Boots for Achilles

20 Pages·2013·0.31 MB·English

Volume88,No.2 THEQUARTERLYREVIEWOFBIOLOGY June2013
BOOTS FOR ACHILLES: PROGESTERONE’S REDUCTION OF
CHOLESTEROL IS A SECOND-ORDER ADAPTATION
Dorsa Amir
CenterforBehavior,Evolution,andCulture,DepartmentofAnthropology,
UniversityofCalifornia,LosAngeles
LosAngeles,California90095-1553USA
e-mail:[email protected]
Daniel M. T. Fessler
CenterforBehavior,Evolution,andCulture,DepartmentofAnthropology,
UniversityofCalifornia,LosAngeles
LosAngeles,California90095-1553USA
e-mail:[email protected]
keywords
progesterone,cholesterol,pregnancy,infection,evolutionarymedicine
abstract
Progesteroneandcholesterolarebothvitaltopregnancy.Amongotherfunctions,progesteronedownregulates
inflammatory responses, allowing for maternal immune tolerance of the fetal allograft. Cholesterol, a key
componentofcellmembranes,isimportantinintracellulartransport,cellsignaling,nerveconduction,and
metabolism.Despitetheimportanceofeachsubstanceinpregnancy,oneexercisesanantagonisticeffectonthe
other,asperiodsofpeakprogesteronecorrespondwithreductionsincholesterolavailability,aconsequence
ofprogesterone’snegativeeffectsoncholesterolbiosynthesis.Thisarrangementisunderstandableinlightof
thethreatposedbypathogensearlyinpregnancy.Progesterone-inducedimmunomodulationentailsin-
creasedvulnerabilitytoinfection,anacuteprobleminthefirst trimester, when fetal development is
highly susceptible to insult. Many pathogens rely on cholesterol for cell entry, egress, and
replication. Progesterone’s antagonistic effects on cholesterol thus partially compensate for the
costsentailedbyprogesterone-inducedimmunomodulation.Amongpathogenstowhichthehost’s
vulnerabilityisincreasedbyprogesterone’seffects,approximately90%utilizecholesterol,andthis
isnotablytrueofpathogensthatposeariskduringpregnancy.Inadditiontohavinganumber
ofpossibleclinicalapplications,ourapproachhighlightsthepotentialimportanceofsecond-order
adaptations,themselvesaconsequenceofthelackofteleologyinevolutionaryprocesses.
Introduction ingly, despite the importance of each, the
CHOLESTEROLandprogesteroneeach latter exercises an antagonistic effect on
play a vital role in pregnancy. Intrigu- the availability of the former. Here, we ar-
TheQuarterlyReviewofBiology,June2013,Vol.88,No.2
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98 THEQUARTERLYREVIEWOFBIOLOGY Volume88
guethatthispuzzlingarrangementreflects duction pathways are disrupted (Linden-
an evolved second-order adaptation, that halletal.2001).Indeed,progesteronedis-
is,anadaptationthataddressesanadaptive ruptspathwaysinvolvedinbothcholesterol
challenge that is itself a consequence of biosynthesis and the processing of LDL-
theeffectsofanotheradaptation.Consider derivedcholesterol(Lindenhalletal.2001).
the following: it is well documented that Whywouldahormonethatisintimately
cholesterol plays an important role in fetal linked to successful pregnancy cause a re-
development (Brizzi et al. 1999; Innis 2005; duction in the availability of a building
Woollett2011).Althoughmaternaltriglyc- block needed for fetal development? Al-
erides cannot directly cross the placental though seemingly paradoxical, we suggest
membrane, free fatty acids and ketones thatthisrelationshipconstitutesacompro-
produced from those trigylcerides can cross mise solution to a problem that arises due
the barrier, and are utilized by the fetus as to tradeoffs inherent in pregnancy. We re-
both fuels and lipogenic substrates (Brizzi viewtherespectiverolesofcholesteroland
et al. 1999). It has been shown that when progesterone, describe the effects of pro-
maternal plasma cholesterol is low (!160 gesteroneoncholesterolavailability,delin-
mg/dL), birthweights are lower than nor- eate the potential costs of this interaction,
mal,andthereisatrendformicrocephaly andthenoutlinethebenefits(intheform
(Edison et al. 2007), suggesting that, al- ofreducedvulnerabilitytopathogens)that
though the fetus can also metabolize its we hypothesize outweigh these costs.
