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8/9/2019 Microbiology and pathogenesis of tuberculosis.docx
http://slidepdf.com/reader/full/microbiology-and-pathogenesis-of-tuberculosisdocx 1/20
Microbiology and pathogenesis of tuberculosisAuthor Lee W Riley, MDSection Editor C Fordham von Reyn, MDDeputy Editor
Elinor L Baron, MD, DTMHDisclosures: Lee W Riley, MD Nothing to disclose. C Fordham on Reyn, MD Nothing to disclose. Elinor L !aron,MD, D"M# Emloyee o! "ToDate, #nc.
Contri$%tor disclos%res are revie&ed !or con!licts o! interest $y the editorial gro%. When !o%nd, these are addressed $yvetting thro%gh a m%lti'level revie& rocess, and thro%gh re(%irements !or re!erences to $e rovided to s%ort thecontent. )roriately re!erenced content is re(%ired o! all a%thors and m%st con!orm to "ToDate standards o!evidence.
Conflict of interest policy
)ll toics are %dated as ne& evidence $ecomes availa$le and o%r eer revie& rocess is comlete.Literature reie$ current through% *e +-. / "his topic last updated% 0%l 1, +-1.
&'"R(D)C"&(' 2 Myco$acteri%m t%$erc%losis is the second most common in!ectio%s ca%se o!
death in ad%lts &orld&ide 3H#4 is the most common5. The h%man host serves as the nat%ral reservoir
!or M. t%$erc%losis. The a$ility o! the organism to e!!iciently esta$lish latent in!ection has ena$led it to
sread to nearly one'third o! individ%als &orld&ide. )ro6imately 7 million ne& cases o! active TB
disease occ%r each year, leading to a$o%t -.8 million deaths. The disease incidence is magni!ied $y
the conc%rrent eidemic o! h%man imm%node!iciency vir%s 3H#45 in!ection. 3*ee 9Eidemiology o!
t%$erc%losis9.5
The micro$iology and athogenesis o! M. t%$erc%losis &ill $e revie&ed here. The imm%nology o! this
in!ection is disc%ssed searately. 3*ee 9#mm%nology o! t%$erc%losis9.5
'A")RAL #&S"(R* (F &'FEC"&(' 2 #nhalation o! M. t%$erc%losis and deosition in the l%ngsleads to one o! !o%r ossi$le o%tcomes:
;#mmediate clearance o! the organism
;Latent in!ection
;#mmediate onset o! active disease 3rimary disease5
;<nset o! active disease many years !ollo&ing e6os%re 3reactivation disease5
)mong individ%als &ith latent in!ection and no %nderlying medical ro$lems, reactivation disease
occ%rs in aro6imately = to - ercent o! cases >-?. The ris@ o! reactivation is mar@edly increased in
atients &ith H#4 >+?. These o%tcomes are determined $y the interlay o! !actors attri$%ta$le to $oth
the organism and the host.
+rimary disease 2 M%ch o! o%r %nderstanding o! the nat%ral co%rse o! t%$erc%losis 3TB5 comes !rom
h%man a%tosy data rior to the era o! antit%$erc%losis dr%gs and !rom e6erimental animal models
>1'8?. )mong the aro6imately - ercent o! in!ected individ%als &ho develo active disease,
aro6imately one'hal! o! them &ill do so &ithin the !irst t&o to three years !ollo&ing in!ectionA s%ch
individ%als are said to develo raidly rogressive or rimary disease.
The t%$ercle $acilli esta$lish in!ection in the l%ngs a!ter they are carried in drolets small eno%gh 3= to
- micron5 to reach the alveolar sace. #! the innate de!ense system o! the host !ails to eliminate the
in!ection, the $acilli roli!erate inside alveolar macrohages and event%ally @ill the cells. The in!ected
macrohages rod%ce cyto@ines and chemo@ines that attract other hagocytic cells, incl%ding
monocytes, other alveolar macrohages, and ne%trohils, &hich event%ally !orm a nod%lar
gran%lomato%s str%ct%re called the t%$ercle. #! the $acterial relication is not controlled, the t%$ercle
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enlarges and the $acilli enter local draining lymh nodes. This leads to lymhadenoathy, a
characteristic mani!estation o! rimary TB. The lesion rod%ced $y the e6ansion o! the t%$ercle into
the l%ng arenchyma and lymh node involvement is called the hon comle6. Bacteremia may
accomany initial in!ection.
The $acilli contin%e to roli!erate %ntil an e!!ective cell'mediated imm%ne 3CM#5 resonse develos,%s%ally t&o to si6 &ee@s a!ter in!ection. Fail%re $y the host to mo%nt an e!!ective CM# resonse and
tiss%e reair leads to rogressive destr%ction o! the l%ng. T%mor necrosis !actor 3TNF5'alha, reactive
o6ygen and nitrogen intermediates, and the contents o! cytoto6ic cells 3granymes, er!orin5 may all
contri$%te to the develoment o! caseating necrosis that characteries a t%$erc%lo%s lesion. Caseo%s
necrosis is !re(%ently associated &ith TB $%t can also $e ca%sed $y other organisms, incl%ding
syhilis, histolasmosis, crytococcosis, and coccidioidomycosis. 3*ee related toics5.
"nchec@ed $acterial gro&th may lead to hematogeno%s sread o! $acilli to rod%ce disseminated TB.
Disseminated disease &ith lesions resem$ling millet seeds has $een termed miliary TB. Bacilli can
also sread mechanically $y erosion o! the caseating lesions into the l%ng air&aysA at this oint the
host $ecomes in!ectio%s to others. #n the a$sence o! treatment, death ens%es in 7 ercent o! cases>7?. The remaining atients develo chronic disease or recover. Chronic disease is characteried $y
reeated eisodes o! healing $y !i$rotic changes aro%nd the lesions and tiss%e $rea@do&n. Comlete
sontaneo%s eradication o! the $acilli is rare.
Reactiation disease 2 Reactivation TB res%lts !rom roli!eration o! a revio%sly dormant $acteria
seeded at the time o! the rimary in!ection. )mong individ%als &ith latent in!ection and no %nderlying
medical ro$lems, reactivation disease occ%rs in aro6imately = to - ercent o! cases >-?.
