Leishmania major degrades murine CXCL1

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Leishmaniasis is a global health problem with an estimated report of 2 million new cases every year. Innate immune system plays a central role in controlling L. major infection by initiating a signaling cascade that results in the production of pro‐inflammatory cytokines and recruitment of both innate and adaptive immune cells. Upon infection with L. major, CXCL1 is produced locally and plays an important role in the recruitment of neutrophils and macrophages to the site of infection. Herein, we report that L. major specifically targets murine CXCL1 for degradation and this allows L. major to establish infection in the host. The degradation of CXCL1 is not dependent on host factors because L. major can directly degrade recombinant CXCL1 in a cell‐free system. This degradation is specific to murine CXCL1 as murine CXCL2 as well as human CXCL1 and CXCL2 are not degraded. Using mass spectrometry, we have determined that the unknown L. major protease cleaves at the C‐terminal end of murine CXCL1. Using protease inhibitors our data suggest that the L. major unknown protease is a metalloprotease involved in the direct degradation of CXCL1. Finally, we have tested a peptide spanning the cleavage site which can be used to inhibit L. major protease activity and pathogenesis.Support or Funding InformationThis work was supported by NIH K22, NIEHS P30 and University of Iowa Start‐up funds to P.G.Upon infection with L. major, CXCL1 is produced locally and plays an important role in the recruitment of neutrophils and macrophages to the site of infection. We have identified that a secreted L. major protease cleaves at the C‐terminal end of murine CXCL1. This protease is likely a metalloproteases as Zn2+ chelators inhibit degradation of CXCL1. The degradation of CXCL1 dampens the hosts ability to resolve infection.Figure 1