Emergency Physicians, Obstetrician & Gynecologist (OB/GYN)
35 years of experience

Accepting new patients
1301 Pennsylvania Ave
Fort Worth, TX 76104
817-882-3331
Locations and availability (4)

Education ?

Medical School
Tulane University (1975)

Awards & Distinctions ?

Awards  
Castle Connolly Top Doctors: Texas™ (2009)

Affiliations ?

Dr. Cox is affiliated with 21 hospitals.

Hospital Affilations

Score

Rankings

  • Texas Health Presbyterian Hospital Plano
    6200 W Parker Rd, Plano, TX 75093
    • Currently 4 of 4 crosses
    Top 25%
  • Texas Health Harris Methodist Hospital Southwest Fort Worth
    6100 Harris Pkwy, Fort Worth, TX 76132
    • Currently 4 of 4 crosses
    Top 25%
  • Texas Health Harris Methodist Hospital Fort Worth
    1301 Pennsylvania Ave, Fort Worth, TX 76104
    • Currently 4 of 4 crosses
    Top 25%
  • Harris Methodist H E B
    1600 Hospital Pkwy, Bedford, TX 76022
    • Currently 4 of 4 crosses
    Top 25%
  • Texas Health Presbyterian Hospital Of Dallas
    8200 Walnut Hill Ln, Dallas, TX 75231
    • Currently 3 of 4 crosses
    Top 50%
  • Texas Health Harris Methodist Hospital Azle
    108 Denver Trl, Azle, TX 76020
    • Currently 3 of 4 crosses
    Top 50%
  • Harris Continued Care Hospital
    1301 Pennsylvania Ave, Fort Worth, TX 76104
  • Texas Health Southwest Fort Worth
  • Texas Health Plano
  • Northside Hospital
  • Texas Health Rockwall
  • Texas Health Fort Worth
  • Texas Health Azle
  • Presbyterian Hospital Of Rockwall
    3150 Horizon Rd, Rockwall, TX 75032
  • Presbyterian Dallas
  • Presbyterian Plano
  • Harris Methodist - Springwood
    1608 Hospital Pkwy, Bedford, TX 76022
  • Children`s Healthcare of Atlanta at Egleston
  • Texas Health Southwest
  • Texas Health Cleburne
  • Texas Health Dallas
  • Publications & Research

    Dr. Cox has contributed to 23 publications.
    Title Espr, a Key Regulator of Mycobacterium Tuberculosis Virulence, Adopts a Unique Dimeric Structure Among Helix-turn-helix Proteins.
    Date November 2011
    Journal Proceedings of the National Academy of Sciences of the United States of America
    Excerpt

    EspR is a transcriptional regulator that activates the ESX-1 secretion system during Mycobacterium tuberculosis infection and is critical for pathogenesis. It is unique among DNA-binding proteins as it is secreted as part of a feedback regulatory loop that serves to mitigate transcriptional activity. Here we report the crystal structure of a functional EspR dimer at 2.5-Å resolution. The amino-terminal half of EspR is a helix-turn-helix (HTH) DNA-binding domain and the carboxy terminus consists of a dimerization domain with similarity to the SinR:SinI sporulation regulator of Bacillus subtilis. Surprisingly, the HTH domains of EspR are arranged in an unusual conformation in which they are splayed at an oblique angle to each other, suggesting that EspR binds DNA in a profoundly different way than most other known HTH regulators. By mapping the EspR binding sites in the espACD promoter, using both in vivo and in vitro binding assays, we show that the EspR operators are located unusually far from the promoter. The EspR dimer binds to these sites cooperatively, but the two "half-sites" contacted by each DNA recognition motif are separated by 177 base pairs. The distinctive structure of EspR and the exceptional arrangement of its operator contacts suggest that it could promote DNA looping in its target promoter. We hypothesize that direct DNA looping mediated by single-site binding of each EspR monomer may facilitate transcriptional control of this important virulence system.

