Metabolic Pathways Required For The Intracellular Survival of Leishmania

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Metabolic Pathways Required

for the Intracellular Survival
of Leishmania
Malcolm J. McConville and Thomas Naderer
Department of Biochemistry and Molecular Biology, University of Melbourne,
Bio21 Institute of Molecular Science and Biotechnology, Parkville, Victoria 3010, Australia;
email: malcolmm@unimelb.edu.au, thomas.naderer@monash.edu
Annu. Rev. Microbiol. 2011. 6:54361
Keywords
First published online as a Review in Advance on

June 20, 2011
leishmaniasis, intracellular pathogens, protozoan parasites,

phagolysosome, macrophage, virulence
The Annual Review of Microbiology is online at

micro.annualreviews.org
This articles doi:
10.1146/annurev-micro-090110-102913
c 2011 by Annual Reviews.
Copyright
All rights reserved
0066-4227/11/1013-0543$20.00
Abstract
Leishmania spp. are sandy-transmitted parasitic protozoa that cause a
spectrum of important diseases and lifelong chronic infections in humans. In the mammalian host, these parasites proliferate within acidied
vacuoles in several phagocytic host cells, including macrophages, dendritic cells, and neutrophils. In this review, we discuss recent progress
that has been made in dening the nutrient composition of the Leishmania parasitophorous vacuole, as well as metabolic pathways required
by these parasites for virulence. Analysis of the virulence phenotype
of Leishmania mutants has been particularly useful in dening carbon
sources and nutrient salvage pathways that are essential for parasite persistence and/or induction of pathology. We also review data suggesting
that intracellular parasite stages modulate metabolic processes in their
host cells in order to generate a more permissive niche.
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Contents

INTRODUCTION . . . . . . . . . . . . . . . . . .
THE LEISHMANIA
PARASITOPHOROUS
VACUOLE . . . . . . . . . . . . . . . . . . . . . . .
Nutrient Levels in the
Leishmania PV . . . . . . . . . . . . . . . . . .
LEISHMANIA DIFFERENTIATION
AND METABOLIC
ADAPTATION TO THE
MAMMALIAN HOST . . . . . . . . . . . .
Carbon Metabolism in Intracellular
Amastigotes . . . . . . . . . . . . . . . . . . . .
Metabolic Pathways Required for
Protection Against Oxidative
Stress . . . . . . . . . . . . . . . . . . . . . . . . . .
Glycosylation Pathways Required
for Thermotolerance and
Virulence . . . . . . . . . . . . . . . . . . . . . . .
MODULATION OF HOST
METABOLISM BY
LEISHMANIA . . . . . . . . . . . . . . . . . . . . .
PERSISTENCE VERSUS
PATHOLOGY . . . . . . . . . . . . . . . . . . . .
CONCLUSIONS . . . . . . . . . . . . . . . . . . . .
544
546
547
548
549
551
551
552
553
554
INTRODUCTION
iNOS: inducible
nitric oxide synthase
or NOS2
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Leishmania spp. comprise an important group

of trypanosomatid parasites that are transmitted by sandy vectors and cause a range of
diseases in humans (72). Depending on the
infecting species and other factors such as host
immunity, these parasites may induce localized,
self-curing, cutaneous lesions (cutaneous leishmaniasis, CL) or disseminate to facial mucosal
tissues or to the liver, spleen, and bone marrow
to cause serious and life-threatening mucocutaneous (ML) and visceral (VL) forms of
leishmaniasis, respectively (72). It is estimated
that 1.5 to 2 million children and adults develop
symptomatic diseases each year, resulting in
more than 70,000 deaths (primarily from VL)
and an infection prevalence of 12 million
people (72). However, these gures are likely
McConville
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to signicantly underestimate the true disease

burden (7). Only a limited number of drugs
are available for treating severe CL and cases
of ML and VL, although none is optimal
due to toxicity or teratogenicity, expense,
requirement for hospitalization, and/or the
widespread emergence of drug resistance (23).
Over 20 species of Leishmania are transmitted by phlebotomine sandies (Phlebotomus spp.
or Lutzomyia spp.) to humans or alternative
animal hosts. Leishmania develop within the
midgut of the sandy vector as agellated
promastigote stages that transform through
a number of physiological states, culminating
in the nondividing, metacyclic promastigotes
that are preadapted for life in the mammalian
host. Metacyclic promastigotes are injected
into the skin when female sandies take a
blood meal, and are phagocytosed by a variety
of host cells, including neutrophils, dendritic
cells, and macrophages, that are equipped to
clear invading microbes. However, internalized promastigotes differentiate to nonmotile
amastigotes that can replicate within lysosomelike compartments, or parasitophorous vacuoles (PVs), within these cells. In the various
murine models of infection and in humans,
Leishmania evade the innate immune responses
of these host cells, as parasite numbers increase
markedly during the rst few weeks of infection
before the development of acquired immunity
(6). Protective acquired immunity is dependent
on CD4+ and CD8+ T cells with T-helper
type 1 (Th1) cytokine proles (72). The release
of proinammatory cytokines such as gamma
interferon (IFN-), interleukin 12 (IL-12),
and tumor necrosis factor (TNF) leads to the
activation of potent anti-leishmanial activities,
such as induction of inducible NO synthesis
(iNOS) and the oxidative burst in infected
host cells and a decrease in parasitemia (72).
Conversely, induction of T-helper type 2
(Th2) cytokines (IL-4, IL-13) and/or production of the antiinammatory IL-10 can lead
to development of disease and a noncuring
phenotype (97). These immune responses
allow Leishmania parasites to persist in multiple
tissues after spontaneous or treatment-induced
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resolution of clinical disease (97). Persistent

