trans

LEISHMANIA 235
knockouts (either LPG1 or LPG2, the GDP-
Man transporter gene) failed to implicate
LPG, or, surprisingly, any phosphoglycancontaining
substances as virulence determinants.
One possible explanation for these
differences may be related to distinctions in
immune responses to L. major and L. mexicana.
Alternatively, the biology of infection by
L. mexicana might place less emphasis on
phosphoglycan-containing molecules separate
from the immune response; perhaps it
arises from differences in the rate of replication
in the host, for example.
Glycosylinositolphospholipids
The glycosylinositolphospholipids (GIPLs) are
a major family of low molecular weight glycolipids
synthesized by Leishmania that are not
attached to either protein or polysaccharides.
GIPLs are expressed in very high copy numbers,
about 10 7 copies per cell on both promastigote
and amastigote surfaces. Three
major lineages of GIPLs have been identified
that are expressed to different levels in different
species or developmental stages. Based on
the pattern of their glycan headgroups, GIPLs
are classified as Type I (analogous to protein
GPI anchors), Type II GIPLs (analogous to LPG
anchors) or hybrid (containing features of
both). The lipid components of the hybrid
(Figure 10.4C) and Type I GIPLs (Figure 10.4B)
are distinct from those of protein or LPG
anchors, in that they are rich in alkyl-acyl-PI
with shorter, namely C18:0 alkyl chains. The
Type II GIPLs (Figure 10.4A) are more heterogeneous
and contain longer alkyl chains,
namely C24:0 or C26:0. Not much is known
about the functions of the GIPLs. The use of
the mannose receptor in parasite attachment
to the macrophage suggests that the mannoserich
GIPLs may play a role in macrophage invasion.
Since the levels of LPG and GP63 are
dramatically downregulated, the GIPLs are the
major constituents of the amastigote surface
and are presumably involved in protecting the
parasite from environmental hazards, as well as
playing some role in parasite–host interactions,
especially in the mammalian stage. In fact,
GIPLs may be involved in modulating signaling
events in the macrophage such as NO
synthesis and the oxidative burst. Enzymes
involved in GPI biosynthesis are essential for
parasite virulence, emphasizing the importance
of protein-free GPI glycolipids in parasite
viability.
Unlike L. major, whose GIPLs are largely
galactosylated, promastigotes of L. donovani
synthesize abundant GIPLs which contain one
to four mannose residues and are not galactosylated.
Although L. donovani amastigotes do
not synthesize LPG, they continue to synthesize
GIPLs in quantities comparable to those
present in promastigotes. The L. donovani
amastigote GIPLs, containing one to three mannose
residues, are structurally different from
promastigote GIPLs and appear to be precursors
to glycolipid anchors of proteins. GIPLs
have also been isolated and characterized
from L. mexicana, L. aethiopica and L. adleri and
show additional features, including the presence
of phosphoethanolamine. The major
GIPLs have lower turnover rates than LPG.
Compartmentalization of different GPI pathways
may be important in regulating the species
and stage-specific expression of different GPI
structures. Of interest, ceramidephosphoinositides
also have been found in L. donovani, and
appear to be further substituted with carbohydrate
residues as observed in Trypanosoma
cruzi, yeast, fungi, and plants. However, the
structures have not yet been elucidated.
GIPLs that are structurally related to the
Leishmania Type II and/or hybrid GIPLs
and the T. cruzi LPPG have been identified
in Leptomonas samueli, Endotrypanum
BIOCHEMISTRY AND CELL BIOLOGY: PROTOZOA