    Title Mycobacterium Tuberculosis Mycp1 Protease Plays a Dual Role in Regulation of Esx-1 Secretion and Virulence.
    Date May 2010
    Journal Cell Host & Microbe
    Excerpt

    Mycobacterium tuberculosis uses the ESX-1 secretion system to deliver virulence proteins during infection of host cells. Here we report a mechanism of posttranscriptional control of ESX-1 mediated by MycP1, a M. tuberculosis serine protease. We show that MycP1 is required for ESX-1 secretion but that, unexpectedly, genetic inactivation of MycP1 protease activity increases secretion of ESX-1 substrates. We demonstrate that EspB, an ESX-1 substrate required for secretion, is a target of MycP1 in vitro and in vivo. During macrophage infection, an inactive MycP1 protease mutant causes hyperactivation of ESX-1-stimulated innate signaling pathways. MycP1 is required for growth in mice during acute infection, while loss of its protease activity leads to attenuated virulence during chronic infection. As the key ESX-1 substrates ESAT-6 and CFP-10 are highly immunogenic, fine-tuning of their secretion by MycP1 may balance virulence and immune detection and be essential for successful maintenance of long-term M. tuberculosis infection.

    Title Systematic Genetic Nomenclature for Type Vii Secretion Systems.
    Date February 2010
    Journal Plos Pathogens
    Title Esx-1-dependent Cytolysis in Lysosome Secretion and Inflammasome Activation During Mycobacterial Infection.
    Date October 2008
    Journal Cellular Microbiology
    Excerpt

    Exocytosis of lysosomes from macrophages has been described as a response to microbial cytotoxins and haemolysins, as well as for releasing pro-inflammatory cytokines interleukin (IL)-1beta and IL-18 during inflammasome activation. The mycobacterial ESX-1 secretion system, encoded in part by the Region of Difference-1, is a virulence factor necessary for phagosome escape and host cell lysis by a contact-dependent haemolysin in Mycobacterium marinum. Here we show that ESX-1 from M. marinum and M. tuberculosis is required for Ca(2+)-dependent induction of lysosome secretion from macrophages. Mycobacteria-induced lysosome secretion was concurrent to release of IL-1beta and IL-18, dependent on phagocytosis of bacteria containing ESX-1. Synthesis but not release of IL-1beta and IL-18 occurred in response to dead bacilli and bacteria lacking ESX-1, indicating that only cytokine release was regulated by ESX-1. Release of these cytokines and exocytosis of lysosomes were independent of intracellular mycobacterial growth, yet correlated with mycobacteria-encoded haemolytic activity, demonstrating a parallel pathway for the two responses. We further identified inflammasome components caspase-1, ASC and NALP3, but not Ipaf, required for release of IL-1beta and IL-18. Collectively, these results reveal a role for ESX-1 in triggering secretion of lysosomes, as well as release of IL-1beta and IL-18 during mycobacteria infection.

    Title Mycobacterium Tuberculosis Senses Host-derived Carbon Monoxide During Macrophage Infection.
    Date July 2008
    Journal Cell Host & Microbe
    Excerpt

    Mycobacterium tuberculosis (MTB) expresses a set of genes known as the dormancy regulon in vivo. These genes are expressed in vitro in response to nitric oxide (NO) or hypoxia, conditions used to model MTB persistence in latent infection. Although NO, a macrophage product that inhibits respiration, and hypoxia are likely triggers in vivo, additional cues could activate the dormancy regulon during infection. Here, we show that MTB infection stimulates expression of heme oxygenase (HO-1) by macrophages and that the gaseous product of this enzyme, carbon monoxide (CO), activates expression of the dormancy regulon. Deletion of macrophage HO-1 reduced expression of the dormancy regulon. Furthermore, we show that the MTB DosS/DosT/DosR two-component sensory relay system is required for the response to CO. Together, these findings demonstrate that MTB senses CO during macrophage infection. CO may represent a general cue used by pathogens to sense and adapt to the host environment.

    Title Role for Lysosomal Enzyme Beta-hexosaminidase in the Control of Mycobacteria Infection.
    Date February 2008
    Journal Proceedings of the National Academy of Sciences of the United States of America
    Excerpt

    The pathogenic mycobacteria that cause tuberculosis (TB) and TB-like diseases in humans and animals elude sterilizing immunity by residing within an intracellular niche in host macrophages, where they are protected from microbicidal attack. Recent studies have emphasized microbial mechanisms for evasion of host defense; less is known about mycobactericidal mechanisms that remain intact during initial infection. To better understand macrophage mechanisms for restricting mycobacteria growth, we examined Mycobacterium marinum infection of Drosophila S2 cells. Among approximately 1,000 host genes examined by RNAi depletion, the lysosomal enzyme beta-hexosaminidase was identified as an important factor in the control of mycobacterial infection. The importance of beta-hexosaminidase for restricting mycobacterial growth during mammalian infections was confirmed in macrophages from beta-hexosaminidase knockout mice. Beta-hexosaminidase was characterized as a peptidoglycan hydrolase that surprisingly exerts its mycobactericidal effect at the macrophage plasma membrane during mycobacteria-induced secretion of lysosomes. Thus, secretion of lysosomal enzymes is a mycobactericidal mechanism that may have a more general role in host defense.

