Why does tuberculosis occur

Dealing with a TB diagnosis in pregnancy is not easy. There is a greater risk to the pregnant person and the baby if TB disease is not treated. Babies born to people with untreated TB disease may have lower birth weight than those babies born to people without TB.

TB in correctional facilities is a public health concern. People living in congregate settings, including correctional facilities and detention centers, are at increased risk of becoming infected with TB bacteria due to shared airspaces.

TB disease in people experiencing homelessness is a public health concern. A disproportionate number of TB cases still occur among populations at higher risk for TB disease, including people experiencing homelessness.

People living in congregate settings, including homeless shelters, are at increased risk of becoming infected with TB bacteria due to shared airspaces. In many countries, TB disease is much more common than in the United States. TB is a serious international public health problem.

These medications are often used to treat infections that are resistant to the more commonly used drugs. A healthy immune system often successfully fights TB bacteria.

However, several conditions and medications can weaken your immune system, including:. Your risk of getting tuberculosis is higher if you live in, emigrate from or travel to areas with high tuberculosis rates.

Areas include:. Without treatment, tuberculosis can be fatal. Untreated active disease typically affects your lungs, but it can affect other parts of your body, as well. If you test positive for latent TB infection, your doctor might advise you to take medications to reduce your risk of developing active tuberculosis. Only active TB is contagious. If you have active TB , it generally takes a few weeks of treatment with TB medications before you're not contagious anymore. Follow these tips to help keep your friends and family from getting sick:.

This is the most important step you can take to protect yourself and others from tuberculosis. When you stop treatment early or skip doses, TB bacteria have a chance to develop mutations that allow them to survive the most potent TB drugs. The resulting drug-resistant strains are deadlier and more difficult to treat. In countries where tuberculosis is more common, infants often are vaccinated with bacille Calmette-Guerin BCG vaccine. The BCG vaccine isn't recommended for general use in the United States because it isn't very effective in adults.

Icl isocitrate lyase is an enzyme that converts isocitrate to succinate in the glyoxalate shunt. This allows bacteria and plants to grow on acetate or fatty acids as sole carbon sources since the glyoxalate shunt provides a source of carbon that can enter the Krebs cycle.

Initial observations made using an in vitro model to study M. It initially grows normally in mice but stops growing in lungs and is cleared at the time when cell-mediated immunity is initiated, a PER phenotype Additional evidence indicating the importance of isocitrate lyase includes the observation that icl mRNA levels increase in the lungs of M.

It was identified in one of the STM experiments that found fadD26 discussed above and had a similar attenuated phenotype in mice Nothing more is known about the function of this protein or why it is essential for bacterial survival in vivo.

There are 36 genes annotated in the M. Inactivation of fadD33 caused a complex virulence phenotype in mice, since the wild-type parent and fadD33 mutant grew normally in the spleens and lungs of infected mice but the mutant grew less well in livers approximately 1 log unit less.

This phenotype was similar to that exhibited by M. The reason for the tissue-specific phenotype of the mutant is not known, and neither is the actual function of the FadD33 protein.

Other annotated fatty acid metabolic genes fadA4 , fadA5 , and echA19 have been identified as being induced in human macrophages by using a promoter trap selection, but only the fadA4 results were tested and validated by mRNA determination Similar promoter trap experiments have now identified nine annotated fad genes as being induced in the lungs of M. Dubnau et al. These mouse results have not been validated yet, and no mutations have been made in any promoter trap-identified genes to determine their virulence phenotypes, but these experiments are under way.

Three of these, plcA , plcB , and plcC , are closely linked to each other, but plcD is not. Disruptions of the plc genes were obtained by screening a transposon mutant library made in M. In addition, some mutations were made by a two-step plasmid procedure Phospholipase C activity was determined in cell extracts of strains that had individual and multiply mutated plc genes, and all individual mutants have lower enzyme activities than that of the wild-type M.

Triple plcABC and quadruple plcABCD mutants have negligible enzyme activity, and strains made by using a plcABC mutant as the recipient for individual plc genes showed that all restore some activity.

However, both of these multiple plc mutants are attenuated in mice, showing a GIV phenotype. Pantothenate is essential for for the synthesis of CoA and other important molecules involved in fatty acid biosynthesis and degradation, intermediary metabolism, and other cellular processes. The mutant was attenuated for virulence, as determined by measuring the survival time of SCID and immunocompetent mice and the bacterial burden in immunocompetent animals In the former experiments, the SCID mice infected with the panCD mutant survived for an average of days while mice infected with the wild-type H37Rv lived an average of 5 weeks.

Similar results were observed for immunocompetent mice. In addition, the histopathologic changes in the lungs of mice infected with the mutant were much smaller than those observed in wild-type infections. Complementation of the mutant with the M. When injected into mice, the mutant was also protective against an aerosol challenge with virulent M. As discussed earlier in this section, initial attempts to isolate attenuated M.