parasites can confer immunity to reinfection
in humans and animals but are also a source of
recrudescence if protective T-cell mechanisms
fail, such as occurs in severe HIV/AIDS (7).
It is generally assumed that macrophages
are the major host cell infected by Leishmania.
However, infected monocytes and monocytederived dendritic cells are often abundant in
inammatory lesions and in draining lymph
nodes, while other host cells in these tissues
(eosinophils, neutrophils, and broblasts) can

also be infected (Figure 1) (12, 27, 70). While
much is known about host immune responses
and the cell biology of Leishmania infection,
we are only just beginning to understand how
amastigotes survive within these hostile niches.
In this review we summarize current information on the nutritional composition of the
Leishmania PV and parasite and host cell
metabolic pathways that are essential for intracellular growth. Much of this knowledge is
Lymph
nodes
Inflammatory
skin lesion
Viscerotropic
species
Hepatic/splenic
granuloma
Promastigote
Neutrophils
Macrophage
mo-DC
Amastigote
Monocyte
Kupffer macrophage
Fibroblasts
Figure 1
Multiple host niches occupied by Leishmania parasites. Metacyclic promastigotes injected into the skin by the
sandy are phagocytosed primarily by neutrophils and resident dendritic cells. Promastigotes released from
apoptotic neutrophils are subsequently phagocytosed by macrophages and monocytes recruited to the site of
infection (blue lines). Dendritic cells derived from recruited monocytes (mo-DC) can be major host cells in
inammatory lesions that develop at the site of the bite or in draining lymph nodes (27, 70). Other host cells,
such as neutrophils and eosinophils, can also harbor parasites. Following resolution of clinical disease,
parasites may persist as a quiescent population in nonprofessional phagocytic cells such as broblasts (12).
Viscerotropic species (Leishmania donovani, L. infantum/chagasi ) can disseminate from dermal tissues to the
liver, spleen, and bone marrow to cause visceral leishmaniasis. The major host cells infected in the liver are
resident Kupffer macrophages (5, 71).
www.annualreviews.org Leishmania Metabolism and Virulence
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derived from analysis of the virulence phenotype of Leishmania mutants that are viable in
culture (as promastigotes) but show reduced
growth and/or survival in macrophages and
mice (63, 76).
THE LEISHMANIA
PARASITOPHOROUS VACUOLE

Leishmania engage a variety of receptors (CR3,

CR1, and Fc-R) on the surface of host cells
and are internalized by the conventional phagocytic pathway (4). The newly formed phagosomes subsequently mature as a result of highly
RE
regulated fusion and ssion events with early

and late endosomes and lysosomes (4, 70), resulting in the formation of an acidied (pH 4.7
5.2) PV containing the markers of a mature
phagolysosome (Figure 2). Whereas phagosome maturation may be transiently delayed
by the promastigote stages of some species
(i.e., Leishmania major, L. donovani, but not
L. mexicana) (57, 108, 116), phagosomes containing amastigotes mature at the same rate as
those containing inert latex beads. The mature
PV continues to fuse with late endosomes, as
well as other organelles, such as phagosomes
and autophagolysosomes (96, 114). Primary
Autophagosomes
EE/LE/Lys
eRBC
Markers
Phagosomes
Nutrient
and cation
transporters
Cathepsins
-hexaminidase
Hyaluronidase
Ferritin
GRP86
BiP
Glc6Pase
Chitinase
LAMP
V-H-ATPase
Gp91phox
MHC class II
SLC11a1
MHC class I
Sec61
Sec22
PV
Amastigote
Cargo
Glycoproteins
Endoplasmic
reticulum
Proteoglycans
Lipoproteins
Figure 2
Nutrient acquisition pathways in the Leishmania PV. Leishmania amastigotes occupy individual or spacious,
communal PVs that are acidied (pH 4.75.2) and retain all the markers of the phagolysosome
compartment. This compartment fuses with LEs and Lys, containing macromolecules and micronutrients
internalized via RE and EE. It can also fuse with other phagosomes (containing eRBCs) and
autophagosomes. ER vesicle/membranes can also fuse with primary phagosomes and secondary PVs. Sample
PV membrane and lumenal markers derived from fusion with endolysosome (black), the ER (blue), and the
parasite (red ) are indicated in the box (from References 4, 34, and 80). Abbreviations: EE, early endosome;
ER, endoplasmic reticulum; eRBC, effete red blood cell; Glc6Pase, glucose-6-phosphatase; LE, late
endosome; LAMP, lysosomal acidic membrane protein; Lys, lysosome; PV, parasitophorous vacuole;
RE, recycling endosome; SLC11a1, iron transporter.
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phagosomes and secondary Leishmania PVs

can also fuse with, or receive vesicular trafc
from, the endoplasmic reticulum (ER) (34, 80)
(Figure 2). The mature Leishmania PV is thus
a highly dynamic organelle that is continuously
receiving membrane and lumenal content from
a wide variety of organelles in the secretory and
endolysosomal system (Figure 2).
The composition of the PV may differ
depending on the Leishmania species and
host cell involved. Specically, whereas most
species of Leishmania reside within individual, tight-tting PVs that segregate with
dividing daughter cells, L. mexicana complex
(L. mexicana, L. amazonensis, L. pifanoi ) amastigotes induce large communal vacuoles that can
contain up to 2030 amastigotes (4). These
large PVs contain the same membrane and
lumenal markers as the tight-tting PVs (80,
96) and may represent a specic adaptation by
members of this complex to minimize the toxic
effects of short-lived reactive nitrogen intermediates (RNIs) generated by the host (117, 120).
On the other hand, different host cells differ
markedly in their permissiveness to Leishmania
infection and growth. Although macrophages
appear to be the most permissive (often
containing greater than 10 amastigotes per
cell), other professional and nonprofessional
phagocytic cells (dendritic cells, eosinophils,
and broblasts) generally support fewer parasites (1 to 3 amastigotes per cell) (27, 70).
Neutrophils are the least permissive host cell
for Leishmania growth, and most promastigote
stages internalized by neutrophils are delivered
to the mature lysosome and killed (40) either
as result of induction of potent microbicidal
responses and/or severe nutrient restriction
(95). However, some promastigotes can avoid
or stall neutrophil phagosome maturation and
survive within an intermediate compartment
that is nonlytic and contains markers for the
ER (40).
Nutrient Levels in the Leishmania PV