own cholesterol, its capacity in this regard
is limited and, hence, inadequate transfer The Functions of Cholesterol and
of maternal cholesterol components nega- Its Role in Fetal Development
tivelyimpactsfetalgrowth(Woolett2011). Cholesterol, a lipid molecule with a
Correspondingly, low intakes of specific characteristic four-ring steroid structure
fatty acids by the mother during gestation (YoshidaandWada2005),isvitaltolife.It
canresultindecreasedneuralgrowthcones is required as the structural component of
in the fetal brain, liver, and the placenta mammaliancellmembranes,helpingtomain-
(Innis2005).Parallelingtheimportanceof tain proper permeability and fluidity (Yeagle
cholesterol, the ovarian hormone proges- 1985).Cholesterolalsofunctionsinintracellu-
terone,vitalforthesuccessofpregnancy,is lar transport, cell signaling (Maxfield and
unequivocallyrequiredinallmammalsfor Tabas2005),andnerveconduction(Saheret
maternalsupportofconceptussurvivaland al. 2011). It is a fundamental mediator of
development (Spencer and Bazer 2002). metabolism through the propagation of
Progesteroneisessentialtoseveralimportant signaling cascades and is essential to both
events in the establishment of pregnancy, the activation and propagation of hedge-
including ovum transport, endometrial cell hog signaling (Woollett 2005). Addition-
proliferation, differentiation, decidualization, ally, cholesterol is the precursor for other
and the process of implantation. It is also necessary compounds, such as steroid hor-
vitalforthemaintenanceofpregnancy,and mones, bile acids, and vitamin D (Lecerf
a loss of progesterone is causally associated and de Lorgeril 2011), and is a significant
with miscarriage in early pregnancy (Mac- component of lipid rafts in the plasma
donald 1989). It is therefore striking that a membrane, which serve as organizing cen-
characteristic action of progesterone is its tersfortheassemblyofsignalingmolecules
reduction of cholesterol. Progesterone (Rosenberger et al. 2000). Lipid rafts them-
hasbeenshowntoinhibittheesterification selves play multiple functions, including po-
ofcholesterolderivedfromlow-densitylipo- larized secretion, membrane transport,
proteins (LDLs), preventing its delivery to transcytosisacrossepithelialmonolayers,and
cellular enzymes (Metherall et al. 1996). thegenerationofcellpolarity(Rosenberger
Treatment of cholesterol with progester- et al. 2000). Two types of lipoproteins are
one also causes the accumulation of sterol associatedwithcholesterol:high-densitylipo-
precursors, implying that cholesterol pro- proteins (HDLs) and low-density lipoproteins
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June2013 BOOTS FOR ACHILLES 99
(LDLs). These function in the transport of lett 2005). Correspondingly, studies consis-
cholesterol throughout the body. LDLs as- tentlyrevealanintimaterelationshipbetween
sist in the transportofcholesteroloutofthe maternal cholesterol levels and healthy fetal
liver, while HDLs act as acceptors of choles- development (Brizzi et al. 1999; Innis 2005;
terolandarebelievedtobringfatandcholes- Woollett2011).
terolbacktotheliver(GrummerandCarroll
1988;AssmannandGotto2004).Regulationof Progesterone-Mediated Reductions
synthesis,influx,andeffluxkeepscellularcho- in Cholesterol During Pregnancy,
lesterol levels tightly controlled (Simons and the Luteal Phase, and Menopause
Ikonen2000).
Early pregnancy is associated with a na-
Reflecting its many important functions
dirinthemeanvalueofserumcholesterol
in the body, cholesterol is a vital factor in
(DarmadyandPostle1982;Basaran2009).
development.Cholesterol’srelationshipto
Althoughcholesterolrisessteadilythrough
the Sonic hedgehog (Shh) group of pro-
gestation, early in the first trimester there
teinsentailsanessentialroleinembryonic
development,astheseproteinsarerequired is an initial decrease in plasma lipids (Basa-
for morphogenesis; cholesterol modulates ran2009;Sepetal.2011).Cholesterollevels
thefunctionoftheShhgroupbybindinga eventuallyclimbdramatically,butrecovery
functional Shh fragment and thereby re- from the initial decline is gradual, such
strictingthedistributionandactivityofthe that LDL levels at the end of the first tri-
Shhsignalonthecellmembrane(Yoshida mester are often still within normal
andWada2005).Correspondingly,choles- ranges (Brizzi et al. 1999); it is generally
terol deficits during embryogenesis cause only by the beginning of the second tri-
severe abnormalities (Koleja´kova´ et al. 2010). mester that cholesterol levels rise substan-
To take one example, Smith-Lemli-Opitz tially above the pre-pregnancy baseline
syndrome, caused by an inherited defect (Basaran2009).
in a specific enzyme in the cholesterol Importantly, the first-trimester decline
biosynthesis pathway, is characterized by in maternal cholesterol levels is not a con-
abnormaldevelopmentandpoorfunction, sequenceofutilizationofmaternalcholes-
especially in cognition (Salen et al. 1996). terol by the conceptus, as total conceptus
This is further supported by evidence
cell mass is small during the first-trimester
showing correlations between statin use in
cholesterol nadir and, moreover, the gen-
pregnancy and fetal neurological damage,
eral pattern of cholesterol decline is not
and impaired placental implantation and
dependentonconception,asitalsooccurs
function (Kenis et al. 2005; Pollack et al.
duringthelutealphaseofmenstrualcycles
2005; Lockshin 2010).
in which conception has not taken place.