#mm%nos%ression is clearly associated &ith reactivation TB, altho%gh it is not clear &hat seci!ic
host !actors maintain the in!ection in a latent state and &hat triggers the latent in!ection to $ecome
overt. #mm%nos%ressive conditions associated &ith reactivation TB incl%de:
;H#4 in!ection and )#D*
;End'stage renal disease
;Dia$etes mellit%s
;Malignant lymhoma
;Corticosteroid %se
;#nhi$itors o! TNF'alha and its recetor
;Dimin%tion in cell mediated imm%nity associated &ith age
The disease rocess in reactivation TB tends to $e localied 3in contrast to rimary disease5A there is
little regional lymh node involvement and less caseation. The lesion tyically occ%rs at the l%ng
aices, and disseminated disease is %n%s%al, %nless the host is severely imm%nos%ressed.
#t is generally $elieved that s%ccess!%lly contained latent t%$erc%losis con!ers rotection against
s%$se(%ent TB e6os%re >?. <ne revie& eval%ating +1 aired cohorts 3total more than -,
individ%als5 noted that individ%als &ith latent t%$erc%losis had 8 ercent lo&er ris@ o! rogressive
t%$erc%losis !ollo&ing rein!ection comared &ith %nin!ected individ%als >-?. Ho&ever, s%ccess!%l
treatment !or TB may not al&ays con!er rotection against a s%$se(%ent eisode o! TB. #n one st%dy
!rom *o%th )!rica incl%ding -+ atients treated !or TB, rec%rrence &as o$served in -7 ercent o!
cases over a !ive'year !ollo&'% eriodA rec%rrence occ%rred a!ter s%ccess!%l treatment in - ercent
o! cases >--?. By comaring DN) !ingerrints o! the M. t%$erc%losis isolates !rom the !irst and second
eisodes o! TB, the investigators sho&ed that 88 ercent o! the rec%rrences &ere ne& in!ections
rather than relase >--?. The rate o! rein!ection TB &as !o%r times the rate o! ne& TB.
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M&CR(!&(L(* 2 M. t%$erc%losis $elongs to the gen%s Myco$acteri%m that incl%des more than =
other secies, o!ten collectively re!erred to as nont%$erc%lo%s myco$acteria. T%$erc%losis 3TB5 is
de!ined as a disease ca%sed $y mem$ers o! the M. t%$erc%losis comle6, &hich incl%des the t%$ercle
$acill%s 3M. t%$erc%losis5, M. $ovis, M. a!rican%m, M. microti, M. canetti, M. carae, and M. inniedii
>-+?. 3*ee9Micro$iology o! nont%$erc%lo%s myco$acteria9.5
Cell enelope 2 The cell enveloe is a disting%ishing !eat%re o! the organisms $elonging to the
gen%s Myco$acteri%m. "nli@e gram'negative $acteria, there is no tr%e o%ter mem$rane in
Myco$acteri%m. The myco$acterial cell enveloe is comosed o! a core o! three macromolec%les
covalently lin@ed to each other 3etidoglycan, ara$inogalactan, and mycolic acids5 and a
lioolysaccharide, lioara$inomannan 3L)M5, &hich is tho%ght to $e anchored to the lasma
mem$rane >-1?.
Mycolic acid, a $eta'hydro6y !atty acid, is the maor constit%ent o! the cell enveloe, acco%nting !or
more than = ercent $y &eightA this str%ct%re de!ines the gen%s. lycoliids are attached to the
o%tside o! the enveloe layer thro%gh a connection to the mycolic acid layerA roteins are also
em$edded in this cell &all comle6. lycoliid comonents are imlicated in 9cord !ormation,9&here$y t%$erc%losis $acilli cl%m together !orming a serigino%s str%ct%re seen on microscoy > -?.
Staining characteristics 2 The cell &all comonents give Myco$acteri%m its characteristic staining
roerties. The organism stains ositive &ith ramGs stain. The mycolic acid str%ct%re con!ers the
a$ility to resist destaining $y acid alcohol a!ter $eing stained $y certain aniline dyes, leading to the
term acid !ast $acill%s 3)FB5.
Microscoy to detect )FB 3%sing iehl'Neelsen or Iinyo%n stain5 is the most commonly %sed
roced%re to diagnose TBA a secimen m%st contain at least -35 colony !orming %nits 3CF"5JmL to
yield a ositive smear >-=?. Microscoy o! secimens stained &ith a !l%orochrome dye 3s%ch as
a%ramine < rovides5 an easier, more e!!icient, and more sensitive alternative. Ho&ever, microscoic
detection o! myco$acteria does not disting%ish M. t%$erc%losis !rom nont%$erc%lo%s myco$acteria.
ro$th characteristics 2 ) disting%ishing !eat%re o! M. t%$erc%losis is its slo& gro&th rate. #n
arti!icial media and animal tiss%es, its generation time is a$o%t + to + ho%rs 3as oosed to +
min%tes !or organisms s%ch as Escherichia coli5.
&solation in the laboratory 2 )rti!icial media %sed to c%ltivate M. t%$erc%losis incl%de otato and
egg $ase media, s%ch as Middle$roo@ 8H- or 8H--, or al$%min in an agar $ase, s%ch as the
Lo&enstein'0ensen 3L05 medi%m >-?. ) li(%id medi%m, s%ch as Middle$roo@ 8H, is %sed !or
s%$c%lt%res and !or roagating the $acill%s to e6tract DN) !or molec%lar diagnostic and strain tying
roced%res >-8?. Three to !o%r &ee@s are re(%ired to recover the organism, deending %on the initial
(%antity o! organisms in the secimen.
Broth'$ased c%lt%re systems to imrove the seed and sensitivity o! detection have $een develoed.
The B)CTEC 3BC Diagnostics, *ar@s, MD5 system is $ased %on Middle$roo@ 8H-+ medi%m
containing -C almitic acid &ith a mi6t%re o! anti$iotics 3K)NT)5 to s%ress other $acterial gro&th
>-7?. The addition o! N)K 3'nitro'alha'acetylamino'$eta'hydro6yroiohenone5 in the medi%m
s%resses gro&th o! other M. t%$erc%losis comle6 organisms, s%ch as M. $ovis, $%t does not
di!!erentiate M. t%$erc%losis !rom other nont%$erc%lo%s myco$acteria.