    Title A Mycobacterium Esx-1-secreted Virulence Factor with Unique Requirements for Export.
    Date September 2007
    Journal Plos Pathogens
    Excerpt

    Specialized secretion systems of pathogenic bacteria commonly transport multiple effectors that act in concert to control and exploit the host cell as a replication-permissive niche. Both the Mycobacterium marinum and the Mycobacterium tuberculosis genomes contain an extended region of difference 1 (extRD1) locus that encodes one such pathway, the early secretory antigenic target 6 (ESAT-6) system 1 (ESX-1) secretion apparatus. ESX-1 is required for virulence and for secretion of the proteins ESAT-6, culture filtrate protein 10 (CFP-10), and EspA. Here, we show that both Rv3881c and its M. marinum homolog, Mh3881c, are secreted proteins, and disruption of RD1 in either organism blocks secretion. We have renamed the Rv3881c/Mh3881c gene espB for ESX-1 substrate protein B. Secretion of M. marinum EspB (EspBM) requires both the Mh3879c and Mh3871 genes within RD1, while CFP-10 secretion is not affected by disruption of Mh3879c. In contrast, disruption of Mh3866 or Mh3867 within the extRD1 locus prevents CFP-10 secretion without effect on EspBM. Mutants that fail to secrete only EspBM or only CFP-10 are less attenuated in macrophages than mutants failing to secrete both substrates. EspBM physically interacts with Mh3879c; the M. tuberculosis homolog, EspBT, physically interacts with Rv3879c; and mutants of EspBM that fail to bind Mh3879c fail to be secreted. We also found interaction between Rv3879c and Rv3871, a component of the ESX-1 machine, suggesting a mechanism for the secretion of EspB. The results establish EspB as a substrate of ESX-1 that is required for virulence and growth in macrophages and suggests that the contribution of ESX-1 to virulence may arise from the secretion of multiple independent substrates.

    Title Nippostrongylus Brasiliensis: Identification of Intelectin-1 and -2 As Stat6-dependent Genes Expressed in Lung and Intestine During Infection.
    Date July 2007
    Journal Experimental Parasitology
    Excerpt

    Elimination of the helminth parasite Nippostrongylus brasiliensis from infected mice is mediated by IL-4 or IL-13 and dependent on the IL-4Ralpha chain and the transcription factor Stat6 in non-hematopoietic cells. However, it is not clear which Stat6-dependent effector molecules mediate worm expulsion. We identified intelectin-1 and -2 as Stat6-dependent genes that are induced during infection. Intelectins can bind galactofuranose, a sugar present only in microorganisms and might therefore serve as microbial pattern element. To analyze whether constitutive expression of intelectin-1 or -2 leads to accelerated pathogen clearance, transgenic mice were generated which express high levels of these genes selectively in the lung. Infection with N. brasiliensis or Mycobacterium tuberculosis did not result in accelerated pathogen clearance in transgenic as compared to wild-type mice. Further, no significant modulation of the immune response in lung or lymph nodes was observed. Thus, under these conditions, intelectins did not enhance pathogen clearance.

    Title Twenty-six-year Results After Broström Procedure for Chronic Lateral Ankle Instability.
    Date October 2006
    Journal The American Journal of Sports Medicine
    Excerpt

    BACKGROUND: The procedure described by Broström has been used to address chronic lateral ankle instability; the long-term results of this procedure have not been reported. HYPOTHESIS: The Broström procedure provides good results over the long term for active patients with chronic lateral ankle instability. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Thirty-one male patients (32 ankles) who underwent the Broström procedure for chronic lateral ankle instability while enrolled as students at the United States Naval Academy were identified. Each patient was mailed a questionnaire that included a functional outcome measure as described by Roos et al, a score described by Good et al, and a single-number ankle functional assessment. The mean age was 20.7 years (range, 18-23 years) at the time of operation. A functional outcome score was completed on each patient, with a mean follow-up of 26.3 years (range, 24.6-27.9 years). RESULTS: The follow-up included 22 of the 31 original patients. The mean numeric score for overall ankle function was 91.2 of 100 (standard deviation, 10.2). The foot and ankle outcome score (described by Roos et al) was 92.0 (92%; standard deviation, 12.8) averaged over 5 functional areas. Ninety-one percent of the patients described their ankle function as good or excellent using the scale devised by Good et al. CONCLUSION: The long-term results of the Broström procedure for chronic lateral ankle instability are excellent with 26-year follow-up.