Nutrient levels in the Leishmania PV are
dependent on the rate of inux of host
macromolecules, the activity of various hydrolases, and the rate of transport of lowmolecular-weight metabolites across the PV
membrane (101). Information on the nutrient
composition of the macrophage PV can be inferred from the known growth requirements of
wild-type parasites as well as the growth phenotype of Leishmania mutants that have additional nutrient requirements (21, 30, 46, 81).
Wild-type Leishmania are auxotrophic for, or
have limited capacity to synthesize de novo, a
wide range of amino acids, purines, vitamins,
lipids, and other metabolites (Figure 3) that
must therefore be available within the PV at sufcient levels to sustain amastigote growth (102,
115, 119). In contrast, parasite mutants lacking enzymes needed for gluconeogenesis (73),
the biosynthesis of specic sugars (37), or myoinositol (43) grow poorly in macrophages, indicating that the PV is generally sugar-poor, as
is the case for other compartments in the endolysosome system (33). As a major site of protein degradation, the PV is thought to be generally rich in amino acids. However, the growth
of intracellular amastigotes can be stimulated by
the addition of exogenous arginine or ornithine
to infected macrophages, indicating that
amastigote growth may be limited by the availability of these amino acids (45, 53). Genetic
disruption of amastigote arginase, the initiating enzyme in arginine catabolism, severely restricts intracellular amastigote growth (38, 89),
conrming that amastigotes are dependent on
the de novo synthesis of polyamines as well as on
salvage of polyamines from the PV. Similarly,
the intracellular growth defect of a L. amazonensis mutant lacking the ferric iron transporter
LIT1 indicates that the PV contains sufcient
heme to supply the porphyrin, but not the iron,
needs of amastigotes (42). Collectively, these
ndings suggest that the Leishmania PVs are nutritionally complex compartments that contain
a range of potential carbon sources and essential
nutrients. In this respect, it is notable that Coxiella burnetii, a bacterial pathogen with complex
nutritional requirements, can also proliferate
long term within Leishmania-conditioned PVs
(114).
ER: endoplasmic
reticulum
Auxotrophy:
a requirement for a
particular nutrient due
to absence of de novo
pathways for its
production
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Glucosamine Mannose
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Glucose
Ribose
Aspartate
Glc6P
Rib6P
Oxaloacetic
acid
Threonine
PM
GlcN6P
Man6P
Succinate
Succinate
PPP
Fru6P
Malate
Malate
Fru1, 6P2

Oxaloacetic
acid
Oxaloacetic
acid
Man6P
Succinyl-CoA
Malate
TCA
cycle
Glutamate
Citrate
Triose-P
Man1P
Phosphoenolpyruvate
Pyruvate
AcCoA
Acetate
Succinate
GDP-Man
3-phosphoglycerate
Man n
KG
Succinyl-CoA
Phosphoenolpyruvate
Man n + 1
Alanine
Fatty acids
Mannogen
cycle
Trypanothione
Nucleotides
Sugar nucleotides
Polyamines
Cysteine*
AdoMet
Glycine*
Cysteine*
Sphingolipids
Ovathiol
Isoprenoids
Ergosterol
Ascorbate, biotin,
biopterin, folate,
heme, lipoic acid,
NAD, pantothenate,
pyridoxal, riboflavin,
thiamine
Arginine
Methionine
Serine
Histidine
Leucine
Vitamins, etc.
PM
Purine
Figure 3
Metabolic pathways associated with core metabolism that are required for amastigote survival in macrophages. Asterisks indicate the
presence of de novo pathways of synthesis that are insufcient to sustain normal growth without salvage from the PV/medium. Other
essential amino acids that must be salvaged from the PV include Lys, Ile, Val, Phe, Tyr, and Trp. Several pathways required for
amastigote survival are compartmentalized in glycosomes ( blue) or a single mitochondrion (red ). Abbreviations: AcCoA, acetylcoenzyme A; Mann , mannogen oligosaccharides; PM, plasma membrane; PPP, pentose phosphate pathway; PV, parasitophorous
vacuole; Triose-P, triose phosphate.
LEISHMANIA DIFFERENTIATION
AND METABOLIC ADAPTATION
TO THE MAMMALIAN HOST
Whereas promastigote to amastigote differentiation is associated with marked changes
in morphology (including rounding up and
contraction of the cell body and retraction of
the agellum), it has been more difcult to dene the extent to which intracellular processes
such as metabolism are remodeled. Recent
genome-wide transcriptomic and proteomic
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studies suggest that transcription (mediated by

polymerase II) and protein synthesis are both
globally downregulated in axenic, in vitro
generated amastigotes (1, 54), suggesting that
intracellular stages enter a slow growth state
with reduced metabolic requirements compared to extracellular promastigotes. However,
transcript-proling studies have consistently
shown that relatively few genes (3%9%) are
modulated at the level of individual mRNAs
during amastigote differentiation (28, 91).
This contrasts with the situation in other

