Pathogen Evasion of Chemokine Response Through Suppression of CXCL10

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 homologs, 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.) spp. employ to suppress host chemokines: a Leishmania- encoded 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.

CXCL10+peripheral activation niches couple preferred sites of Th1 entry with optimal APC encounter

“…Many pathogens evade immune cell recognition by modulating the local chemokine milieu, through local inhibition of chemokine production or the deployment of chemokine-decoys (Antonia et al, 2019;Katzman and Fowell, 2008;Mantovani et al, 2006). Therefore, effector function may be enhanced by a sequential two-step process (Ley, 2014) whereby amplification of the frequency or function of incoming antigen-specific T cells (step 1, exemplified here by inducible PAC-10 niches) is kinetically and spatially separated from the pathogen-infection foci (step 2, movement from activation niches to pathogen foci).…”

Modeling of variables in cellular infection reveals CXCL10 levels are regulated by human genetic variation and the Chlamydia-encoded CPAF protease

“…We previously identified a mechanism of CXCL10 suppression in the context of Leishmania infection mediated by the Leishmania -encoded matrix metalloprotease, GP63 57 . We found that this mechanism of immune evasion is beneficial to the parasite as it inhibits recruitment of anti-parasitic CXCR3 + T-cells.…”

Protective or Detrimental? Understanding the Role of Host Immunity in Leishmaniasis

“…Lypophosphoglycan (LPG) and the zinc-metalloprotease GP63: major surface components of Leishmania implicated in the impairment of various macrophage functions, including inhibition of phagolysosomal maturation [69,70], cytokine cleavage [71], and activation of negative regulatory factors [72]. ii.…”