    Title The Modified Bristow Procedure for Anterior Shoulder Instability: 26-year Outcomes in Naval Academy Midshipmen.
    Date October 2006
    Journal The American Journal of Sports Medicine
    Excerpt

    BACKGROUND: Many procedures have been proposed for the correction of anterior shoulder instability. Some of these procedures address the problem anatomically, such as the Bankart procedure, and some prevent instability nonanatomically, such as the Bristow-Latarjet procedure. A modified Bristow procedure was the procedure of choice for anterior shoulder instability among midshipmen at the United States Naval Academy from 1975 to 1979. HYPOTHESIS: The modified Bristow procedure for anterior shoulder instability provides good shoulder function and stability in the long term. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: There were 52 shoulders in 49 patients reviewed at a mean follow-up of 26.4 years. The Rowe score, Single Assessment Numeric Evaluation, and Western Ontario Shoulder Instability Index were used to assess outcomes. RESULTS: The mean Rowe score was 81.8 (range, 5-100), and the mean Single Assessment Numeric Evaluation score was 82.9 (range, 30-100), with an overall Single Assessment Numeric Evaluation of 71.2% (37 of 52 shoulders) rated as good and excellent. The mean Western Ontario Shoulder Instability Index was 376 of 2100 (range, 0-1560). Overall, recurrent instability occurred in 8 of 52 shoulders (15.4%), with recurrent dislocation in 5 shoulders (9.6%) and recurrent subluxation in 3 shoulders (5.8%). The mean time to recurrent dislocation was 7.0 years. CONCLUSION: This study represents the longest follow-up in the literature of the modified Bristow procedure. The authors have shown nearly 70% good and excellent results and recurrent instability comparable with other long-term follow-up studies of open instability procedures.

    Title C-terminal Signal Sequence Promotes Virulence Factor Secretion in Mycobacterium Tuberculosis.
    Date September 2006
    Journal Science (new York, N.y.)
    Excerpt

    Mycobacterium tuberculosis uses the ESX-1/Snm system [early secreted antigen 6 kilodaltons (ESAT-6) system 1/secretion in mycobacteria] to deliver virulence factors into host macrophages during infection. Despite its essential role in virulence, the mechanism of ESX-1 secretion is unclear. We found that the unstructured C terminus of the CFP-10 substrate was recognized by Rv3871, a cytosolic component of the ESX-1 system that itself interacts with the membrane protein Rv3870. Point mutations in the signal that abolished binding of CFP-10 to Rv3871 prevented secretion of the CFP-10 (culture filtrate protein, 10 kilodaltons)/ESAT-6 virulence factor complex. Attachment of the signal to yeast ubiquitin was sufficient for secretion from M. tuberculosis cells, demonstrating that this ESX-1 signal is portable.

    Title Long-term Evaluation of the Roux-elmslie-trillat Procedure for Patellar Instability: a 26-year Follow-up.
    Date August 2005
    Journal The American Journal of Sports Medicine
    Excerpt

    BACKGROUND: Few published articles exist reporting the long-term evaluation of the Roux-Elmslie-Trillat procedure. PURPOSE: To assess the long-term effect of the Roux-Elmslie-Trillat procedure in preventing recurrent subluxation and dislocation of the patella. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Eighteen patients who underwent the Roux-Elmslie-Trillat procedure for dislocation or subluxation of the patella were identified from a group previously evaluated at a mean follow-up of 3 years. The prevalence of recurrent subluxation or dislocation at a mean follow-up of 26 years was compared with the prevalence reported at the mean follow-up of 3 years. Although not the focus of this study, Cox functional scores were obtained from the smaller group and compared with the results at the 3-year follow-up. RESULTS: Seven percent (95% confidence interval, 0.00-0.32) of the patients had recurrent subluxation at 26 years compared with 7% (95% confidence interval, 0.03-0.13) of the study population reported at 3 years (P = 1.00). Fifty-four percent (95% confidence interval, 0.27-0.79) rated their affected knee as good or excellent at 26 years compared with 73% (95% confidence interval, 0.64-0.81) of the larger study population reported at 3 years (P = .14). CONCLUSION: The prevalence of recurrent subluxation and dislocation in patients with patellofemoral malalignment who underwent the Roux-Elmslie-Trillat procedure for dislocation or subluxation of the patella is similar at 3 and 26 years after the procedure. The long-term functional status of the affected knee in patients who underwent the Roux-Elmslie-Trillat procedure declined.