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trypanosomatids, such as Trypanosoma brucei

and T. cruzi, where extensive posttranscriptional control of mRNA levels occurs during
differentiation and can underpin stage-specic
changes in metabolism (87). Although proteomic analyses of axenic and intracellular
Leishmania amastigotes have identied a
number of key enzymes in central carbon
metabolism that do change during promastigote to amastigote differentiation (84, 93), these
changes are again modest when compared with
those observed in T. brucei or in other model
eukaryotic organisms such as Saccharomyces
cerevisiae under different nutrient and growth
conditions (14). These observations highlight
the potential importance of posttranslational
mechanisms in regulating Leishmania adaptive
responses to stresses encountered in the mammalian host. Indeed, changes in the L. donovani
phosphoproteome have been associated with
adaptive responses to elevated temperature
(66), and a number of protein kinases and
phosphatases have been shown to be required
for thermotolerance and adaptation to nutrient
limitation (59, 75, 118).
Carbon Metabolism in
Intracellular Amastigotes
From the transcript and proteomic proling
data it is likely that the core pathways in carbon
metabolism outlined in Figure 3 are present in
both promastigote and amastigote stages (100).
In Leishmania and other trypanosomatids the
rst ve enzymes in glycolysis and several enzymes required for succinate fermentation are
compartmentalized in modied peroxisomes
termed glycosomes (65, 81, 99, 100) (Figure 3).
Whereas both developmental stages of Leishmania preferentially utilize glucose or other
sugars when cultured in vitro (41), the extent to
which glycolysis occurs in intracellular amastigotes is unclear, as this stage is also dependent on
gluconeogenesis for intracellular growth (73).
Nonetheless, hexose catabolism is essential
for amastigote survival in macrophages, as
L. mexicana and L. major mutants with defects
in hexose uptake or sugar catabolism are highly
attenuated in vivo (16, 74). Exogenous hexoses

may be needed to sustain essential pathways,
such as the pentose phosphate pathway and
RNA/DNA synthesis, N-glycosylation, and
myo-inositol synthesis (43, 78). Despite growing
in a sugar-poor niche (73), amastigotes accumulate a unique intracellular carbohydrate reserve
material termed mannogen (88). Mannogen
comprises short oligosaccharides of 1-2linked mannose residues that accumulate in
the cytosol to concentrations of 10 mM in
amastigote stages (88, 104) (Figure 3). These
oligosaccharides are degraded under sugarlimiting conditions, and their accumulation
in intracellular stages indicates that rates of
de novo synthesis or uptake of sugars are not
normally limiting for amastigote growth (88).
Leishmania can catabolize a range of sugars in vitro, including mannose, galactose,
(55) and the amino sugars glucosamine and
N-acetylglucosamine (74). Disruption of glucosamine catabolism has a profound effect on
the establishment of L. major infection in
mice and subsequent lesion development, suggesting that amino sugars are a major class
of sugars in the PV (74, 78), most likely
as a result of the internalization and degradation of extracellular matrix proteoglycans
and glycosoaminoglycans by macrophages (48).
Amastigotes may contribute to the nal degradation of glycosoaminoglycan fragments by secreting a chitinase, as overexpression of the
L. mexicana chitinase enhanced intracellular
growth (50).
In addition to hexose, Leishmania amastigotes may use a variety of other carbon sources.
Specically, L. donovani amastigotes upregulate the expression of several enzymes involved
in gluconeogenesis (93), whereas a L. major mutant lacking the gluconeogenic enzyme,
fructose-1,6-bisphosphatase, grows poorly in
macrophages and is unable to induce lesions in
mice (73). Peptides and amino acids generated
by PV proteases are obvious carbon sources
for amastigotes. The Leishmania genomes encode a large number of putative amino acid
permeases, and several of these are expressed
in amastigote stages (44, 105). Leishmania also
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13 C-isotopologuelabeling study:
an approach for
measuring the activity
of many metabolic
pathways in live
parasites following
metabolic labeling
with 13 C-labeled
substrates and analysis
of labeled intracellular
and extracellular
metabolites by mass
spectrometry or NMR
Axenic amastigotes:
amastigotes stages that
have been generated in
in vitro culture, usually
by subjecting
stationary-phase
promastigote to
elevated temperature
(33 C37 C) and low
pH
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produce an extensive repertoire of lysosomal

proteases that can be upregulated in amastigotes (8). L. mexicana mutants lacking different
classes of cysteine proteinase are attenuated in
vivo, consistent with a role in parasite nutrition
(8). However, direct evidence for a dependency
of amastigotes on amino acid catabolism in vivo
is lacking. Although amino acid uptake is increased in L. mexicana amastigotes (41), recent
13
C-isotopologue-labeling studies suggest that
only a limited number of amino acids, such as
aspartate and alanine, are used as carbon sources
(99).
Fatty acids derived from complex host lipids
are used as an alternative carbon source by
several intracellular pathogens (33). Whereas
fatty acid -oxidation occurs to a negligible
extent in rapidly dividing promastigotes (73),
increased fatty acid -oxidation is evident
in nondividing promastigotes and in axenic
amastigotes (10, 41), and enzymes involved
in fatty acid -oxidation are upregulated in
L. donovani and L. major amastigotes (84,
93). Fatty acid -oxidation would provide
amastigotes with a source of acetyl-CoA for
mitochondrial respiration. However, Leishmania lack the glyoxylate cycle enzymes needed
for use of acetyl-CoA in gluconeogenesis and
are therefore unable to use fatty acids as their
sole carbon source (73). Leishmania amastigotes could obtain lipids from lipoproteins
internalized by infected macrophages (98).
Interestingly, human high-density lipoproteins
contain lytic factors (apoA-1 and Hpr) that are
delivered to the PV and can kill intracellular
promastigote, but not amastigote, stages (98).
Alternatively, lipid exchange may occur across
adhesion zones/tight junctions between the
amastigote plasma membrane and the PV
membrane (76). Host glycosphingolipids
associated with the PV membrane become
intercalated into the amastigote membrane and
contribute to the minimal surface glycocalyx
of this stage (76, 77). Other abundant PV
lipids, such as sphingomyelin, are apparently
internalized by amastigotes and degraded
(123). Intriguingly, a neutral sphingomyelinase
enzyme in L. major was localized to the
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mitochondria, suggesting that scavenged sphingomylin is catabolized in the mitochondria in