Consonantwiththeabove,reflectingthe
During the follicular phase of the men-
substantialneedforcholesterolduringthis
strual cycle, total cholesterol levels peak
time of rapid growth, fetal sterol synthesis
(Kim and Kalkhof 1979; Ahumada Hemer
ratesaregreaterthanthoseinotherextra-
et al. 1985; Jones et al. 1988), as do levels
hepatic tissues (Woollett 2005). Impor-
of LDL (Ahumada Hemer et al. 1985;
tantly, however, although the fetus is able
Tikkanen et al. 1986). During the luteal
to synthesize its own cholesterol, because
phase, in which the endometrium is pre-
demand generally outstrips supply—such
thatmaternalcontributionisalimitingfac- paredforimplantation,levelsofbothtotal
torinfetalgrowth(GluckmanandHanson serumcholesterolandtriglyceridesdecline
2004)—thefetusisdependentonmaternal (De Leo´n et al. 1992). The luteal phase
supply. Maternal cholesterol, in the form constitutespreparationforpregnancyand,
of lipoproteins, can enter into fetal circu- correspondingly, pregnancy can be con-
lationthroughuptakebytheplacentaand ceptualized as a continuation of changes
trophoblasts, via both receptor-mediated present mid-luteally—declines in choles-
and receptor-independent transport (Wool- terol thus occur in anticipation of, rather
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100 THEQUARTERLYREVIEWOFBIOLOGY Volume88
than as a consequence of, the presence Wearethusfacedwiththeapparentcon-
and growth of a conceptus. tradictionthatahormonethatiscentralto
Progesterone is the principal candidate pregnancycausesareductioninlipidsthat,
for the cause of the decline in cholesterol being vital to cellular activity and cell divi-
in the luteal phase and the early first tri- sion,arecrucialtosuccessfulfetaldevelop-
mester. Progesterone remains at a rela- ment. To date, this question has not been
tively low level throughout the follicular explored.Severalauthors(Butte2000;Toescu
phase and during ovulation, but increases et al. 2002) have noted in passing that low
sharply during the luteal phase (De Leo´n cholesterollevelsearlyinpregnancycorre-
etal.1992).Intheeventofconceptionand spond to an anabolic phase during which
implantation, progesterone continues to fat deposition is enhanced in anticipation
climb across the first trimester (Tay and oflatepregnancy,whenrapidfetalgrowth
Lenton2002).Importantly,progesterone’s will require maternal catabolism. In this
cholesterol-reducing effects are well estab- view, the initial reduction in gestational
lished. Studies have shown that progester- cholesterol levels is simply a side effect of
one inhibits the delivery of LDL-derived the need to lay in energy stores for later.
cholesterol to processing enzymes such as However,theratioofcholesteroltotriglyc-
acetyl-Coenzyme A acetyltranferase (ACAT; eridesinfatcellsisbothconstantandlargely
Metheralletal.1996).Progesteroneinhibits independentofcellsize,indicatingthatboth
the movement of LDL-derived cholesterol arelikelydepositedsimultaneouslyinafixed
from lysosomes to the plasma membrane ratio(Kovanenetal.1975)—afeatureincon-
(Plemenitas et al. 1990), and the move- sistent with progesterone’s disruption of
ment of cholesterol from the plasma mem- cholesterol production. Hence, while
branetotheendoplasmicreticulum(Lange thereisconclusiveevidenceofapatterned
1994). This movement of sterols from the shift from anabolism to catabolism across
plasmamembranetotheendoplasmicreticu- pregnancy, this pattern provides neither
lum is required for cholesterol biosynthesis proximate nor ultimate explanations of
(Metherall et al. 1996); thus, progesterone’s the antagonistic effects of progesterone
impedimentofLDL-derivedcholesterolmove- on cholesterol synthesis. Rather, we pro-
mentinturnimpedescholesterolbiosynthesis. pose that the solution to this puzzle lies
Consistent with the disruption of cholesterol in the intersection of the effects of pro-
production pathways, treating tissue with gesteroneontheimmunesystemandthe
progesterone leads to an accumulation of role of cholesterol in infection.
sterol precursors (Lindenhall et al. 2001).
