Comparisons of mutants lacking the Golgi UDP-galactose or GDP-mannose transporters establish that phosphoglycans are important for promastigote but not amastigote virulence in Leishmania major.

Content Provider	Semantic Scholar
Author	Capul, Althea A. Hickerson, Suzanne M. Barron, Tamara L. Turco, Salvatore Joseph Beverley, Stephen M.
Copyright Year	2007
Abstract	Abundant surface Leishmania phosphoglycans (PGs) containing [Gal(beta1,4)Man(alpha1-PO(4))]-derived repeating units are important at several points in the infectious cycle of this protozoan parasite. PG synthesis requires transport of activated nucleotide-sugar precursors from the cytoplasm to the Golgi apparatus. Correspondingly, null mutants of the L. major GDP-mannose transporter LPG2 lack PGs and are severely compromised in macrophage survival and induction of acute pathology in susceptible mice, yet they are able to persist indefinitely and induce protective immunity. However, lpg2(-) L. mexicana amastigotes similarly lacking PGs but otherwise normal in known glycoconjugates remain able to induce acute pathology. To explore this further, we tested the infectivity of a new PG-null L. major mutant, which is inactivated in the two UDP-galactose transporter genes LPG5A and LPG5B. Surprisingly this mutant did not recapitulate the phenotype of L. major lpg2(-), instead resembling the L. major lipophosphoglycan-deficient lpg1(-) mutant. Metacyclic lpg5A(-)/lpg5B(-) promastigotes showed strong defects in the initial steps of macrophage infection and survival. However, after a modest delay, the lpg5A(-)/lpg5B(-) mutant induced lesion pathology in infected mice, which thereafter progressed normally. Amastigotes recovered from these lesions were fully infective in mice and in macrophages despite the continued absence of PGs. This suggests that another LPG2-dependent metabolite is responsible for the L. major amastigote virulence defect, although further studies ruled out cytoplasmic mannans. These data thus resolve the distinct phenotypes seen among lpg2(-) Leishmania species by emphasizing the role of glycoconjugates other than PGs in amastigote virulence, while providing further support for the role of PGs in metacyclic promastigote virulence.
Starting Page	42
Ending Page	52
Page Count	11
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Alternate Webpage(s)	https://digitalcommons.wustl.edu/cgi/viewcontent.cgi?article=3386&context=open_access_pubs&httpsredir=1&referer=
Alternate Webpage(s)	http://digitalcommons.wustl.edu/cgi/viewcontent.cgi?article=3386&context=open_access_pubs
Alternate Webpage(s)	http://beverleylab.wustl.edu/PDFs/176.%20%20Capul%20et%20al%20PGs%20and%20Virulence%20I&I%202007.pdf
PubMed reference number	17606605v1
Volume Number	75
Issue Number	9
Journal	Infection and immunity
Language	English
Access Restriction	Open
Subject Keyword	Galactose Genus: Leishmania Glycoconjugates Guanosine Diphosphate Host-Parasite Interactions Leishmania major Leishmania tropica Membrane Transport Proteins Null Value Penicillin G Phenotype Protozoa Sugars Uridine Diphosphate Virulence amastigote lipophosphonoglycan mutant
Content Type	Text
Resource Type	Article