order to generate ceramide or parasite-specic
lipids, such as inositol phosphoceramides (123).
Amastigotes downregulate their own sphingolipid biosynthetic pathways, suggesting that
this salvage pathway fullls all the sphingolipid
requirements of this stage (122). Lipid salvage
from the PV lumen and membrane may thus
play important roles in both carbon metabolism
and provision of important lipid precursors.
The increased use of both amino acids and
fatty acids as carbon sources by intracellular
amastigotes requires the presence of an active
tricarboxylic acid (TCA) cycle (41). 13 Cisotopologue-labeling studies in L. mexicana
suggest that the TCA cycle is required for the
catapleurotic production of glutamate as well
as ATP synthesis (99). Mitochondrial function
appears to be essential for amastigote viability,
as L. major and L. donovani mutants with defects
in cytochrome c oxidase activity are highly
attenuated or avirulent in mice (29, 113, 124).
Intracellular amastigotes are also killed by the
human antimicrobial peptide histatin 5, which
targets mitochondrial ATP synthesis (58),
while disruption of the mitochondrial neutral
sphingomylinase in L. major leads to increased
thermosensitivity (a hallmark of mitochondrial
dysfunction) and loss of viability in intracellular
amastigote stages (123). Similarly, amastigotes
are acutely sensitive to inhibitors of ergosterol
synthesis, which is required for mitochondrial
function in other eukaryotes (3). Although these
observations are consistent with amastigotes
being dependent on mitochondrial metabolism
for energy and key metabolites, mitochondrial
dysfunction can lead to oxidative stress due to
electron leakage from the respiratory chain.
Furthermore, the single mitochondrion of
Leishmania and other trypanosomatids is
physically tethered to the agellum basal body,
and ongoing mitochondrial metabolism and/or
protein import may also be required for cell
division (113, 124). Thus, the acute sensitivity
of Leishmania amastigotes to mitochondrial
dysfunction may reect the involvement of this
organelle in multiple cellular processes.

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Amastigotes must salvage other metabolites,

such as purines, from the PV (Figure 3). Many
of the transporters and proteins involved in
purine salvage have been identied and genetically disrupted (13, 56). Whereas disruption
of individual transporters or purine salvage
enzymes has little impact on intracellular
growth, indicating substantial redundancy in
purine salvage, a L. donovani mutant lacking
two key purine phosphoribosyltransferases
(HGPRT and XPRT) was severely attenuated
in vivo (13). Suppressor strains of this mutant
were readily isolated, in which genes encoding
for another phosphoribosyltransferase were
amplied, highlighting the genomic exibility
of these parasites and their capacity to adapt
to nutrient deprivation (13). The surface expression of several nucleobase and nucleoside
transporters is also upregulated when parasites
are starved of purines (19, 82). Although these
observations show that Leishmania can adapt to
low nutrient levels in vivo, the surface expression of most nutrient transporters, with the
notable exception of the LitA iron transporter
(42), either remains constant or is signicantly
downregulated following differentiation of
promastigotes to intracellular amastigotes (31,
90), consistent with the notion that amastigotes
enter a metabolically quiescent state and/or
that the levels of particular nutrients in the PV
are sufcient for growth.
Metabolic Pathways Required for

Protection Against Oxidative Stress
Leishmania are exposed to varying levels of
oxidative stress during the initial innate and
subsequent adaptive immune phases of infection. Gene deletion studies suggest that
the oxidative defenses of these parasites are
nely balanced to cope with these stresses and
that impairment of any of these systems leads
to attenuation of virulence. The major thiol
of Leishmania (and other trypanosomes) is
trypanothione, a conjugate of two glutathione
molecules linked by the polyamine spermidine
(32, 110, 111). Trypanothione has a much
higher capacity to neutralize toxic nitric oxide
than glutathione, possibly accounting for

its existence in pathogenic trypanosomatids
(11), and is required for protection against
oxidative/nitrosative stress in vivo (32, 68,
111). Glutathione and trypanothione are continuously turned over (121), and maintenance
of cellular levels would require high rates of
uptake and/or de novo synthesis of precursor
amino acids, such as arginine, glutamate,
methionine, and serine (102, 119) (Figure 3).
Leishmania amastigotes also accumulate ovothiol, a low-molecular-weight thiol that acts as
a direct oxygen scavenger and is synthesized
from histidine (110). The regeneration of
these thiols is also energetically expensive and
requires continuous production of reductant in
the form of NADPH, which could be supplied
by metabolic pathways such as the pentose
phosphate pathway, a malic enzyme, and the
TCA cycle isocitrate dehydrogenase (30).
A recent genome-wide screen for genes that
conferred resistance to oxidative stress indicated that pteridine reductase 1 (PTR1) may
also play a role in Leishmania oxidative defenses
(79). PTR1 is a well-characterized trypanosomatid enzyme that reduces salvaged biopterin
to dihydrobiopterin and tetrahydrobiopterin.
Deletion of L. major PTR1 enhances the
differentiation of noninfective promastigotes
to infective metacyclic promastigotes, leading
to increased virulence in mice (24). However,
recent studies have shown that loss of PTR1
in several Leishmania species compromises
growth in activated macrophages (67, 79). It
remains to be determined whether the reduced
biopterins generated by PTR1 (or salvaged
from the macrophage) are directly involved in
scavenging reactive oxygen species or whether
their synthesis activates other oxidative defense
mechanisms.
Glycosylation Pathways Required for