Bacterial gro&th is indicated $y the detection o! -C released $y M. t%$erc%losis as it meta$olies the
almitic acid. #n )FB smear'ositive secimens, the B)CTEC system can detect M. t%$erc%losis in
aro6imately eight days 3comared to aro6imately - days !or smear'negative secimens5 > -,+?.
Ho&ever, the high cost o! the e(%iment and the need !or radioactive material that re(%ires disosal
e6cl%de its %se in most endemic settings.
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<ther $roth'$ased systems incl%de *eti'Che@ )FB 3BBL5 and the Myco$acterial ro&th #ndicator
T%$e 3M#T, BD Diagnostics5 >+-,++?. *eti'Che@ )FB is a $ihasic system comrised o! a caed
$ottle containing modi!ied Middle$roo@ 8H $roth %nder C<+ and a addle coated &ith solid agar,
s%ch as Middle$roo@ 8H-- and L0 media >+-?. The recovery rate o! M. t%$erc%losis comle6 !rom )FB
smear'negative secimens $y this roced%re is a$o%t -= to 1 ercent higher than conventional
media and the average n%m$er o! days to recovery is t&o to !ive days shorter > +-?.
M#T is $ased on Middle$roo@ 8H $roth containing silicon r%$$er imregnated &ith r%theni%m
entahydrate that serves as a !l%orescence (%enching'o6ygen sensor. )s o6ygen is cons%med $y
meta$oliing $acteria, !l%orescence o! the li(%id gro&th medi%m is detected vis%ally. )mong smear'
negative samles in a st%dy o! -= clinical secimens, the recovery rate o! the M. t%$erc%losis
comle6 &as a$o%t -= ercent less $y the M#T system 37 ercent5 comared to that o$tained $y
the radiometric B)CTEC system, $%t the mean time to detection &as similar 3. vers%s .8 days5
>++?. The lac@ o! need !or e6ensive instr%mentation and radioactive materials sho%ld render M#T
&idely acceta$le and s%ita$le in many la$oratories.
) similar $roth'$ased and colorimetric detection system is the MBJBacT system 3$ioMrie%6, D%rham,NC5. #n this system, a colorimetric sensor is em$edded at the $ottom o! a $ottle, and &hen car$on
dio6ide is rod%ced $y a gro&ing microorganism, the sensor changes !rom dar@ green to yello&. This
change in color is monitored contin%o%sly $y a detection device. ) systematic revie& o! this system
3comared &ith the B)CTEC 5 !o%nd that the MBJBacT system had a sensitivity o! to -
ercent and a seci!icity o! 87 to - ercent >+1?.
The 4ersa TREI 3Tre@ Diagnostic *ystems, West La@e, <hio5 system is an a%tomated detection
system $ased on discerning a change in gas ress%re 3o6ygen cons%mtion $y a gro&ing
microorganism5 in a sealed container. The systematic revie& comaring 4ersa TREI &ith B)CTEC'
, !o%nd a sensitivity !rom 7+ to - ercent and a seci!icity o! = to - ercent > +1?.
) contin%o%s a%tomated myco$acterial li(%id c%lt%re system 3C)MLiC5 has also $een descri$ed >+?.
This system is more sensitive than L0 c%lt%re in identi!ying M. t%$erc%losis comle6 organisms 37
vers%s 7= to ercent5 &ith a mean time to recovery o! -1. days. #t has not $een comared yet to
B)CTEC, *eti'Che@ )FB, or M#T and is not availa$le in the "nited *tates.
&dentification of the organism 2 <nce the organism is isolated, identi!ication is $ased %on
morhologic and $iochemical characteristics, altho%gh n%cleic acid'$ased detection methods have
o$viated many o! the conventional tests. M. t%$erc%losis is identi!ied $y its ro%gh, nonigmented, so'
called corded colonies on al$%min'$ased agars. #t is tyically ositive in the niacin test, has a &ea@
catalase activity, &hich is inactivated at 7C, and red%ces nitrate >-?. 3*ee 9Diagnosis o! %lmonary
t%$erc%losis in H#4'negative atients9, section on GN%cleic acid amli!icationG .5
The only other maor slo&'gro&ing myco$acteri%m that is niacin test'ositive is M. simiae. )ltho%gh all
mem$ers o! the myco$acteria secies rod%ce niacin 3%s%ally %ndetecta$le $y the niacin test5, the
di!!erences in the activity o! the enymes involved in the salvage ath&ay o! N)D $iosynthesis in M.
t%$erc%losis determines niacin ositivity in M. t%$erc%losis. Niacin acc%m%lates in M. t%$erc%losis
$eca%se nicotinamidase that converts nicotinamide to niacin is several'!old more active, and the
enyme that recycles niacin to rod%ce N)D is less active than in mem$ers o! most other
myco$acterial secies >+=?.
The niacin, nitrate red%ctase, and catalase tests are the three $iochemical tests most !re(%ently %sed
to disting%ish M. t%$erc%losis !rom other myco$acterial secies >-?. Tests !or yrainamidase
rod%ction as &ell as s%sceti$ility to thiohen'+'car$o6ylic acid hydraide 3TCH5 &ill disting%ish M.t%$erc%losis !rom M. $ovis, another mem$er o! the M. t%$erc%losis comle6. M. $ovis does not
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e6ress yrainamidase 3or nicotinamidase5 and is s%sceti$le to less than = mcgJmL o! TCH >-,+?.
