Abstract

SummaryBardet–Biedl syndrome (BBS) is a human genetic disorder with a spectrum of symptoms caused by primary cilium dysfunction. The disease is caused by mutations in one of at least 17 identified genes, of which seven encode subunits of the BBSome, a protein complex required for specific trafficking events to and from the primary cilium. The molecular mechanisms associated with BBSome function remain to be fully elucidated. Here, we generated null and complemented mutants of the BBSome subunit BBS1 in the protozoan parasite, Leishmania. In the absence of BBS1, extracellular parasites have no apparent defects in growth, flagellum assembly, motility or differentiation in vitro but there is accumulation of vacuole-like structures close to the flagellar pocket. Infectivity of these parasites for macrophages in vitro is reduced compared with wild-type controls but the null parasites retain the ability to differentiate to the intracellular amastigote stage. However, infectivity of BBS1 null parasites is severely compromised in a BALB/c mouse footpad model. We hypothesize that the absence of BBS1 in Leishmania leads to defects in specific trafficking events that affect parasite persistence in the host. This is the first report of an association between the BBSome complex and pathogen infectivity.

Highlights

  • Bardet–Biedl syndrome (BBS) is a rare autosomal recessive disorder in humans characterized by primary cilium dysfunction (Forsythe and Beales, 2013)

  • Bardet–Biedl syndrome (BBS) is a human genetic disorder with a spectrum of symptoms caused by primary cilium dysfunction

  • In the absence of BBS1, extracellular parasites have no apparent defects in growth, flagellum assembly, motility or differentiation in vitro but there is accumulation of vacuole-like structures close to the flagellar pocket

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Summary

Introduction

Bardet–Biedl syndrome (BBS) is a rare autosomal recessive disorder in humans characterized by primary cilium dysfunction (Forsythe and Beales, 2013). Mutations in 17 different genes have been implicated in this condition, many of which are restricted to ciliated and flagellated species (Chiang et al, 2004; Fan et al, 2004; Hodges et al, 2010; Forsythe and Beales, 2013). Seven of these genes encode subunits which (together with BBIP10) assemble into an octomeric complex termed the BBSome (Nachury et al, 2007). Disruption of Bbs, Bbs or Bbs protein function in Chlamydomonas reinhardtii disrupts phototaxis due to a defect in export of signalling proteins including phospholipase D from the cilium (Lechtreck et al, 2009; 2013)

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