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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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. D%$os, R, D%$os, 0. The White Klag%e: T%$erc%losis, Man, and *ociety, Little, Bro&n, Boston-=+.

=. L%rie, MB. Resistance to T%$erc%losis: E6erimental *t%dies in Native and )c(%ired De!ense

Mechanisms, Harvard "niversity Kress, Cam$ridge -.

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--=.  )gerton TB, 4al&ay *E, Blin@horn R0, et al. *read o! strain W, a highly dr%g'resistant straino! Myco$acteri%m t%$erc%losis, across the "nited *tates. Clin #n!ect Dis -A +:7=.

--. Marais B0, 4ictor TC, Hesseling )C, et al. Beiing and Haarlem genotyes are

overreresented among children &ith dr%g'resistant t%$erc%losis in the Western Cae Krovince o!*o%th )!rica. 0 Clin Micro$iol +A :1=1.

--8. B%% TN, H%yen MN, van *oolingen D, et al. The Myco$acteri%m t%$erc%losis Beiinggenotye does not a!!ect t%$erc%losis treatment !ail%re in 4ietnam. Clin #n!ect Dis +-A =-:78.

--7. Kar&ati #, )lisah$ana B, )riani L, et al. Myco$acteri%m t%$erc%losis Beiing genotye is anindeendent ris@ !actor !or t%$erc%losis treatment !ail%re in #ndonesia. 0 #n!ect Dis +-A +-:==1.

--. Iong S, Cave MD, hang L, et al. )ssociation $et&een Myco$acteri%m t%$erc%losis BeiingJWlineage strain in!ection and e6trathoracic t%$erc%losis: #nsights !rom eidemiologic and clinicalcharacteriation o! the three rincial genetic gro%s o! M. t%$erc%losis clinical isolates. 0 Clin

Micro$iol +8A =:.

-+. Ca&s M, Th&aites , *tenie&s@a I, et al. Beiing genotye o! Myco$acteri%m t%$erc%losisis signi!icantly associated &ith h%man imm%node!iciency vir%s in!ection and m%ltidr%g resistance incases o! t%$erc%lo%s meningitis. 0 Clin Micro$iol +A :11.

-+-. 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+.

-+. Friedman CR, [%inn C, Ireis&irth BN, et al. Widesread dissemination o! a dr%g's%sceti$le strain o! Myco$acteri%m t%$erc%losis. 0 #n!ect Dis -8A -8:87.

-+=. 4al&ay *E, *anche MK, *hinnic@ TF, et al. )n o%t$rea@ involving e6tensive transmission o! avir%lent strain o! Myco$acteri%m t%$erc%losis. N Engl 0 Med -7A 117:11.

-+. Firmani M), Riley LW. Myco$acteri%m t%$erc%losis CDC-==- is resistant to reactive nitrogenand o6ygen intermediates in vitro. #n!ect #mm%n ++A 8:1=.

-+8. Cantrell *), Kascoella L, Flood 0, et al. Comm%nity'&ide transmission o! a strain o!Myco$acteri%m t%$erc%losis that ca%ses red%ced l%ng athology in mice. 0 Med Micro$iol +7A=8:+-.

-+7. Ne&ton *M, *mith R0, Wil@inson I), et al. ) deletion de!ining a common )sian lineage o!

Myco$acteri%m t%$erc%losis associates &ith imm%ne s%$version. Kroc Natl )cad *ci " * ) +A-1:-==.

-+. agne%6 *, Long CD, *mall KM, et al. The cometitive cost o! anti$iotic resistance inMyco$acteri%m t%$erc%losis. *cience +A 1-+:-.

-1. Comas #, Borrell *, Roeter ), et al. Whole'genome se(%encing o! ri!amicin'resistantMyco$acteri%m t%$erc%losis strains identi!ies comensatory m%tations in RN) olymerase genes. Natenet +-+A :-.

-1-. Bellamy R, Beyers N, Mc)dam IK, et al. enetic s%sceti$ility to t%$erc%losis in )!ricans: agenome'&ide scan. Kroc Natl )cad *ci " * ) +A 8:7=.

-1+. Mitsos LM, Cardon LR, Ryan L, et al. *%sceti$ility to t%$erc%losis: a loc%s on mo%sechromosome - 3Trl'5 reg%lates Myco$acteri%m t%$erc%losis relication in the l%ngs. Kroc Natl )cad*ci " * ) +1A -:-.

-11. Kan H, San B*, Roas M, et al. #r- gene mediates innate imm%nity to t%$erc%losis. Nat%re+=A 1:88.

-1. Tosh I, Cam$ell *0, Fielding I, et al. 4ariants in the *K-- gene are associated &ithgenetic s%sceti$ility to t%$erc%losis in West )!rica. Kroc Natl )cad *ci " * ) +A -1:-1.

-1=. Iammann B, Heming&ay C, *tehens ), et al. )c(%ired redisosition to myco$acterial

disease d%e to a%toanti$odies to #FN'gamma. 0 Clin #nvest +=A --=:+7.