Clinical isolates o! M. t%$erc%losis lac@ing yrainamidase activity have $een descri$ed &hich contain
n%cleotide oint m%tations in the gene 3nc)5 that encodes yrainamidaseA these isolates are
resistant to yrainamide 3K)5, one o! the !irst'line dr%gs %sed to treat TB >+8?. 3*ee 9Eidemiology
and molec%lar mechanisms o! dr%g'resistant t%$erc%losis9.5
Drug susceptibility tests 2 Dr%g s%sceti$ility testing is o! gro&ing imortance &ith emergence o!
increasingly resistant M. t%$erc%losis isolates. Dr%g'resistant t%$erc%losis re!ers to M. t%$erc%losis
that is resistant to one o! the !irst'line antit%$erc%losis dr%gs: isoniaid, ri!amin, yrainamide,
or etham$%tol. M%ltidr%g'resistant t%$erc%losis 3MDR'TB5 re!ers to M. t%$erc%losis that is resistant to
at least isoniaid and ri!amin, and ossi$ly additional chemotherae%tic agents. E6tensively dr%g'
resistant TB 3DRTB5 re!ers to M. t%$erc%losis resistant to at least isoniaid and ri!amin as &ell as at
least one o! three inecta$le second'line dr%gs 3careomycin, @anamycin, and ami@acin5 and a
!l%oro(%inolone.
#n addition to the conventional methods to test M. t%$erc%losis dr%g s%sceti$ility, methods that rely
%tiliing a%tomated systems and KCR'$ased tests have $een develoed >+7,+?. #n a%tomatedsystems 3B)CTEC and the others5, gro&th detected $y the indicator system in dr%g'containing $roth
is interreted as resistance to the dr%g. ) colorimetric microlate'$ased )lamar Bl%e assay eval%ated
in Ker% !or 1 M. t%$erc%losis isolates &as comara$le &ith the B)CTEC dr%g's%sceti$ility test 377
to ercent5 >1?. The test is $ased on colorimetric determination o! an o6idation'red%ction indicator
dye resa%rin >1-?.
The microscoic o$servation dr%g s%sceti$ility 3M<D*5 test is another li(%id c%lt%re $ased dr%g'
s%sceti$ility test $ased on o$servation o! M. t%$erc%losis gro&th in li(%id $roth medi%m containing a
test dr%g. C%lt%re ali(%ots are e6amined daily via inverted light microscoy !or cording, a
characteristic gro&th attern o! M. t%$erc%losis $%t not non't%$erc%lo%s myco$acteria >1+?. )$sence o!
gro&th or cording indicates s%sceti$ility to the $roth test dr%g. #n an eval%ation o! 18 s%t%msamles %sing M<D*, a%tomated MBJBacT system, and LO&enstein'0ensen c%lt%re, sensitivity &as
7, 7, and 7 ercent, resectively and the median time to the test res%lts &as 8, ++, and 7 days,
resectively >11?. The agreement $et&een M<D* and the re!erence tests !or s%sceti$ility &as high
!or all standard anti't%$erc%losis dr%gs.
Line'ro$e assays 3s%ch as #nnoLiK) and enoTyeMTBDR5 are gene ro$e assays to detect dr%g'
resistant M. t%$erc%losisA these com$ine hy$ridiation assays and a n%cleic acid amli!ication test,
s%ch as KCR. The KCR target is the M. t%$erc%losis roB geneA m%tation o! this gene is associated
&ith ri!amin resistance, &hich is %sed as a s%rrogate !or m%ltidr%g resistance 3ri!amin
monoresistance is %ncommon5. Meta'analyses o! these assays have noted high sensitivity and
seci!icity !or ri!amin resistance o! c%lt%re isolates 3P= ercent5 >1,1=?. *ensitivity decreases !ordirect clinical secimens, s%ch as s%t%m. Res%lts can $e o$tained the same day i! the test is
er!ormed on isolated M. t%$erc%losis, or i! the clinical secimen 3eg, s%t%m5 contained a large
n%m$er o! the t%$ercle $acilli.
The ert MTBJR#F is an integrated system that com$ines samle rearation in a mod%lar cartridge
system and real'time KCR. #n +- this techni(%e &as recommended $y the WH< to $e %sed in lace
o! traditional smear microscoy !or diagnosis dr%g'resistant TB or TB in H#4'in!ected atients >1?.
3*ee 9Diagnosis o! %lmonary t%$erc%losis in H#4'negative atients9.5
#n vario%s validation st%dies in $oth develoed and develoing co%ntries, this test has $een sho&n to
have a sensitivity o! P7 ercent in s%t%m smear'ositive TB cases and 8= to ercent in smear'
negative TB cases >18'1?. The sensitivity in the detection o! ri!amin'resistant M. t%$erc%losis
e6ceeded 8 ercent, &hile seci!icity ranged 7 to - ercent in di!!erentiating TB or ri!amin'
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resistant TB. The test can yield res%lts in less than t&o ho%rs >18'1?. Here, ri!amin resistance is
assessed as a s%rrogate !or m%ltidr%g'resistant M. t%$erc%losis.
Myco$acteriohages carrying reorter l%ci!erase have $een eval%ated !or the detection and
s%sceti$ility testing o! M. t%$erc%losis. #n an eval%ation o! = isolates in Me6ico, the overall
agreement &ith the B)CTEC method &as 7.= ercent >?. "sing the c%lt%red organisms, themedian s%sceti$ility t%rnaro%nd time &as t&o days 3- days &ith B)CTEC5. ) KCR'$ased method
%sing molec%lar $eacons 3!l%orogenic reorter molec%les5 is a romising raid method to detect dr%g'
resistant strains o! M. t%$erc%losis >-?. Ho&ever, these methods are not clinically availa$le d%e to
cost and sta$ility o! the reagents.
)nother myco$acteriohage'$ased system relies on the a$ility o! hage to in!ect M. t%$erc%losis
resent in a s%t%m samle >+?. #n this test, decontaminated s%t%m samles are inc%$ated &ith a
s%sension o! target'seci!ic $acteriohage. The hage relicates &ithin the in!ected $acilli, i!
resent, and lyses them. The s%sension containing released hages is inc%$ated &ith !ast gro&ing,
non'athogenic myco$acteria 3M. smegmatis5 heler cells on an agar late. The released
myco$acteriohages in!ect, relicate, and lyse these heler cells to !orm clear ones 3la(%es5 o! celllysis, &hich indicate the resence o! M. t%$erc%losis in the original secimen. #! this assay is done in
the resence o! an antimicro$ial agent, the resence o! la(%es s%ggests dr%g resistance o! the
organism resent in the clinical secimen. ) meta'analysis o! -1 st%dies eval%ating
myco$acteriohage'$ased tests demonstrated that the tests had high seci!icity 371 to - ercent5
$%t varia$le sensitivity 3+- to 77 ercent5 comared to c%lt%re >1'=?.
enome 2 The comlete genome se(%ence o! M. t%$erc%losis strain H18Rv has $een determined
and is annotated 3&&&.sanger.ac.%@JKroectsJMQt%$erc%losisJ 5 >?. The !ollo&ing characteristics have
$een descri$ed:
;The genome has ,--,=+ $ase airs, containing a$o%t , genes, &ith a C content o!
