SODB1 is essential for Leishmania major infection of macrophages and pathogenesis in mice

PLoS Negl Trop Dis. 2018 Oct 29;12(10):e0006921. doi: 10.1371/journal.pntd.0006921. eCollection 2018 Oct.

Abstract

Leishmania species are sand fly-transmitted protozoan parasites that cause leishmaniasis, neglected tropical diseases that affect millions of people. Leishmania amastigotes must overcome a variety of host defenses, including reactive oxygen species (ROS) produced by the NADPH oxidase. Leishmania species encode three superoxide dismutases (SODs): the mitochondrial SODA and two glycosomal SODs (SODB1 and SODB2). SODs are metalloenzymes that function in antioxidant defense by converting superoxide to oxygen and hydrogen peroxide. Here, we investigated a role for SODB1 in Leishmania infection of macrophages and virulence in mice. We found that a single allele deletion of SODB1 (SODB1/Δsodb1) had minimal effects on the replication of axenically-grown L. major promastigotes or differentiation to infective metacyclic promastigotes. Disruption of a single SODB1 allele also did not affect L. donovani differentiation to amastigotes induced axenically, or the replication of axenically-grown L. donovani promastigotes and amastigotes. In contrast, the persistence of SODB1/Δsodb1 L. major in WT macrophages was impaired, and the development of cutaneous lesions in SODB1/Δsodb1 L. major-infected C57BL/6 and BALB/c mice was strongly reduced. The reduced disease severity in mice was associated with reduced burdens of SODB1/Δsodb1 L. major parasites in the foot at late, but not early times post-inoculation, as well as an impaired capacity to disseminate from the site of inoculation. Collectively, these data suggest that SODB1 is critical for L. major persistence in macrophages and virulence in mice.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Disease Models, Animal
  • Female
  • Gene Deletion
  • Leishmania donovani / enzymology
  • Leishmania donovani / genetics
  • Leishmania donovani / pathogenicity
  • Leishmania major / enzymology*
  • Leishmania major / genetics
  • Leishmania major / pathogenicity*
  • Leishmaniasis, Cutaneous / parasitology
  • Leishmaniasis, Cutaneous / pathology*
  • Macrophages / immunology*
  • Macrophages / parasitology*
  • Male
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Parasite Load
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism*
  • Virulence
  • Virulence Factors / genetics
  • Virulence Factors / metabolism*

Substances

  • Virulence Factors
  • Superoxide Dismutase