Attheorganismiclevel,exogenousproges- Progesterone-Induced
teronehasbeenshowntoreduceHDLcho- Immunomodulation and
lesterol both when administered through Compensatory Prophylaxis
progestin-only oral contraceptives (Wynn Withhalfofitsgenomebeingpaternally
and Niththyananthan 1982) and when ad- derived,fromtheperspectiveofthemater-
ministered through hormone-replacement nal immune system, the conceptus consti-
therapiesinpostmenopausalwomen(Lamon- tutes a genetically incompatible allograft.
Favaetal.2006). As a consequence, changes must occur in
Menopause is accompanied by a dra- the maternal immune system in order to
matic decline in progesterone levels and, preventmaternallymphocytesfromattack-
consistent with the above portrait, across ing the conceptus (Szekeres-Bartho et al.
diversepopulations,thereisacorrespond- 1983). Pregnancy is facilitated by a shift in
ing increase in serum cholesterol during theTh1/Th2balanceinmaternalimmune
this period independent of the effects of functioning, a move away from those in-
age (Wu et al. 1990; Akahoshi et al. 1996; flammatory responses that pose the great-
Matthews et al. 2009); correspondingly, est danger to the invasive blastocyst and
surgical menopause has a similar effect thesubsequentlysemiparasiticembryo(re-
(Akahoshi et al. 1996). viewed in Fessler 2002; Doyle et al. 2007;
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June2013 BOOTS FOR ACHILLES 101
Fleischman and Fessler 2011). Importantly, ing the first trimester often can have dras-
progesteroneplaysacentralroleintheimmu- tic consequences (Wright 1966).
nomodulation necessary to tolerate the half- Progesterone’s effects on the immune
foreign conceptus (Siiteri et al. 1977). The systemclearlyconstituteanadaptationthat
downregulation of maternal inflammation is servestoallowforgestation.Yet,thisadap-
achieved through decreased levels of proin- tation comes at the cost of increased sus-
flammatory cytokines and natural killer cells. ceptibilitytoinfectionduringaparticularly
These changes are the downstream conse- vulnerableperiod.Importantly,naturalse-
quence of progesterone-induced blocking lectionisnotateleologicalprocess—inno-
factor(PIBF),whichshiftsthematernalimmu- vations that solve one problem can create
nological balance toward anti-inflammatory another. Moreover, the liabilities entailed
signals(reviewedinFessler2001;seealsoSze- byonetraitcan,inturn,constituteasource
keres-Bartho et al. 1995; Doyle et al. 2007). of selective pressure leading to the evolu-
Hence, progesterone is essential to preg- tion of new traits that mitigate the costs of
theseliabilities.Suchsecond-orderadapta-
nancy in part because it commands an im-
tions have been variously referred to as
munomodulatory cascade that allows for
adaptive workarounds (Eastwick 2009) or
tolerance of the half-foreign parasitic con-
the product of compensatory mutations
ceptus.
(Maisnier-Patin and Andersson 2004). Of
Maternal immune tolerance of the con-
relevance to the matter at hand, recent
ceptuscomesatapriceas,byloweringhost
evidence suggests that changes in other
defenses, it increases the chances of infec-
systems adaptively mitigate the vulnerabil-
tion(reviewedinFessler2001,2002;Doyle
itytopathogensentailedbyprogesterone’s
etal.2007).PIBFaltersthecytokinesecre-
effectsontheimmunesystem.Specifically,
tion profile by increasing the production
alterationsinbehaviorprovideoneavenue
of Th2 cytokines and decreasing the pro-
for such mitigation. The compensatory
ductionofTh1cytokines(Faustetal.1999).
prophylaxishypothesisholdsthat,because
PIBF has also been shown to inhibit natu-
prophylacticbehaviorentailstime,energy,
ralkillercellactivity,throughablockadeof
attention, and opportunity costs, rather
degranulation (Faust et al. 1999). Both of
than remaining constant, prophylactic be-
these changes increase vulnerability to
haviorshouldbeenhancedduringperiods
infection by lowering defenses in regard
of increased susceptibility to infection,
to both the detection and elimination of
when the greater benefits obtained merit
pathogens. Indeed, some pathogens may
increased expenditures (Fessler and Na-
haveevolvedtheabilitytoexploitthistem-
varrete 2003). Hence, because progester-
porary weakening of host defenses; for
one regulates a cascade of physiological
example, progesterone not only increases
eventsthatresultinincreasedvulnerability
theprobabilityofinfectionbycytomegalo-
toinfection,progesteronecanbeexpected
virus but, moreover, actually increases the toalsomediateincreasedbehavioralpro-
pathogen’s virulence (Chong and Mims phylaxis (Fessler and Navarrete 2003).