Thermotolerance and Virulence
The biosynthesis of the sugar nucleotides
GDP-Man and UDP-GlcNAc is required
for Leishmania thermotolerance and virulence in the mammalian host (36, 78). Both
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LPG:
lipophosphoglycan

PPG:
proteophosphoglycan
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sugar donors are required for the synthesis

of the paucimannose N-glycans (containing
ve to six mannose residues and two Nacetylglucosamine residues) that are linked to
a variety of cell surface and lysosomal proteins
(64). Leishmania retains a basic ER glycoprotein quality control machinery that includes a
UDP-Glc:glycoprotein
glucosyltransferase,
calreticulin, and glucosidase I, and it is likely
that protein N-glycosylation is required for
the correct folding and/or ER export of one
or more proteins at the elevated temperatures
(33 C37 C) encountered in the mammalian
host (64, 78).
Leishmania promastigotes and amastigotes
synthesize a number of other surface glycolipids and secreted proteophosphoglycans that
contribute to virulence (64). The major surface
macromolecule of promastigote stages is a
complex lipophosphoglycan (LPG) that has
dened functions in both the sandy vector
and in promastigote-initiated infection in the
mammalian host (40, 64, 76, 77, 108, 116).
LPG is essential for the intracellular survival of
L. major and L. donovani promastigotes, but not
L. mexicana promastigotes, possibly reecting
differences in the PV induced by these species
(64, 108). In contrast, amastigotes produce little or no LPG and parasite strains with defects
in LPG biosynthesis retain full virulence when
amastigotes are used to initiate infections (64).
However, amastigotes retain the capacity to
synthesize the structurally related proteophosphoglycans (PPGs), which are secreted into
the PV lumenal space and transported within
vesicular structures in the host cytoplasm (62,
64). The secreted PPGs play an important role
in conditioning the initial host cell response
(92). However, a L. major mutant lacking all
phosphoglycans (LPG and PPG) as a result
of genetic disruption of the Golgi UDP-Gal
transporters exhibited the same delayed lesion
virulence phenotype as mutants lacking LPG
alone (18), indicating that the PPGs and LPGs
have overlapping functions in experimental infections. Intriguingly, L. major and L. donovani
mutants lacking phosphoglycans as a result of
disruption of the Golgi GDP-Man transporter,
McConville
Naderer
LPG2, exhibited a much more severe loss of

virulence phenotype in mice (39, 109). This
transporter can import other sugar nucleotides
into the Golgi apparatus, such as GDP-Fuc,
raising the possibility that additional, and as
yet uncharacterized, glycosylation reactions
occur in the Golgi apparatus that could contribute to amastigote virulence in these species
(103, 112).
MODULATION OF HOST
METABOLISM BY LEISHMANIA
There is increasing evidence that host cell
metabolism can be modulated by the presence
of intracellular pathogens and/or by induction
of specic immune responses in ways that either
promote or retard microbial growth (25). In
particular, activation of macrophages with Th1
cytokines (INF-, TNF, IL-12) leads to the
upregulation of iNOS and the downregulation
of enzymes such as arginase-1 that collectively
reduce arginine and polyamine available for intracellular pathogens. Conversely, activation of
macrophages with Th2 cytokines (IL-4, IL-10,
and IL-13) leads to increased arginase-1 expression at the expense of iNOS (25) and increased
polyamine availability. Leishmania induce the
latter response in susceptible mouse strains,
and parasite proliferation in these mice strongly
correlates with elevated arginase-1 activity (2,
45, 52, 69). Paradoxically, members of the
L. mexicana complex can induce a mild proinammatory response in susceptible mouse
strains (with production of Th1 cytokines such
as INF-) that results in increased surface
expression of the macrophage cationic amino
acid transporter and the bioavailability of
both arginine and ornithine (117). L. mexicana amastigotes may prevent increased NO
synthesis under these conditions by rapidly
depleting host arginine pools via their own
endogenous arginase (38). In contrast, disruption of arginine catabolism in L. major
amastigotes had no effect on host cell NO
production (69). Intriguingly, host arginase
expression increased with increasing parasite
load in L. majorinfected mice, independent

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of the expression of parasite arginase or the

host immune and cytokine response (69).
Parasite proliferation may lead to the release
of host-derived factors, such as prostaglandins
that activate host arginase expression, further
promoting parasite proliferation (69, 92).
Although Leishmania lack the secretory systems that allow many bacterial pathogens to
export proteins to the host cytoplasm, there
is now compelling evidence that intracellular
stages actively modulate macrophage signaling pathways (9, 51). Two Leishmania proteins
that are normally targeted to the lysosome in
amastigotes, the cysteine protease CBP and a
soluble form of gp63, proteolytically activate
tyrosine-specic phosphatases in the host cell
and degrade transcription factors that mediate host cell responses to INF- (9, 17, 22,
61). Gp63 may also degrade the mammalian
target of rapamycin (mTOR) kinase, leading
to inhibition of protein translation and activation of the amino acid starvation responses in
the host cell (47). The latter responses include
increased lysosomal protein turnover, which
could contribute to the observed increase in
L. major amastigote growth in the presence
of rapamycin (47). These amastigote proteases
could be secreted into the PV lumen and transported across the PV membrane via protein
translocons, such as Sec61 (34). Alternatively,
they could be released in membrane-bound
exosomes and subsequently budded into the
host cytoplasm (107). Another host enzyme activated by intracellular amastigotes is the heme
oxygenase-I, a rate-limiting enzyme in heme
degradation (85). Increased heme degradation
leads to incomplete processing of gp91phox ,
a heme-containing glycoprotein that recruits
components of the NADPH oxidase to the PV
membrane (85). The increased activation of this
protein by L. pifanoi amastigote stages, compared with promastigote stages, is consistent
with the former stage inducing a lower rate of
superoxide production during infection.
Leishmania infection of macrophages also
leads to reduced secretion of the proinammatory cytokine IL-12 (9, 51). This has recently
been linked to Leishmania-induced alterations
in cholesterol levels in the macrophage plasma