=. ercent.
;Consistent &ith the recognied str%ct%re o! its cell enveloe, many genes are devoted to liid
$iosynthesis and meta$olism.
;The organism contains liid and oly@etide $iosynthetic enymes that are normally !o%nd in
mammals and lants, and a$o%t += enymes involved in !atty acid degradation.
;#t has only -- comlete airs o! t&o'comonent reg%latory systems, as oosed to more than
1 s%ch airs in organisms li@e E. coli.
)ro6imately - ercent o! the genes in M. t%$erc%losis are devoted to the rod%ction o! t&o !amilies
o! glycine'rich roteins called KE 3roline'gl%tamine moti!s5 and KKE 3roline'roline'gl%tamine
moti!s5. These genes are comosed o! olymorhic C'rich reetitive se(%ences 3KR*s5 and maor
olymorhic tandem reeats, &hich have served as a $asis !or strain'tying M. t%$erc%losis clinical
isolates >8,7?. The !%nctions o! these !amilies o! roteins are %n@no&n. Ho&ever,
the KEJKR* genes in Myco$acteri%m marin%m, the ca%se o! !ish and amhi$ian t%$erc%losis, are
re!erentially e6ressed inside gran%lomas and macrohages >?.
+A"#(E'ES&S 2 ) variety o! aroaches to st%dy M. t%$erc%losis vir%lence have $een devised,
incl%ding those e6amining M. t%$erc%losis vir%lence !actors, $acterial !actors associated &ith
intracell%lar s%rvival, and genotyic di!!erences in the comm%nity revalence o! clinical strains.
-irulence factors 2 The !ollo&ing M. t%$erc%losis rod%cts &ere descri$ed as vir%lence !actors rior
to the introd%ction o! molec%lar $iology tools to st%dy M. t%$erc%losis >='==?:
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lyases - and + 3#CL-J+5, &hich allo& the %tiliation o! !atty acids as a sole car$on so%rce >,8?.
3*ee 9#mm%nology o! t%$erc%losis9.5
The M. t%$erc%losis cell &all contains three classes o! mycolic acids: alha, @eto, and metho6y
mycolates. The relative comosition o! o6ygenated mycolates in!l%ences gro&th o! M. t%$erc%losis
inside macrohages and in vivo >7?. )n M. t%$erc%losis m%tant lac@ing trans cycloroane rings3cma)+ m%tant5 in its metho6y and @eto'mycolic acids $ecomes hyervir%lent in the mo%se model o!
in!ection >?. <n the other hand, another cycloroane synthase gene m%tant 3ca)5 lac@ing cis
cycloroane rings in its alha'mycolates is atten%ated >8?. <ther liid molec%les sho&n to have an
e!!ect on innate and adative imm%ne resonse incl%des lioglycans, s%l!oliids, and hthiocerol
dimycocerosate >==,8-'81?.
"se o! signat%re'tagged transoson m%tagenesis to create M. t%$erc%losis m%tants has identi!ied
several candidate genes associated &ith vir%lence in the mo%se modelA these have incl%ded genes
encoding rotein secretion systems >8? as &ell as rod%cts involved in liid $iosynthesis >8=?. M.
t%$erc%losis secretion systems incl%de:
;The E*'- system, a secretion system involved in the secretion o! imm%nodominant roteins
E*)T' and CFK'-, has $een sho&n to romote escae o! M. t%$erc%losis into the cytolasm
>8,8,88?. This secretion system is encoded $y an M. t%$erc%losis chromosome loc%s called the
region o! di!!erence 3RD'-5. RD'- gene m%tants o! M. t%$erc%losis demonstrate macrohage
gro&th atten%ation in mice >87,8?. #n addition, the RD'- loc%s is a$sent in all BC vaccine
strains, &hich is $elieved to $e the $asis !or the atten%ation o! BC. E*'- homolog%es have
$een identi!ied in other athogenic and nonathogenic $acteria, and its role in athogenesis is
not !%lly %nderstood.
;*ec secretion system 3also called the general secretion ath&ay5, &hich is an essential
secretion ath&ay !o%nd in all $acterial secies.
;The t&in arginine transorter 3T)T5, &hich translocates across the lasma mem$rane roteins%$strates &ith do%$le arginine resid%es at the N'termin%s. #ts role in athogenesis in
Myco$acteria is not certain, $%t the same system !o%nd in other athogens, s%ch as
Kse%domonas aer%ginosa, enterohemorrhagic E. coli, Legionella ne%mohila, is re(%ired !or
vir%lence >7'7+?.
Factors associated $ith intracellular surial 2 #n mice, M. t%$erc%losis can $e o$served inside
alveolar macrohages and dendritic cells in the l%ngs - days a!ter aerosol in!ection >71?. M.
t%$erc%losis enters these cells a!ter $inding to a variety o! recetors on these cells, incl%ding C'tye
lectin recetors 3mannose recetor, DC'*#N5, scavenger recetors, and comlement recetors > 7?.
#t is $elieved that the engagement o! certain recetors can determine the intracell%lar !ate o! M.
t%$erc%losis.
#n addition, M. t%$erc%losis liids, incl%ding lioara$inomannan, liomannans, hoshatidylinositol
mannosides, and a -'@dal liorotein, are considered athogen'associated molec%lar attern
3K)MK5 molec%les recognied $y toll'li@e recetor + 3TLR'+5 >7=,7?. Engagement o! these ligands $y
TLR'+ on macrohages ind%ces a roin!lammatory resonse, incl%ding the e6ression o! t%mor
necrosis !actor 3TNF'a5, interle%@in 3#L'5, #L'-$, and #L'-+ >8-,78?. TLR' may also engage M.
t%$erc%losis K)MKs >77,7?. Di!!erent clinical strains o! M. t%$erc%losis have $een sho&n to ind%ce
distinct atterns o! roin!lammatory resonse a!ter engaging these recetors on macrohages, &hich
may determine the clinical o%tcome o! an in!ection >?.
