structural Basis ◽

Cc Chemokine ◽

Gi Protein ◽

Agonist And Antagonist ◽

Cc Chemokine Receptor 5 ◽

Chemokine Receptor 5

AbstractThe human CC chemokine receptor 5 (CCR5) is a G protein-coupled receptor (GPCR) that plays a major role in inflammation and is involved in the pathology of cancer, HIV, and COVID-19. Despite its significance as a drug target, the activation mechanism of CCR5, i.e. how chemokine agonists transduce the activation signal through the receptor, is yet unknown. Here, we report the cryo-EM structure of wild-type CCR5 in an active conformation bound to the chemokine super-agonist [6P4]CCL5 and the heterotrimeric Gi protein. The structure provides the rationale for the sequence-activity relation of agonist and antagonist chemokines. The N-terminus of agonist chemokines pushes onto an aromatic connector that transmits activation to the canonical GPCR microswitch network. This activation mechanism differs significantly from other CC chemokine receptors that bind shorter chemokines in a shallow binding mode and have unique sequence signatures and a specialized activation mechanism.One-sentence summaryThe structure of CCR5 in complex with the chemokine agonist [6P4]CCL5 and the heterotrimeric Gi protein reveals its activation mechanism

Download Full-text

Agonist-induced Endocytosis of CC Chemokine Receptor 5 Is Clathrin Dependent

Molecular Biology of the Cell ◽

10.1091/mbc.e04-08-0687 ◽

2005 ◽

Vol 16 (2) ◽

pp. 902-917 ◽

Cited By ~ 67

Author(s):

Nathalie Signoret ◽

Lindsay Hewlett ◽

Silène Wavre ◽

Annegret Pelchen-Matthews ◽

Martin Oppermann ◽

...

Keyword(s):

Chemokine Receptor ◽

Chemokine Receptors ◽

Endocytic Pathway ◽

Small Interfering Rnas ◽

Coated Pits ◽

Cc Chemokine ◽

Early Endosomes ◽

Raft Domains ◽

Cc Chemokine Receptor 5 ◽

Chemokine Receptor 5

The signaling activity of several chemokine receptors, including CC chemokine receptor 5 (CCR5), is in part controlled by their internalization, recycling, and/or degradation. For CCR5, agonists such as the chemokine CCL5 induce internalization into early endosomes containing the transferrin receptor, a marker for clathrin-dependent endocytosis, but it has been suggested that CCR5 may also follow clathrin-independent routes of internalization. Here, we present a detailed analysis of the role of clathrin in chemokine-induced CCR5 internalization. Using CCR5-transfected cell lines, immunofluorescence, and electron microscopy, we demonstrate that CCL5 causes the rapid redistribution of scattered cell surface CCR5 into large clusters that are associated with flat clathrin lattices. Invaginated clathrin-coated pits could be seen at the edge of these lattices and, in CCL5-treated cells, these pits contain CCR5. Receptors internalized via clathrin-coated vesicles follow the clathrin-mediated endocytic pathway, and depletion of clathrin with small interfering RNAs inhibits CCL5-induced CCR5 internalization. We found no evidence for CCR5 association with caveolae during agonist-induced internalization. However, sequestration of cholesterol with filipin interferes with agonist binding to CCR5, suggesting that cholesterol and/or lipid raft domains play some role in the events required for CCR5 activation before internalization.

Download Full-text

Structural basis of the activation of the CC chemokine receptor 5 by a chemokine agonist

Science Advances ◽

10.1126/sciadv.abg8685 ◽

2021 ◽

Vol 7 (25) ◽

pp. eabg8685

Author(s):

Polina Isaikina ◽

Ching-Ju Tsai ◽

Nikolaus Dietz ◽

Filip Pamula ◽

Anne Grahl ◽

...

Keyword(s):

Chemokine Receptor ◽

Chemokine Receptors ◽

Binding Mode ◽

Activation Mechanism ◽

Structural Basis ◽

Cc Chemokine ◽

Agonist And Antagonist ◽

Cc Chemokine Receptor 5 ◽

G Protein Coupled ◽

Chemokine Receptor 5

The human CC chemokine receptor 5 (CCR5) is a G protein–coupled receptor (GPCR) that plays a major role in inflammation and is involved in cancer, HIV, and COVID-19. Despite its importance as a drug target, the molecular activation mechanism of CCR5, i.e., how chemokine agonists transduce the activation signal through the receptor, is yet unknown. Here, we report the cryo-EM structure of wild-type CCR5 in an active conformation bound to the chemokine super-agonist [6P4]CCL5 and the heterotrimeric Gi protein. The structure provides the rationale for the sequence-activity relation of agonist and antagonist chemokines. The N terminus of agonist chemokines pushes onto specific structural motifs at the bottom of the orthosteric pocket that activate the canonical GPCR microswitch network. This activation mechanism differs substantially from other CC chemokine receptors that bind chemokines with shorter N termini in a shallow binding mode involving unique sequence signatures and a specialized activation mechanism.

Download Full-text