membrane (20, 94). Decreased cholesterol
levels lead to the preferential association of
the important costimulatory protein CD40
with signalosome complexes that activate the
Erk1/2 mitogen-activated protein pathway and
IL-10 secretion. As a result, CD40 signaling
via other pathways involving the activation of
p38 mitogen-activated protein and the production of IL-12 is reduced (94). Paradoxically,
macrophages infected with L. mexicana upregulate the expression of many genes required
for de novo sterol biosynthesis (83), possibly
reecting a response to cholesterol depletion.
Alterations in host cell cholesterol homeostasis
may lead to alterations in other signaling
pathways. For example, dyslipidemia is sensed
by the peroxisome proliferator-activated receptors (PPAR-, ) and the liver X receptors (49,
60), both of which increase arginase I and II
expression and/or repression of iNOS synthesis and promote Leishmania infection (15, 35,
106). These studies suggest that subtle changes
in the activities of host metabolic enzymes may
have profound effects on infection outcomes.
Exosomes: small
microvesicles
generated within the
endolysosomal
pathway of eukaryotic
cells and released by
exocytosis
PERSISTENCE VERSUS
PATHOLOGY
An increasing number of Leishmania metabolic
mutants have been shown to establish lowlevel chronic infections without causing
overt pathology. Examples include Leishmania strains with defects in gluconeogenesis
(L. major fbp), iron uptake (L. amazonensis
lit1), purine metabolism (L. major hprt/
xprt), and glycoconjugate synthesis (L. major/
L. donovani lpg2) (13, 39, 42, 73). These mutants characteristically survive in macrophages
but grow slowly and may assume a metabolic
state similar to wild-type parasites that persist
after spontaneous or drug-induced resolution of disease. Analysis of the in vivo host
responses to infection with the L. major
arg mutant indicates that macrophages may
become progressively more permissive as
parasitemia increases, independent of the host
cytokine response (69). Thus, maintenance of a
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persistent state may be critically dependent on

keeping parasite numbers below a threshold
level, beyond which rapid expansion of the
parasite population can occur. Other mutants,
including the L. major gcc, arg, and gnd
mutants (69, 74, 102) and the L. mexicana arg
mutant (38), induce lesions after a signicant
delay regardless of whether promastigotes or
amastigotes are used to initiate the infection.
This phenotype might arise if host cells
infected during the initial innate immune
phase are nutritionally more restrictive than
those infected following the development of
an acquired host immune response. In this
respect it is notable that intracellular growth of
L. mexicana is promoted by moderate activation
of macrophages with INF- (86). It is therefore
possible that induction of inammatory lesions
initially facilitates expansion and possibly dissemination of parasites, as has been proposed
to occur in mycobacterial infections (26).

MI65CH27-McConville
CONCLUSIONS
Leishmania spp. are one of the few pathogens to
proliferate in the long term in the phagolysosome of macrophages and other phagocytes.
Recent genomic and biochemical analyses of
the metabolic potential of these parasites, as
well as analysis of the virulence phenotypes
of metabolic mutants, have led to the identication of many metabolic processes that are
essential for intracellular survival and pathogenesis. These studies suggest that intracellular
amastigotes exploit multiple carbon sources
(sugars, amino acids, and lipids) and have
complex transport and salvage pathways for obtaining the large number of essential nutrients
for which they lack pathways of de novo synthesis. Indeed, it is tempting to speculate that
the complex nutritional needs of an ancestral
(monogenetic) trypanosomatid may have been
a key factor in driving these parasites to colonize
this hazardous but comparatively nutrient-rich
intracellular niche (63). Leishmania may further
increase the permissiveness of this compartment by enhancing the fusagenic properties of
the PV with less lytic compartments (such as
the ER), by generating large spacious vacuoles
(in the case of the L. mexicana complex),
and by modulating macrophage signaling
pathways to inhibit microbicidal processes and
increase the availability of essential nutrients.
Residence in such a nutritionally complex
compartment may also confer a high degree
of robustness on Leishmania metabolism. This
is supported by the fact that relatively few
Leishmania mutants lacking nonessential genes
are completely avirulent in vivo, and has important implications for drug development. In
contrast, recent studies have shown that several
Leishmania mutants lacking protein kinases
and phosphatases that might be involved in
regulating parasite metabolism are highly
attenuated or completely avirulent in vivo (59,
75, 118). Elucidating aspects of amastigote
metabolism that are essential for survival and
the delineation of signaling pathways that
regulate these processes should provide further
insights into the molecular basis of Leishmania
pathogenesis and facilitate the development of
new drugs to tackle these devastating diseases.
SUMMARY POINTS
1. Leishmania establish a unique PV compartment in macrophages that is nutritionally complex as a result of continuous fusion and/or membrane transport with other compartments
in the endomembrane system.
2. Obligate intracellular amastigote stages enter a slow growth state. These stages are dependent on the uptake of sugars, particularly amino sugars, as well as the catabolism of
carbon sources, such as amino acids and fatty acids, requiring mitochondrial metabolism.
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3. Other metabolic pathways required for growth are those associated with cellular oxidative
defenses (i.e., trypanothione and biopterin synthesis) and thermotolerance (i.e., protein
N-linked glycosylation).
4. Leishmania amastigotes can modulate metabolic and signaling pathways in their host cell
in order to enhance access to essential nutrients.