1984). Furthermore, increased maternal Consonant with this hypothesis, studies
susceptibility to infection comes at a par- have shown increases in disgust sensitivity
ticularly dangerous time. Later in preg- (a proximate mechanism subserving dis-
nancy the fetus eventually develops some easeavoidance)duringthevulnerablefirst
autonomous defenses against pathogens, trimester(Fessleretal.2005).Morespecif-
but these are absent early in development ically, disgust sensitivity, disease-avoidance
(HoltandJones2000).Moreover,theearly behaviors, and related perceptions and at-
first trimester is a critical period in fetal titudesallincreaseasafunctionofproges-
development, as organogenesis, concen- teronelevels(Conwayetal.2007;Navarete
trated during this phase, is a process that et al. 2007; Fleischman and Fessler 2011;
is especially vulnerable to insult (Arnold but see also Fessler and Navarrete 2003).
1990)and,correspondingly,infectiondur- Likewise, preferences for healthy over un-
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102 THEQUARTERLYREVIEWOFBIOLOGY Volume88
healthyfaces(acueofdiseaserisk)areelevated produced by more than 20 species from
during periods of elevated progesterone the genera Clostridium, Streptococcus, Liste-
(Jones et al. 2005). Although compensatory ria, Bacillus, and Arcanobacterium (Tweten
prophylaxisisbehavioral,webelievethatasim- 2005). Cholesterol-dependent cytolysins func-
ilar logic explains the effects of progesterone tionbothassimplehemolysinsandasgeneral
oncholesterol,asthelatterplaysacentralrole cell-lyticagentsthatarecrucialinbacterialin-
ininfection. fection (Tweten 2005). Conversely, bacterial
sepsiscausesdecreasesintheconcentrationsof
Cholesterol and Infection totalcholesterol,HDL,andapoproteinsAand
Critically, cholesterol plays a key role in B of patients; the return of serum lipids to
infection. Lipid rafts are sites of entry and more normal concentrations parallels the
exitforawidevarietyofviruses(Medigeshi recovery from sepsis (Alvarez and Ramos
etal.2008).Lipidraftscanbeexploitedby 1986).Althoughatpresentthereisnocon-
pathogens in a number of ways. Some vi- sensus as to why this correlation exists, it
ruses, such as human immunodeficiency may be that hypocholesterolemia in cases
virustype1,coxsackievirus,simianvirus40, of sepsis is a component of defensive re-
and severe acute respiratory syndrome co- sponses (Das et al. 2011).
ronavirus, depend on lipid rafts for bind- Consonant with the thesis that the avail-
ing to and entry into the host cell; other ability of cholesterol is a determinant of
viruses,suchasrotavirus,Newcastledisease the ability of pathogens to proliferate, in-
virus,influenzavirus,Ebolavirus,andMar- triguing indications are emerging regard-
burg virus, utilize raft-mediated pathways ing a relationship between statin therapy,
for assembly and egress (Chazal and Ger- which decreases cholesterol, and a lower
lier 2003; Man˜es et al. 2003; Ono and incidence of severe sepsis (Almog 2003).
Freed 2005; Pelkmans 2005). Statinsdisplayantimicrobialeffectsin many
A number of bacteria similarly exhibit studies. Both in vivo and in vitro, statins
cholesteroldependence,includingAnaplasma reduce the intracellular growth of a sub-
phagocytophilum(Xiongetal.2009),Escherichia species of Salmonella enterica (Catron et al.
coli (Goluszko and Nowicki 2005), Mycobacte- 2004),whilesimvastatinhasshownasignif-
rium(GatfieldandPieters2000),Staphylococcus icantantimicrobialeffectagainstMSSAand,
aureus(Liuetal.2008),Salmonella(Haywardet to a lesser extent, against MRSA (Jerwood
al.2005),andShigella(Haywardetal.2005), andCohen2008).
amongothers.Some,suchasMycobacterium Given that cholesterol plays a role in
tuberculosis, utilize cholesterol as a primary infectious disease, it is tempting to ask
carbon source throughout the course of whether epidemiological studies reveal a
infection,suchthatdegradationofthissterol link between cholesterol and infection.
