Pathogen evasion of chemokine response through suppression of CXCL10

Antonia, Alejandro

Alvarez, Monica

Trahair, Esme

Gibbs, Kyle

Pittman, Kelly

Barnes, Alyson

Smith, Jeffrey

Smith, Jeffrey

Rajagopal, Sudarshan

Thompson, Will

Reinhardt, Lee

Ko, Dennis

2019-10-02T01:28:48Z

2019-10-02T01:28:48Z

2019-02-22

2019-10-02T01:28:47Z

Abstract Clearance of intracellular pathogens, such as Leishmania ( L. ) major , depends on an immune response with well-regulated cytokine signaling. Here we describe a pathogen-mediated mechanism of evading CXCL10, a chemokine with diverse antimicrobial functions, including T cell recruitment. Infection with L. major in a human monocyte cell line induced robust CXCL10 transcription without increasing extracellular CXCL10 protein concentrations. We found that this transcriptionally independent suppression of CXCL10 is mediated by the virulence factor and protease, glycoprotein-63 ( gp63) . Specifically, GP63 cleaves CXCL10 after amino acid A81 at the base of a C-terminal alpha-helix. Cytokine cleavage by GP63 demonstrated specificity, as GP63 cleaved CXCL10 and its homologues, which all bind the CXCR3 receptor, but not distantly related chemokines, such as CXCL8 and CCL22. Further characterization demonstrated that CXCL10 cleavage activity by GP63 was produced by both extracellular promastigotes and intracellular amastigotes. Crucially, CXCL10 cleavage impaired T cell chemotaxis in vitro , indicating that cleaved CXCL10 cannot signal through CXCR3. Ultimately, we propose CXCL10 suppression is a convergent mechanism of immune evasion, as Salmonella enterica and Chlamydia trachomatis also suppress CXCL10. This commonality suggests that counteracting CXCL10 suppression may provide a generalizable therapeutic strategy against intracellular pathogens. Importance Leishmaniasis, an infectious disease that annually affects over one million people, is caused by intracellular parasites that have evolved to evade the host’s attempts to eliminate the parasite. Cutaneous leishmaniasis results in disfiguring skin lesions if the host immune system does not appropriately respond to infection. A family of molecules called chemokines coordinate recruitment of the immune cells required to eliminate infection. Here, we demonstrate a novel mechanism that Leishmania (L.) major employs to suppress host chemokines: an L. major protease cleaves chemokines known to recruit T cells that fight off infection. We observe that other common human intracellular pathogens, including Chlamydia trachomatis and Salmonella enterica , reduce levels of the same chemokines, suggesting a strong selective pressure to avoid this component of the immune response. Our study provides new insights into how intracellular pathogens interact with the host immune response to enhance pathogen survival.

https://hdl.handle.net/10161/19381

Cold Spring Harbor Laboratory

10.1101/557876

Pathogen evasion of chemokine response through suppression of CXCL10

Journal article

Rajagopal, Sudarshan|0000-0002-3443-5040

Ko, Dennis|0000-0002-0113-5981

School of Medicine

Duke

Biochemistry

Basic Science Departments

Medicine, Cardiology

Medicine

Clinical Science Departments

Published