    Title Identification of Mycobacterium Tuberculosis Counterimmune (cim) Mutants in Immunodeficient Mice by Differential Screening.
    Date September 2004
    Journal Infection and Immunity
    Excerpt

    Tuberculosis (TB) is characterized by lifetime persistence of Mycobacterium tuberculosis. Despite the induction of a vigorous host immune response that curtails disease progression in the majority of cases, the organism is not eliminated. Subsequent immunosuppression can lead to reactivation after a prolonged period of clinical latency. Thus, while it is clear that protective immune mechanisms are engaged during M. tuberculosis infection, it also appears that the pathogen has evolved effective countermechanisms. Genetic studies with animal infection models and with patients have revealed a key role for the cytokine gamma interferon (IFN-gamma) in resistance to TB. IFN-gamma activates a large number of antimicrobial pathways. Three of these IFN-gamma-dependent mechanisms have been implicated in defense against M. tuberculosis: inducible nitric oxide synthase (iNOS), phagosome oxidase (phox), and the phagosome-associated GTPase LRG-47. In order to identify bacterial genes that provide protection against specific host immune pathways, we have developed the strategy of differential signature-tagged transposon mutagenesis. Using this approach we have identified three M. tuberculosis genes that are essential for progressive M. tuberculosis growth and rapid lethality in iNOS-deficient mice but not in IFN-gamma-deficient mice. We propose that these genes are involved in pathways that allow M. tuberculosis to counter IFN-gamma-dependent immune mechanisms other than iNOS.

    Title Acute Infection and Macrophage Subversion by Mycobacterium Tuberculosis Require a Specialized Secretion System.
    Date January 2004
    Journal Proceedings of the National Academy of Sciences of the United States of America
    Excerpt

    Although many bacterial pathogens use specialized secretion systems for virulence, no such systems have been described for Mycobacterium tuberculosis, a major pathogen of humans that proliferates in host macrophages. In a screen to identify genes required for virulence of M. tuberculosis, we have discovered three components and two substrates of the first Sec-independent secretion pathway described in M. tuberculosis, which we designate the Snm pathway. Here we demonstrate that the proteins Snm1, -2, and -4 are required for the secretion of ESAT-6 and CFP-10, small proteins previously identified as major T cell antigens. Snm2, a member of the AAA ATPase family, interacts with substrates and with Snm1, another AAA ATPase. We show that M. tuberculosis mutants lacking either the Snm system or these substrates exhibit defects in bacterial growth during the acute phase of a mouse infection and are attenuated for virulence. Strikingly, snm mutants fail to replicate in cultured macrophages and to inhibit macrophage inflammatory responses, two well established activities of wild-type M. tuberculosis bacilli. Thus, the Snm secretion pathway works to subvert normal macrophage responses and is a major determinant of M. tuberculosis virulence.

    Title Requirement for Kasb in Mycobacterium Mycolic Acid Biosynthesis, Cell Wall Impermeability and Intracellular Survival: Implications for Therapy.
    Date December 2003
    Journal Molecular Microbiology
    Excerpt

    Mycobacterium tuberculosis infects one-third of the world's population and causes two million deaths annually. The unusually low permeability of its cell wall contributes to the ability of M. tuberculosis to grow within host macrophages, a property required for pathogenesis of infection. Mycobacterium marinum is an established model for discovering genes involved in mycobacterial infection. Mycobacterium marinum mutants with transposon insertions in the beta-ketoacyl-acyl carrier protein synthase B gene (kasB) grew poorly in macrophages, although growth in vitro was unaffected. Detailed analyses by thin-layer chromatography, nuclear magnetic resonance (NMR), matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, infrared spectroscopy, and chemical degradations showed that the kasB mutants synthesize mycolic acids that are 2-4 carbons shorter than wild type; the defect was localized to the proximal portion of the meromycolate chain. In addition, these mutants showed a significant (approximately 30%) reduction in the abundance of keto-mycolates, with a slight compensatory increase of both alpha- and methoxy-mycolates. Despite these small changes in mycolate length and composition, the kasB mutants exhibited strikingly altered cell wall permeability, leading to a marked increase in susceptibility to lipophilic antibiotics and the host antimicrobial molecules defensin and lysozyme. The abnormalities of the kasB mutants were fully complemented by expressing M. tuberculosis kasB, but not by the closely related gene kasA. These studies identify kasB as a novel target for therapeutic intervention in mycobacterial diseases.