The leuD auxotroph was also able to protect against virulent M. TrpD is anthranilate phosphoribosyl transferase, which is involved in the tryptophan biosynthetic pathway. The mutant was severely attenuated in murine macrophages, hardly grew in SCID mice suggesting a SGIV phenotype , and did not kill any of these mice ProC is a pyrrolinecarboxlate reductase, which is involved in proline biosynthesis, and the M.

Its virulence phenotype is intermediate between that of the the wild-type M. It is killed in murine macrophages but not as rapidly as the trpD strain, and it kills SCID mice with median killing time of days, in contrast to the wild-type infection, in which all mice are killed by 29 days. PurC is 1-phosphoribosylaminoimidazole-succinocarboxamide synthase, which is involved in purine biosynthesis, and it was inactivated in both M. The growth of both mutants in inactivated murine macrophages is attenuated, with the M.

Both mutants are severely attenuated in mice with an SGIV phenotype. Magnesium and iron are essential for life, and defects in the uptake of these elements frequently lessen the virulence of bacterial pathogens.

Following this rationale, two mutants have been made in M. Since there is an mgtC ortholog annotated in the M. The mutant is also severely attenuated for growth in mice, exhibiting a SGIV phenotype.

However, a similar mgtC mutant made in M. The reasons for these discordant results in two laboratories are not known, but different M.

The actual role of mgtC in M. The mbt operon, consisting of mbtA through mbtJ , encodes enzymes whose function is to synthesize mycobactin and carboxymycobactin 72 , , the major siderophores in M.

This regulon is repressed by IdeR in high-iron conditions , MbtB is an enzyme in this pathway and catalyzes the formation of an amide bond between salicylate and serine, a step in mycobactin synthesis. Since iron is essential for most lifeforms but is usually in the form of the largely insoluble ferric salts in the environment, iron uptake systems are required to solubilize these salts and to transport the iron into the cell.

In bacteria, siderophores usually perform this chelation and solubilization function, and the iron they carry is taken into cells by high-affinity transporters. In addition, pathogens require iron acquisition systems, usually siderophores, during infection to obtain iron from host iron-containing proteins such as transferrin and lactoferrin. In response to infection, the host frequently sequesters iron to prevent bacterial growth Since mutations in siderophore-biosynthetic genes frequently cause attenuation of virulence in bacterial pathogens, the M.

The mutant shows wild-type growth in iron-rich media, grows poorly when iron is limiting, and is unable to synthesize the two mycobactin-derived siderophores. It also grows more slowly than the wild type in human macrophages, as measured by a luminescence assay, indicating the mycophagosome may be low in iron. This latter hypothesis is supported by experiments which show that levels of mbtB and mbtI mRNA are increased during M.

There is no published report on the growth phenotype of the mbtB mutant in mice, but several lines of evidence, in addition to its macrophage growth phenotype, suggest that it will be attenuated. These all indicate that iron is limiting in the M.

Timm et al. The identity of this gene is currently under investigation and, when found, should be an important tool with which to study M. Another reason suggesting that iron is limiting for M. IdeR is the major mycobacterial regulator of iron uptake and storage genes, repressing the former and activating the latter 79 , , , However, it is included in this section on virulence factors because of a report that the presence of a mutated DtxR, which exhibits iron-independent repression in other contexts, decreases the growth of M.

Although it was not demonstrated directly in vitro or during infection, it was postulated that the mutated DtxR is repressing M. Despite certain caveats, this interesting observation suggests that iron acquisition is essential for M. On the other hand, most aerobic organisms, including bacteria, have enzymes that degrade peroxides and H 2 O 2 , which are normal by-products of aerobic respiration and can give rise to toxic ROIs if allowed to accumulate.

These enzymes, generally superoxide dismutases and catalases, as well as related enzymes, are also important for the response to various external oxidative stresses. Since phagocytic cells produce ROIs to kill invading bacteria, it is not surprising that these enzymes are important for M. NarG is a subunit of the prokaryotic respiratory anaerobic nitrate reductase that plays major role in respiration in the absence of oxygen, and anaerobic nitrate reductase activity increases when M.

The mutant had no anaerobic nitrate reductase activity, but its growth under aerobic or anaerobic conditions was unaffected. When the M. When SCID mice were infected, the wild-type parent grew well while the mutant showed no replication but was not cleared. In normal mice, the wild-type BCG strain did not replicate but the mutant was rapidly cleared from the lungs, livers, and kidneys, exhibiting a SGIV phenotype These results have not been confirmed for M. KatG is a catalase:peroxidase that degrades H 2 O 2 and organic peroxides.

It is the only enzyme with catalase activity in M. In addition, an M. Another katG mutant of M. Complementation with the wild-type katG restored enzyme activity and virulence The role of FurA in virulence is not currently known. AhpC is an alkyl hydroperoxide reductase, and enzymes of this type function to detoxify organic hydroxyperoxides. Attempts to inactivate this gene in the M. The resulting phenotypic mutant produced less AhpC than did the wild type and was more sensitive to H 2 O 2 and cumene hydroperoxide.