<nce inside the hagosomal comartment, M. t%$erc%losis may inhi$it the mat%ration o! the
hagosome. Khagosomal mat%ration re(%ires conversion o! Ra$= into TK'$o%nd Ra$8 and thegeneration o! hoshatidylinositol 1'hoshate 3K#1K5 in the hagosomal mem$rane >-,+?. M.
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t%$erc%losis rod%cts can inhi$it these rocesses >1,?. Th%s, !rom the very early hase o! in!ection,
M. t%$erc%losis can initiate control o! its intracell%lar !ate.
<nce M. t%$erc%losis esta$lishes an in!ection, another imortant athogenic !eat%re is the a$ility o!
the organism to esta$lish latent in!ection, &hich can then give rise to reactivation disease. *ince
reactivation t%$erc%losis is the most common !orm o! the disease, $acterial !actors associated &ithlatency are considered imortant vir%lence !actors.
#n the -=s and -s, investigators develoed a mo%se model to st%dy latency >='8?. Mice &ere
intraveno%sly in!ected &ith M. t%$erc%losis and immediately treated &ith isoniaid 3#NH5
and yrainamide !or -+ &ee@s. C%lt%res o! the animal tiss%es !or % to si6 &ee@s !ollo&ing
comletion o! the treatment &ere negative, $%t nearly one'third o! the animals develoed TB a!ter
a$o%t -+ &ee@s and t&o'thirds develoed disease a!ter a$o%t + &ee@s. #t is not clear ho&
reresentative this model is !or latent M. t%$erc%losis in!ection in h%mans. *everal variants o! this
model @no&n as the Cornell model have $een eval%ated >7?. The model is highly deendent on the
arameters %sed to esta$lish latency and each version o! the model has its o&n set o! limitations.
)n in vitro model has $een develoed that mimics the hysiologic state o! M. t%$erc%losis d%ring
latency in vivo >?. When M. t%$erc%losis is gro&n %nder microaerohilic conditions, a state called
nonrelicating, ersistent 3NRK-5 is rod%ced and glycine dehydrogenase activity is ind%ced. #n
contrast, gro&th %nder anaero$ic conditions rod%ces a state called NRK+ in &hich glycine
dehydrogenase activity decreases, $%t the organism still s%rvives as long as the loss o! o6ygen
occ%rred slo&ly and it assed thro%gh the NRK- stage !or a eriod o! time. When o6ygen is
reintrod%ced to organisms gro&n anaero$ically, the athogen goes o%t o! the NRK+ state. *%ch an in
vitro system co%ld otentially $e %sed to e6amine di!!erential gene e6ression and th%s to identi!y
$acterial !actors seci!ically re(%ired %nder these gro&th conditions.
Bacterial s%rvival in stationary hase gro&th can $e %sed as an in vitro model !or st%dying intracell%lar
ersistence. ) sigma !actor gene sigF has $een identi!ied in M. t%$erc%losis > -?. This gene is a
homolog%e o! alternate sigma !actor gene 3ro*5, &hich is imortant !or stationary hase s%rvival o! E.
coli and *almonella s. #n M. t%$erc%losis, sigF is e6ressed d%ring stationary hase, nitrogen
deletion, and cold shoc@, $%t not d%ring e6onential hase gro&th.
<ne st%dy identi!ied at least seven roteins seci!ically e6ressed d%ring the stationary hase gro&th
o! M. t%$erc%losisA the redominant e6ressed rotein &as an alha'crystallin'li@e heat shoc@ rotein
3acr5 >--?. )cr transcrit &as also ind%ced in M. t%$erc%losis inside macrohagesA acr gene
relacement $y homologo%s recom$ination in M. t%$erc%losis H18Rv led to imaired gro&th o! the
organism inside mo%se $one marro&'derived macrohages >-+?. Th%s, acr aears to $e imortant
!or intracell%lar s%rvival and relication. *ince alha'crystallin heat shoc@ rotein is !o%nd in a variety
o! cell tyes, its seci!ic role in the o$served henotye o! M. t%$erc%losis needs !%rther el%cidation.
*everal investigators have reorted that isocitrate lyase 3icl5, an enyme essential !or !atty acid
meta$olism, is seci!ically %reg%lated d%ring gro&th o! M. t%$erc%losis inside macrohages
>,-1,-?. There are t&o icl genes in M. t%$erc%losisA the redicted roteins are +8 ercent
identical. #n a mo%se model o! M. t%$erc%losis in!ection, deletion o! $oth icl genes led to comlete
imairment o! intracell%lar relication and raid elimination o! the do%$le m%tant !rom the l%ngs >-=?.
The a$ove st%dies s%ggest that $acterial latency is associated &ith a hyo6ic state in the host. "sing
a &hole genome microarray, a large n%m$er o! genes that are ind%ced %nder de!ined hyo6ic
conditions &ere identi!ied >-?. <ne o! these genes &as !o%nd to $e a transcritional reg%lator
involved in the ind%ction o! acr, dosR >-8?. Whether dosR is essential !or M. t%$erc%losis to esta$lishlatent in!ection or is merely a 9ho%se@eeing9 stress resonse reg%lator !or the $acill%s to resond to
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a hyo6ic condition has yet to $e determined. The dosR genes are also resent in non't%$erc%lo%s
myco$acteria 3NTM5 and may contri$%te to the cross rotection against TB a!!orded $y rior NTM
in!ection >-7?.