is crucial for bacterial persistence (Miner et However,beforereviewingthisevidence,it
al. 2009). In other cases, in species such as is important to note that it is difficult to
Staphylococcus aureus that do not use choles- predict in advance how such correlations
terol as a significant energy source (Shine willplayout.Ontheonehand,pathogens’
et al. 1993), disruption of cholesterol bio- dependence on cholesterol suggests that
synthesisneverthelessblocksbacterialviru- we might expect a straightforward positive
lence (Liu et al. 2008), as cholesterol is a correlation between the host’s systemic
key component of the cytoplasmic mem- cholesterol levels and morbidity and mor-
brane (Yeagle 1985). Cholesterol depen- talityduetoinfection.Ontheotherhand,
dency can be a distinguishing feature of if the body is able to facultatively adjust
the pathogenic adaptations of bacteria; in- cholesterol levels as a function of the indi-
deed, an entire family of bacterial cytoly- vidual’s capacity to resist infection, then
sinsisreferredtoascholesterol-dependent the opposite pattern may obtain, as indi-
cytolysins (CDCs) because they can only viduals who are vulnerable to pathogens
functioneffectivelyinthepresenceofhost for reasons other than cholesterol avail-
cholesterol.Thesepore-formingtoxinsare ability may both exhibit lower cholesterol
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June2013 BOOTS FOR ACHILLES 103
levels (reflecting an attempt to reduce efforttocompensatefortheirvulnerability
vulnerability) and suffer higher rates of to pathogens.
morbidity and mortality due to infection A less direct route to exploring the rela-
(reflecting the incomplete success of tionshipbetweencholesterollevelsandin-
such efforts). Lastly, complicating the fection is to consider cholesterol’s effects
picturestillfurther,itmaybeimportantto on overall mortality. One difficulty in in-
distinguish between different affordances terpreting such patterns is the question of
of cholesterol from the perspective of the how to evaluate the respective effects of
host.Althoughcholesterolfacilitatesinfec- cholesterol on susceptibility to infection
tion and pathogen proliferation, once in- and cardiovascular disease. Although con-
fection is established, cholesterol may ventional wisdom holds that cholesterol
sometimesbenefitthehostbyreducingthe contributes directly to cardiovascular dis-
destructiveeffectsofendotoxinsproduced ease, consonant with the view advanced
by some bacterial pathogens (Feingold et here, Ewald (2008) presents a strong case
al. 1995; Ravnskov 2003). Accordingly, that this correlation actually reflects the
amongindividualswhoareabletomounta role of cholesterol in facilitating infection
robust immune response to infection, by pathogens such as Chlamydia that, in
those having high cholesterol levels may turn, damage blood vessels. Nevertheless,
suffer less pathogen-driven morbidity and giventhatthisremainsaminorityview,itis
mortalitythanthosehavinglowcholesterol conservative to evaluate the contributions
levels. of cholesterol to mortality independent of
Hospital studies reveal that low levels of deaths due to cardiovascular disease. Al-
HDL increase the probability of nosoco- thoughanumberofstudieshavesoughtto
mial infections (Delgado-Rodr´ıguez et al. elucidate the relationship between choles-
1997;Canturketal.2002),andarepredic- terol and noncardiovascular mortality, at
torsofin-hospitaldeathandlengthofstay present there is no consensus in the liter-
(Delgado-Rodr´ıguez et al. 2002). These atureinthisregard.Agemaybeanimpor-
patterns are consistent with the thesis that tant factor. In adults over the age of 85,
cholesterol availability directly determines high total cholesterol concentrations are
riskofinfection,asHDLfunctionstotrans- associated with longevity, seemingly from
portexcesscholesterolfromtheperiphery lower mortality due to cancer and infec-
to the liver for excretion into bile (Zhang tion(Weverling-Rijnsburgeretal.1997).A
etal.2003),hencelowerHDLlevelsequateto similar pattern of the protective effects of
less reverse cholesterol transport and or- cholesterol has also been found among
gan clearance, which, in turn, could con- adultsolderthan55,whoevinceaninverse
ceivably lead to an increase in the amount relationship between total cholesterol and
of cholesterol available to pathogens else- several infectious diseases (Iribarren et al.
where in the body. Conversely, however, 1998). Conversely, studies of younger adults
outside of the hospital, among men, total reveal that the effect of total cholesterol
cholesterol is inversely related to urinary on noncardiovascular mortality is neutral
tract,venereal,musculoskeletal,andallin- (Kronmaletal.1993;Krumholzetal.1994;
fections and, among women, to urinary Gould et al. 1995). Another study finds a
tract, all genitourinary, septicaemia, bacte- trendofincreasednoncardiovascularmor-
raemia, miscellaneous viral site unspeci- talitywithdecreasedLDL,inbothplacebo
fied, and all infections (Iribarren et al. and treatment groups (Razzolini et al.