5. Leishmania metabolic mutants that establish persistent, low-level infections may provide
insights into the metabolic state of persistent wild-type parasites that are responsible for
recrudescence of disease in humans.
FUTURE ISSUES
1. To what extent do amastigotes exist in different growth or physiological states during
preimmune, acute, and chronic stages of infection?
2. What other metabolic pathways are required for intracellular survival and proliferation?
3. How do Leishmania spp. sense and respond to changes in nutrient levels in the host?
4. How does Leishmania infection affect host cell metabolism beyond the few pathways
investigated to date?
DISCLOSURE STATEMENT
The authors are not aware of any afliations, memberships, funding, or nancial holdings that
might be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS
We thank Drs. Eleanor Saunders and Julie Ralton for critical reading of the manuscript. We
also thank other members of the McConville group for discussions. We apologize to colleagues
whose references we have not cited due to space constraints or ignorance. Work from the authors
laboratory was supported by the Australian National Health and Medical Research Council. The
present address for Dr. Naderer is Department of Biochemistry and Molecular Biology, Monash
University, Clayton, Victoria, 3800 Australia.
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Contents
Volume 65, 2011

To the Happy Few

Hiroshi Nikaido p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
Regulation of DnaA Assembly and Activity: Taking Directions from
the Genome
Alan C. Leonard and Julia E. Grimwade p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p19
Regulation of Alternative Sigma Factor Use
Soa Osterberg,
Teresa del Peso-Santos, and Victoria Shingler p p p p p p p p p p p p p p p p p p p p p p p p p p p p37
Fungal Protein Production: Design and Production
of Chimeric Proteins
Peter J. Punt, Anthony Levasseur, Hans Visser, Jan Wery, and Eric Record p p p p p p p p p p p p p57
Structure and Function of MARTX Toxins and Other Large
Repetitive RTX Proteins
Karla J.F. Satchell p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p71
Eukaryotic Picoplankton in Surface Oceans
Ramon Massana p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p91
Life on the Outside: The Rescue of Coxiella burnetii from Its Host Cell
Anders Omsland and Robert A. Heinzen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 111
Molecular Mechanisms of Staphylococcus aureus Iron Acquisition
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Protein Quality Control in the Bacterial Periplasm
Melisa Merdanovic, Tim Clausen, Markus Kaiser, Robert Huber,
and Michael Ehrmann p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 149
Prospects for the Future Using Genomics and Proteomics
in Clinical Microbiology
Pierre-Edouard Fournier and Didier Raoult p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 169
The RpoS-Mediated General Stress Response in Escherichia coli
Aurelia Battesti, Nadim Majdalani, and Susan Gottesman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 189
Bacterial Osmoregulation: A Paradigm for the Study
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Lipoprotein Sorting in Bacteria

Suguru Okuda and Hajime Tokuda p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 239
Ligand-Binding PAS Domains in a Genomic, Cellular,
and Structural Context
Jonathan T. Henry and Sean Crosson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 261
How Viruses and Toxins Disassemble to Enter Host Cells
Takamasa Inoue, Paul Moore, and Billy Tsai p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 287

Turning Hepatitis C into a Real Virus

Catherine L. Murray and Charles M. Rice p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 307
Recombination and DNA Repair in Helicobacter pylori
Marion S. Dorer, Tate H. Sessler, and Nina R. Salama p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 329
Kin Discrimination and Cooperation in Microbes
Joan E. Strassmann, Owen M. Gilbert, and David C. Queller p p p p p p p p p p p p p p p p p p p p p p p p p p 349
Dinoagellate Genome Evolution
Jennifer H. Wisecaver and Jeremiah D. Hackett p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 369
Motility and Chemotaxis in Campylobacter and Helicobacter
Paphavee Lertsethtakarn, Karen M. Ottemann, and David R. Hendrixson p p p p p p p p p p p p 389
The Human Gut Microbiome: Ecology and Recent
Evolutionary Changes
Jens Walter and Ruth Ley p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 411
Approaches to Capturing and Designing Biologically Active Small
Molecules Produced by Uncultured Microbes
Jorn Piel p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 431
Epidemiological Expansion, Structural Studies, and Clinical
Challenges of New -Lactamases from Gram-Negative Bacteria
Karen Bush and Jed F. Fisher p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 455
Gene Regulation in Borrelia burgdorferi
D. Scott Samuels p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 479
Biology of Clostridium difcile: Implications for Epidemiology
and Diagnosis
Karen C. Carroll and John G. Bartlett p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 501
Interactions of the Human Pathogenic Brucella Species
with Their Hosts
Vidya L. Atluri, Mariana N. Xavier, Maarten F. de Jong,
Andreas B. den Hartigh, and Renee M. Tsolis p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 523
Contents
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Metabolic Pathways Required for the Intracellular Survival

of Leishmania
Malcolm J. McConville and Thomas Naderer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 543
Capsules of Streptococcus pneumoniae and Other Bacteria: Paradigms for
Polysaccharide Biosynthesis and Regulation
Janet Yother p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 563
Synthetic Poliovirus and Other Designer Viruses: What Have We
Learned from Them?
Eckard Wimmer and Aniko V. Paul p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 583
Regulation of Antigenic Variation in Giardia lamblia

Cesar G. Prucca, Fernando D. Rivero, and Hugo D. Lujan p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 611
Alternative Pathways of Carbon Dioxide Fixation: Insights into the
Early Evolution of Life?
Georg Fuchs p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 631
Index
Cumulative Index of Contributing Authors, Volumes 6165 p p p p p p p p p p p p p p p p p p p p p p p p p p p 659
Errata
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