M. t%$erc%losis has a artic%lar redilection !or the l%ngs. #n imm%nocometent mice, vir%lent strains
o! M. t%$erc%losis gro& rogressively in the l%ngs $%t not in the sleen or liver > -?. Even in severecom$ined imm%node!icient 3*C#D5 mice, M. $ovis BC 3a relatively avir%lent 3vaccine5 strain5 gro&s
!aster in the l%ngs than in other organs >--?. #n the mo%se model, !e&er organisms are re(%ired to
esta$lish a l%ng lesion $y the inhalation than $y intraveno%s challenge >-?. None o! the other
athogenic Myco$acteri%m secies aears to share this tiss%e troism. The !actors associated &ith
M. t%$erc%losis that !acilitate this %ni(%e characteristic are %n@no&n.
Differences in irulence of clinical isolates 2 enotying o! M. t%$erc%losis isolates has
demonstrated a n%m$er o! clades that acco%nt !or a large roortion o! ne& TB cases in di!!erent
geograhic regions, s%ggesting that s%ch strains may $e more vir%lent than others. M. t%$erc%lo%s
lineages have $een associated &ith clinical mani!estations o! disease. #n one st%dy, !or e6amle, East
)sian lineage &as less li@ely to $e associated &ith e6tra%lmonary t%$erc%losis than E%ro')merican,#ndo'<ceanic, or East')!rican #ndian lineage >---?. #mroved %nderstanding o! the role o! MTB
lineages may rovide insights into athogenicity, in!ectio%sness, rogression !rom in!ection to active
disease, and, erhas, resonse to treatment.
The W'Beiing !amily o! M. t%$erc%losis strains has a glo$al distri$%tion and aears to have a
selective advantage !acilitating raid e6ansion in regions &ith high $ac@gro%nd TB incidence > --+'
--?. The $iological reasons !or this o$servation are not !%lly %nderstood. These strains have $een
doc%mented to ca%se o%t$rea@s involving m%ltidr%g resistant organisms, altho%gh in some regions the
maority o! W'Beiing strains remain dr%g s%sceti$le >--='--8?. M. t%$erc%losis Beiing genotye
strains aear caa$le o! &ithstanding t%$erc%losis treatment, even in the a$sence o! dr%g resistance
>--7?. W'Beiing strains have $een associated &ith e6trathoracic disease and H#4 in!ection, altho%gh itis not clear &hether H#4 in!ection has contri$%ted to the emergence o! these strains >--,--,-+?. #n
e6erimental animal models, these strains &ere highly vir%lent and BC vaccination &as not
rotective >-+-'-+1?.
)nother strain called CB1.1 ca%sed over - ercent o! ne& TB cases in Ne& Sor@ City $et&een -+
and - >-+?. This strain &as !o%nd to $e resistant to reactive nitrogen intermediates 3RN#5
generated in vitro $y acidi!ied sodi%m nitrite >-+?. ) strain called CDC-==-, also !o%nd to $e resistant
to RN# and reactive o6ygen intermediates 3R<#5, ca%sed a large o%t$rea@ in a r%ral area near the
Ient%c@y'Tennessee $order in -' >-+=,-+?.
)nother strain called K, resonsi$le !or a large cl%ster o! TB cases in one northern Cali!ornia
comm%nity, &as not resistant to these e!!ector molec%les. #nstead, in mice this strain rod%ced
relatively mild l%ng disease, in &hich loosely organied gran%lomas aarently !ailed to limit the
sread o! in!ection and allo&ed the escae o! M. t%$erc%losis into alveolar air saces >-+8?. This
st%dy s%ggested that an M. t%$erc%losis strain that ca%ses mild l%ng disease may allo& individ%als
&ith s%$clinical disease more time to sread in!ection in the o%lation. There!ore, s%ch strains &o%ld
$e overly reresented in a comm%nity. This demonstrates that the redominance o! an M. t%$erc%losis
strain in a comm%nity is not necessarily a mar@er o! enhanced athogenicity 3eg, transmissi$ility is not
e(%ivalent to vir%lence5.
) large school o%t$rea@ in the "nited Iingdom &as ca%sed $y an M. t%$erc%losis strain called CH in
+-. )mong += ne&ly'in!ected children, 88 develoed active disease &ithin a year o! e6os%re
>-+7?.
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The reasons &hy some lineages ca%se large o%t$rea@s o! raidly rogressive disease and others
ca%se reactivation t%$erc%losis are oorly %nderstood.
The $iological !itness costU o! dr%g'resistant M. t%$erc%losis may $e in!l%enced $y comensatory
m%tations. Krevio%sly, an e6erimental model sho&ed that ri!amin resistance in M. t%$erc%losis &as
associated &ith cometitive !itness cost and that resistant isolates !rom atients &ith rolongedtreatment e6hi$ited no !itness cost >-+?. Ho&ever s%$se(%ently many clinical m%ltidr%g'resistant
strains have $een sho&n to have m%tations in the RN) olymerase gene associated &ith high
cometitive !itness in vitro and high !itness in vivo >-1?. #n regions o! the &orld &ith a high revalence
o! MDR TB, % to 1 ercent o! their MDR isolates had s%ch m%tations > -1?.
#(S" FAC"(RS
enetic susceptibility to infection 2 enetic analysis o! si$ling airs has $een %sed to eval%ate
%tative genetic mar@ers !or enhanced s%sceti$ility to t%$erc%losis 3TB5 in o%lations in )!rica > -1-?.
Kossi$le mar@ers on chromosomes -=( and ( &ere identi!iedA the investigators sec%late that
!inding a s%sceti$ility gene on an chromosome may artially e6lain the increased incidence o! TB
in males in some o%lations.
#n a mo%se model, a loc%s on chromosome - &as !o%nd to reg%late relication o! M. t%$erc%losis in
the l%ngs o! DB)J+ mice that die raidly o! TB comared to C=8BLJ mice that are more resistant to
in!ection >-1+?. #n a second st%dy in a mo%se model, a single iso!orm o! the intracell%lar athogen
resistance - gene 3#r-5 &as !o%nd to $e resonsi$le !or the increased resistance to M. t%$erc%losis
in!ection >-11?. Resistance &as characteried $y smaller l%ng lesions containing !e&er macrohages,
slo&er M. t%$erc%losis gro&th in macrohages, and death o! M. t%$erc%losis'in!ected macrohages
$y aotosis rather than necrosis.
The closest h%man homolog%e to lr- is *K--. ) st%dy o! !amilies !rom %inea'Bissa% and the
Re%$lic o! %inea, identi!ied three olymorhisms in the *K-- gene that are associated &iths%sceti$ility to t%$erc%losis >-1?.
