Pathogen evasion of chemokine response through suppression of CXCL10

Abstract

Clearance of intracellular pathogens, such as Leishmania (L.) major, depends on a well-regulated adaptive T cell response. Here we describe a pathogen-encoded mechanism to alter T cell recruitment by suppressing CXCL10, a chemokine that recruits CD4+ and CD8+ T cells by signaling through the CXCR3 receptor. L. major suppresses CXCL10 through the virulence factor and protease, glycoprotein-63 (gp63). GP63 cleaves CXCL10 after amino acid A81, impairing T-cell chemotaxis in vitro. GP63 from either extracellular promastigotes or intracellular amastigotes is capable of cleaving CXCL10. Consistent with CXCL10 cleavage during infection, we observed GP63-mediated impairment of activated CD8+ T-cells in the draining lymph nodes of C57BL/6JWT mice. Correspondingly, in C57BL/6JWT mice, gp63 deletion resulted in slower lesion development and a smaller maximum lesion size. However, infection in C57BL/6Jcxcr3-/- mice revealed the delay to lesion development required CXCR3 signaling. Finally, Salmonella enterica and Chlamydia trachomatis infection also suppress CXCL10, demonstrating convergent evolution of this immune evasion strategy in diverse intracellular pathogens. Understanding mechanisms of CXCL10 evasion may facilitate the development of novel therapeutic strategies to treat intracellular pathogens. Author SummaryLeishmaniasis is an infectious disease that affects over one million people annually. It is caused by intracellular parasites that have evolved to evade the hosts attempts to eliminate the parasite. The most common form of disease, cutaneous leishmaniasis, causes disfiguring skin lesions if the host immune system does not appropriately respond to the infection. A family of molecules called chemokines are critical for the recruitment of specific subsets of immune cells required to eliminate infection. Here, we demonstrate a novel mechanism that the parasite Leishmania (L.) major employs to disrupt the immune response by interfering with chemokine signaling. By this strategy, L. major uses a protease to cleave chemokines known to recruit T-cells required for fighting off infection. We show that L. major cleavage of these immune signals changes the recruitment of CD8+ T-cells and alters disease progression in mice. Finally, we observe that multiple common human intracellular pathogens, including Chlamydia trachomatis and Salmonella enterica, interfere with 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 and exacerbate disease outcomes.