    Title Pyrazinamide Inhibits the Eukaryotic-like Fatty Acid Synthetase I (fasi) of Mycobacterium Tuberculosis.
    Date October 2000
    Journal Nature Medicine
    Excerpt

    Tuberculosis treatment is shortened to six months by the indispensable addition of pyrazinamide (PZA) to the drug regimen that includes isoniazid and rifampin. PZA is a pro-drug of pyrazinoic acid (POA) (ref. 3), whose target of action has never been identified. Although PZA is active only against Mycobacterium tuberculosis, the PZA analog 5-chloro-pyrazinamide (5-Cl-PZA) displays a broader range of anti-mycobacterial activity. We have found that the eukaryotic-like fas1 gene (encoding fatty acid synthetase I, FASI) from M. avium, M. bovis BCG or M. tuberculosis confers resistance to 5-Cl-PZA when present on multi-copy vectors in M. smegmatis. 5-Cl-PZA and PZA markedly inhibited the activity of M. tuberculosis FASI, the biosynthesis of C16 to C24/C26 fatty acids from acetyl-CoA (ref. 6). Importantly, PZA inhibited FASI in M. tuberculosis in correlation with PZA susceptibility. These results indicate that FASI is a primary target of action for PZA in M. tuberculosis. Further characterization of FASI as a drug target for PZA may allow the development of new drugs to shorten the therapy against M. tuberculosis and may provide more options for treatment against M. bovis, M. avium and drug resistant M. tuberculosis.

    Title A Novel Mycolic Acid Cyclopropane Synthetase is Required for Cording, Persistence, and Virulence of Mycobacterium Tuberculosis.
    Date July 2000
    Journal Molecular Cell
    Excerpt

    Colonial morphology of pathogenic bacteria is often associated with virulence. For M. tuberculosis, the causative agent of tuberculosis (TB), virulence is correlated with the formation of serpentine cords, a morphology that was first noted by Koch. We identified a mycobacterial gene, pcaA, that we show is required for cording and mycolic acid cyclopropane ring synthesis in the cell wall of both BCG and M. tuberculosis. Furthermore, we show that mutants of pcaA fail to persist within and kill infected mice despite normal initial replication. These results indicate that a novel member of a family of cyclopropane synthetases is necessary for lethal chronic persistent M. tuberculosis infection and define a role for cyclopropanated lipids in bacterial pathogenesis.

    Title Complex Lipid Determines Tissue-specific Replication of Mycobacterium Tuberculosis in Mice.
    Date December 1999
    Journal Nature
    Excerpt

    Tuberculosis is the leading cause of death in the world resulting from a single bacterial infection. Despite its enormous burden on world health, little is known about the molecular mechanisms of pathogenesis of Mycobacterium tuberculosis. Bacterial multiplication and concomitant tissue damage within an infected host, including experimentally infected mice, occurs primarily in the lungs-the favoured niche of M. tuberculosis. Although it has been proposed that the distinctive cell wall of M. tuberculosis is important for virulence, rigorous genetic proof has been lacking. Here, using signature-tagged mutagenesis, we isolated three attenuated M. tuberculosis mutants that cannot synthesize or transport a complex, cell wall-associated lipid called phthiocerol dimycocerosate (PDIM) which is found only in pathogenic mycobacteria. Two mutants have transposon insertions affecting genes implicated in PDIM synthesis; the third has a disruption in a gene encoding a large transmembrane protein required for proper subcellular localization of PDIM. Synthesis and transport of this complex lipid is only required for growth in the lung; all three mutants are unaffected for growth in the liver and spleen. This clearly shows that a lipid is required for M. tuberculosis virulence.

    Title Patellofemoral Pain.
    Date June 1992
    Journal Instructional Course Lectures
    Title Dry Powder Aerosols. I. A New Powder Inhalation Device.
    Date February 1972
    Journal Journal of Pharmaceutical Sciences
    Title Administration of Disodium Cromoglycate.
    Date September 1969
    Journal British Medical Journal
    Title Valency Investigations of Iron Dextran ("imferon").
    Date July 1966
    Journal Nature
    Title Cephalosporanic Acids. Ii. Displacement of the Acetoxy-group by Nucleophiles.
    Date February 1966
    Journal Journal of the Chemical Society. Perkin Transactions 1

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