Ac.uired susceptibility to infection 2 #nvestigators e6amined the inter!eron'gamma 3#FN'gamma5
resonse ath&ay in three atients &ith severe, %ne6lained nont%$erc%lo%s myco$acterial in!ection
>-1=?. #n all three atients, #FN'gamma &as %ndetecta$le !ollo&ing stim%lation o! &hole $lood, $%t &as
detecta$le &hen stim%lated in the a$sence o! the atientsG o&n lasma. )n a%toanti$ody against #FN'
gamma &as isolated !rom the atientsG lasma and &as !o%nd to $e caa$le o! $loc@ing the
%reg%lation o! TNF'alha rod%ction in resonse to endoto6in, in $loc@ing ind%ction o! #FN'gamma'
ind%ci$le genes, and in inhi$iting %reg%lation o! HL) class ## e6ression on eriheral $lood
monon%clear cells 3KBMCs5. These ac(%ired de!ects in the #FN'gamma ath&ay may e6lain %n%s%al
s%sceti$ilities to intracell%lar athogens, incl%ding myco$acteria, in atients &itho%t %nderlying,genetically determined imm%nologic de!ects.
)ll o! the host genes associated &ith TB s%sceti$ility acco%nt !or a tiny !raction o! all t%$erc%losis
cases identi!ied in the &orld. The most imortant host !actor that determines TB s%sceti$ility to TB is
H#4 co'in!ection, !ollo&ed $y other imm%nos%ressive conditions, incl%ding cancer, dia$etes, and
imm%nos%ressive medications. Environmental !actors, s%ch as cro&ding, lo& socioeconomic
stat%s, oor access to healthcare, and !amily history, also contri$%te s%$stantially to the incidence o!
TB &orld&ide, and these are imortant to %nderstanding TB athogenesis.
S)MMAR*
;#nhalation o! Myco$acteri%m t%$erc%losis and deosition in the l%ngs leads to one o! !o%rossi$le o%tcomes: immediate clearance o! the organism, raid rogression to active disease
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3rimary disease5, or latent in!ection 3&ith or &itho%t s%$se(%ent reactivation disease5.
3*ee GNat%ral history o! in!ectionGa$ove.5
;The cell enveloe is a disting%ishing !eat%re o! the organisms $elonging to the gen%s
Myco$acteri%m. Mycolic acid is the maor constit%ent o! the cell enveloeA this str%ct%re de!ines
the gen%s. The mycolic acid str%ct%re con!ers the a$ility to resist destaining $y acid alcohol a!ter
$eing stained $y certain aniline dyes, leading to the term acid !ast $acill%s. 3*ee GCell
enveloeG a$ove.5
;Microscoy to detect acid !ast $acill%s 3%sing iehl'Neelsen or Iinyo%n stain5 is a commonly
%sed roced%re !or the raid diagnosis o! t%$erc%losis 3TB5A a secimen m%st contain at least
-35 colony !orming %nits 3CF"5JmL to yield a ositive smear. Microscoy o! secimens stained
&ith a !l%orochrome dye 3s%ch as a%ramine < rovides5 is a more sensitive and e!!icient
techni(%e. Microscoic detection o! myco$acteria does not disting%ish M. t%$erc%losis !rom
nont%$erc%lo%s myco$acteria. 3*ee G*taining characteristicsG a$ove.5
;The slo& gro&th rate is a disting%ishing !eat%re o! M. t%$erc%losis. #n arti!icial media and
animal tiss%es, the generation time is a$o%t + to + ho%rs, &hich means that c%lt%res may ta@e
!rom t&o to si6 &ee@s !or detecta$le gro&th, deending on the c%ltivation systems %sed !orla$oratory isolation 3*ee G#solation in the la$oratoryG a$ove.5
;<nce the organism is isolated, identi!ication is $ased %on morhologic and $iochemical
characteristics, altho%gh n%cleic acid'$ased detection methods have o$viated many o! the
conventional tests. The niacin, nitrate red%ctase, and catalase tests are the three $iochemical
tests most !re(%ently %sed to disting%ish M. t%$erc%losis !rom other myco$acterial secies
3*ee G#denti!ication o! the organismG a$ove.5
;The !ollo&ing vir%lence !actors have $een descri$ed: mycolic acid glycoliids and trehalose
dimycolate 3&hich can elicit gran%loma !ormation in animal tiss%e5, catalase'ero6idase 3&hich
resists the host cell o6idative resonse5, s%l!atides and trehalose dimycolate 3&hich can trigger
to6icity in animal models5, and lioara$inomannan 3L)M5 3&hich can ind%ce cyto@ines and resisthost o6idative stress5. Molec%lar $iology techni(%es have identi!ied many other gene rod%cts
that may $e involved in the a$ility o! M. t%$erc%losis to enter cells, resist intracell%lar @illing,
esta$lish ersistence, and come o%t o! latency. 3*ee G4ir%lence !actorsG a$ove.5
;Eidemiologic st%dies have revealed a !e& @ey M. t%$erc%losis lineages to $e overly
reresented or cl%stered in certain comm%nities. *%ch occ%rrences may relate to these strainsV
distinct $iological !itnessU or transmissi$ility. 3*ee GDi!!erences in vir%lence o! clinical
isolatesG a$ove.5
"se o! "ToDate is s%$ect to the *%$scrition and License )greement.
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Micro$iol +8A =:.
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-+-. Manca C, Tsenova L, Freeman *, et al. Hyervir%lent M. t%$erc%losis WJBeiing strains%reg%late tye # #FNs and increase e6ression o! negative reg%lators o! the 0a@'*tat ath&ay. 0#nter!eron Cyto@ine Res +=A +=:.
-++. Tsenova L, Ellison E, Har$ache%s@i R, et al. 4ir%lence o! selected Myco$acteri%mt%$erc%losis clinical isolates in the ra$$it model o! meningitis is deendent on henolic glycoliidrod%ced $y the $acilli. 0 #n!ect Dis +=A -+:7.
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-+1. rode L, *eiler K, Ba%mann *, et al. #ncreased vaccine e!!icacy against t%$erc%losis o!recom$inant Myco$acteri%m $ovis $acille Calmette'%rin m%tants that secrete listeriolysin. 0 Clin#nvest +=A --=:+8+.
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