1998). Given the role of cholesterol in in- 2008).However,ateachgivenLDLcholes-
fection,thelatterpatternstronglysuggests terol level, noncardiovascular mortality is
that individual differences in cholesterol lower in patients treated with statins (Raz-
levelsmayreflectunderlyingdifferencesin zolini et al. 2008).
immunologic robustness, such that more To summarize the above, at the cellular
vulnerableindividualsmaintainlowercho- level,thereissubstantialevidencethatcho-
lesterollevelsinanincompletelysuccessful lesterol can play a key role in infection. At
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104 THEQUARTERLYREVIEWOFBIOLOGY Volume88
TABLE 1
Summaryofsurveyofpathogenswithregardtolimitingandexacerbatingcytokineresponses,threatposed
duringpregnancy,andutilizationofcholesterol
Limitingcytokine Exacerbating Threatduring Cholesterolutility/
Pathogen response cytokineresponse pregnancy dependence?
Th1:IL-12,IL-6,TNF-alpha
Toxoplasmagondii (1,2) Th2:IL-4(1,2) Earlypregnancy(3) Yes(4)
Th1:IL-1,IL-2,
Escherichiacoli IFN-gamma(5) Th2:IL-10(6) Earlypregnancy(7) Yes(8)
Brucellaabortus,
Brucella Th1:IL-12,IFN-gamma,
melitensis TNF-alpha(9) Th2:IL-10,IL-4(10) Earlypregnancy(83) Yes(11)
Shigelladysenteriae Th1:IL-8,IL-2(12) Earlypregnancy(64) Yes(13)
Campylobacter
jejuni Th1:TNF-alpha,IL-8(14) Earlypregnancy(15) Yes(16)
Mycobacterium Th1(19) Th2(19) Yes(17)
CoxsackievirusB Th1:IFN-gamma(20) Th2(20) Earlypregnancy(54) Yes(35)
Lassavirus Th1:IL-6,IL-1beta(29) Thirdtrimester(53) Yes(18)
Poliovirus Th1:IL-6,IL-8(21),IFN
response(24) Yes(23)
CVB4 Th1:IFN-gamma(25) Yes(26)
Helicobacterpylori Th1:IFN-gamma(27) Th2:IL-4(28) Yes(36)
Leishmania Th1:IFN-gamma, Th2:IL-4,IL-5,IL-10
donovani IL-12(30) (30) Yes(31)
Plasmodium Th1:IFN-gamma(32),
falciparum TNF-alpha(33) Yes(37)
Ehrlichia
chaffeensis Th1:IFN-gamma(34) Yes(38)
Salmonellaenterica Th1:IFN-gamma, Th2:IgG1/IgE
TNF-alpha(39) (40,41) Yes(42)
SemlikiForest
virus Th1(44) Anti-Th1:decreases Yes(45)
inIL-12,
IFN-gammacause
increasedand
prolonged
infection(43)
Epstein-Barr
virus Th1:IFN-gamma(46) Th2(47) Yes(48)
Vesicular
stomatitisvirus Th1(49) Yes(50)
Denguevirus Th1:IFN-gamma(51) Yes(52)
Varicella Th1:IL-6(57),IFN-gamma,
(Chickenpox) IL-10,IL-12(58) Earlypregnancy(59) Yes(56)
Parvovirus Th1:IL-10,IFN-gamma(60) Earlypregnancy(59) Yes(61)
Rubella Th1:IL-2,TNF-alpha(62) Earlypregnancy(59) Yes.Maydependon
macropinocytosis
forentry(69),
whichrequires
cholesterol(70)
Influenzavirus Th1:IL-6(63) Th2:IL-4(64) Earlypregnancy(66) Yes,decreasein
infectivitywhen
cholesteroldepleted
(65)
continued
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June2013 BOOTS FOR ACHILLES 105
TABLE 1
Continued
Limitingcytokine Exacerbating Threatduring Cholesterolutility/
Pathogen response cytokineresponse pregnancy dependence?
Seasonal
InfluenzaA Mixedresponse:TNF-alpha,
(H1N1) IL-6,IL-8,IL-15(87) Earlypregnancy(86)
Adenoviruses Th1:IL-6,IL-8,TNF(67) Earlypregnancy(72) Yes(71)
Respiratory
SyncytialVirus Th1(68) Th2:IL-4(73) Yes(74)
Anaplasma
phagocytophilum Th1:IFN-gamma(77) Th2(76) Yes(75)
Listeria
monocytogenes Th1:IL-12(79) Earlypregnancy(80) Yes(78)
Clostridium
perfringens Th1:IL-10(82) Yes(81)
Leptospira Th1:IL-12,TNF-alpha,
IFN-gamma(85)
BornaVirus Inacuteinfections,Th1: Yes(84)
TNF-alpha,IL-2,IL-6,
IFN-gamma(88)In
chronic,switchesto
Th2(88)
Cytomegalovirus Candamagefetusat
anystagein
pregnancy(55)
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the population level, the picture is more gesterone’s effects on the immune system.
