The Leishmania major BBSome subunit BBS1 is essential for parasite virulence in the mammalian host

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.

Loss of the BBSome perturbs endocytic trafficking and disrupts virulence of Trypanosoma brucei

“…Alternatively, it might reflect T. brucei-specific adaptations given the extensive elaboration of the flagellar pocket as the sole site of endocytosis in these organisms (24). In either case, our data suggest a TbBBSome role in vesicle trafficking at the flagellar pocket, a function in agreement with the phenotypes of Leishmania, nematode, and vertebrate BBS mutants (20,(35)(36)(37)(38).…”

“…Despite broad awareness of the cilium's role in the pathology of inherited human diseases, the contribution of cilia and ciliary modules, such as the BBSome, to infection by eukaryotic parasites is mostly unknown (20). Parasite survival and virulence depend on successful interaction with the host environment, and this interaction is mediated, at least in part, by cilia and ciliary proteins (21).…”

“…However, in certain cases, loss of BBSome proteins leads to severe defects in cilium assembly (12,17,38,44) or vesicle accumulation at the cilium base (20,35), suggesting organism-and cell-specific requirements for the complex. Depletion of the TbBBSome had no discernible effect on parasite motility (SI Appendix, Fig.…”

“…KO of the BBS1 gene in the parasite Leishmania major reduced virulence in a mouse footpad model of infection (20), but underlying mechanisms and presence of a BBSome were not examined. Given the localization of the TbBBSome, we hypothesized that virulence defects in T. brucei stem from failure to orchestrate trafficking events at the flagellar pocket, a critical host-parasite interface responsible for endocytosis of host antibodies and uptake of host-derived growth factors (24).…”

Transcriptional profiling of the spleen in progressive visceral leishmaniasis reveals mixed expression of type 1 and type 2 cytokine-responsive genes

“…For some ESTs assigning a gene symbol was challenging. A case in point is Bbs1, in which there is a Leishmania ortholog of the mammalian gene [30]. This EST was identified as the most highly upregulated gene in the 28-day infected hamster spleen (Additional file 4: Table S4).…”