mixed, possibly reflecting both complex Given the extent to which pathogens are
relationships between cholesterol levels dependent on cholesterol, if humans have
and immunological robustness and the ef- indeed evolved mechanisms capable of
fects of cholesterol on other aspects of such compensatory adjustment, then we
health. Here, we are concerned with the should expect to find evidence of an evo-
possibility that patterned changes in sys- lutionary arms race between human hosts
temic cholesterol can adaptively mitigate andavarietyofpathogens,aseachseeksto
vulnerability to infection entailed by pro- gain control of cholesterol availability in
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106 THEQUARTERLYREVIEWOFBIOLOGY Volume88
order to determine the outcome of infec- viral growth (Munger et al. 2008). West Nile
tion. virusactssimilarly,modulatinghostcellcholes-
terol homeostasis by upregulating cholesterol
arms races between host and biosynthesis and redistributing cholesterol to
pathogens over cholesterol viralreplicationmembranes(Mackenzieetal.
regulation/synthesis 2007); the same pattern has been shown in
There appears to be a correlation be- both Dengue virus (Heaton et al. 2010) and
tween innate immune signaling processes HIV (Taylor et al. 2011). It is thus quite
and the regulation of sterol metabolism likely that natural selection has favored
(Castrillo et al. 2003; Ogawa et al. 2005; host mechanisms that reduce or sequester
Zelcer and Tontonoz 2006; Wang et al. cholesterolasameansofcombatingpatho-
2009a).Inkeepingwiththeroleofcholes- gens.
terol in infection and the corresponding
the conjunction of
strategic value of its regulation, a relation-
progesterone-driven risk of infection
ship has been demonstrated between the
and cholesterol dependence in
cholesterol-metabolic pathway and protec-
pathogens
tion against, or susceptibility to, infection
(Blanc et al. 2011). Specifically, mamma- In order to test our hypothesis that pro-
lian hosts produce high levels of interfer- gesterone’s effects on cholesterol consti-
ons after infection with a range of viruses; tute a second-orderadaptationthatreduces
in turn, via interferon receptors, high lev- thecostsofprogesterone’simmunomodula-
els of interferons lower enzyme levels on toryeffects,weturntoanexaminationofthe
the cholesterol pathway, resulting in a net postulatedselectionpressuresatissue.Spe-
reductionincholesterolavailability(Blanc cifically,ifcholesterolreductionisapreemp-
et al. 2011). Host reduction of cholesterol tivedefensivemaneuveraimedatdecreasing
asadefensemechanismisalsoobservedin the threat posed by those pathogens that
conjunction with the hepatitis C virus (HCV) standtobenefitfromprogesterone’simmu-
(Walters et al. 2006). However, in keeping nomodulatoryeffects—mostnotablyinclud-
with the advantages to the pathogen of ingthosepathogensthatposeasubstantial
cholesterol abundance, HCV counters this risk to mother and conceptus—then it
move by impairing lipid metabolism and should be the case that a majority of such
causinganunregulatedincreaseincholes- pathogensareimportantlydependentonhost
terolandfattyacidsynthesis(Nakamutaet cholesterolfortheirsuccess.Wethereforecon-
al. 2009). In response, infected cells cata- ducted an extensive literature search to
lyze rate-limiting steps in the cholesterol identifysuchpathogens,thenexploredthe
pathway to reduce the amount of choles- extent to which they are known to be de-
terolproduced,whileincreasedexpression pendent on cholesterol. Table 1 presents
of genes associated with peroxisomes, which our findings.
are capable of breaking down cholesterol, As evident in Table 1 and illustrated in
suggests attempts to prevent the pathogen Figure1,awiderangeofpathogensutilize
fromutilizingpreviouslyproducedcholesterol cholesterolformaximalinfectivity.Asillus-
(Waltersetal.2006).Thus,itappearsthatthe trated in Figure 2, almost all of these are
hostisengagedinanarmsracewithHCVto bestcounteredbyaTh1cytokineresponse
regulatetheproductionandavailabilityofcho- inthehostand,asillustratedinFigure3,a
lesterol. The same is likely true of other large number are exacerbated by a Th2
pathogens as well as, in a variety of viral cytokine response. Progesterone shifts the
pathogens, there is a correlation between Th1/Th2 balance toward the latter; there-
increased virulence and increase in fatty fore, it follows that progesterone increases
acid supply and synthesis. Human cyto- the susceptibility of the host to the patho-
megalovirus has been shown to alter fatty genslisted.AsevidentinFigure4,manyof
acidbiosynthesispathwaystoincreasefatty thesepathogensalsoposeasubstantialrisk
acid supply, which is essential for optimal during early pregnancy, a period charac-
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