The mutant was also much less virulent in a guinea pig model, showing 3 log units fewer CFUs than the wild type. It has been postulated that AhpC can compensate for the lack of lack of catalase:peroxidase activity in M. However, levels of AhpC are not correlated with the virulence of katG mutants SodA is the iron-factored superoxide dismutase that degrades superoxides, which are normal by-products of normal aerobic respiration and are also produced by the phagocytic repiratory burst enzyme.

It is therefore important for the survival of intracellular pathogens during infections. SodA is the major enzyme with this activity in M. To circumvent this problem, as was done with the ahpC gene discussed above, an antisense approach was used to make a phenotypic sodA mutation in M. The phenotypic mutant produced much less SodA protein and was severely attenuated in mice, showing up to 5 log units fewer CFUs than the wild type in lungs and spleens, and it was rapidly cleared, demonstrating an SGIV phenotype.

Recent results have indicated that M. Kernodle, personal communication. SodC is the Cu,Zn-factored superoxide dismutase that is responsible for a small part of total Sod activity in M.

Two laboratories have inactivated this gene in M. In one case, sodC was inactivated in M. It was not affected in inactivated murine macrophages or activated macrophages from respiratory burst-deficient mice In the other study, the M.

The reasons for the discrepant results are not known, but different M. Since transcriptional regulators control the transcription of many genes, a directed mutational strategy to inactivate regulatory genes would be expected to find some that are important for M. One of the major strategies used by prokaryotes to radically change their life-style in response to a changed environment involves using RNA polymerase holoenzymes with different promoter specificities.

This is achieved by the formation of new holoenzymes containing different sigma factors, which allows the transcription of genes required for the new conditions. Pathogens, including M. Sigma A is the essential principal mycobacterial sigma factor and is presumably necessary for most mycobacterial housekeeping gene transcription , Unlike the products of most of the other transcriptional regulatory genes that were directly inactivated, sigma A was identified as a virulence factor by complementation of an attenuated M.

The original mutation in sigA that causes attenuation is a partial loss of function that allows the sigma A protein to function in general transcription, since the mutant grows normally in vitro broth cultures and solid media , but it is presumably unable to transcribe at least one virulence gene. The attenuating mutation is an arginine-to-histidine change at amino acid residue RH of the protein and is localized to a C-terminal domain that, in other sigma factors, interacts with transcriptional activators.

This suggested that sigma A must interact with a transcriptional activator that allowed the expression of a gene s necessary for virulence Recent experiments have confirmed this hypothesis since it has been shown that WhiB3 Rv interacts with sigma A This important finding is discussed below. Hopefully, DNA array analyses will soon compare the global expression profiles of strain ATCC and its complemented derivative strain to see which genes are not transcribed in the mutant strain, as has been done for other M.

These analyses should allow the identification of genes in the sigma A regulon that require WhiB3 and should ultimately lead to the identification of those that are essential for virulence.

The derived amino acid sequence of M. It was speculated that the latency of M. The mutant has no macrophage phenotype and is attenuated for virulence in mice, using mortality as a criterion. Recently, direct transcription assays have identified genes transcribed by RNAP-sigma F, and a promoter sequence has been identified that strongly resembles the B. This information and future DNA array analyses should allow the identification of sigma F-dependent M. Interestingly, this latter work also showed that the activity of sigma F is controlled posttranslationally by its binding to an anti-sigma protein Rvc that previously had been identified as having sequence similarity to the anti-sigma F and anti-sigma B proteins of B.

In turn, the activity of the M. Significantly, the function of Rvc is regulated by the redox potential, while it is proposed that Rvc activity is controlled by phosphorylation Since these stresses might be found during M. To test this idea, sigE was inactivated in M. The mutant is more sensitive to detergent, high temperature, and oxidative stress than is the wild-type parent M.

Preliminary results show that the mutant is attenuated in wild-type mice with a GIV phenotype and kills SCID mice more slowly than the wild type does: all mice infected with the mutant were dead by 70 days, while M. Manganelli et al. DNA array analyses comparing the sigE mutant and the wild-type parent showed that 38 genes required sigma E for their expression during normal growth while 23 other genes in 13 transcription units required this transcription factor for their induction after sodium dodecyl sulfate SDS stress.

Nine of these transcription units had a conserved ECF sigma factor-like promoter sequence in the region directly upstream of the first gene in each unit. Among the genes requiring sigma E for their expression during unstressed growth are some encoding proteins involved in translation, transcriptional control mycolic acid biosynthesis, electron transport and the oxidative stress response.

Genes requiring sigma E during SDS stress encode proteins that are involved in fatty acid degradation, some that are heat shock proteins, and several that are putative transcriptional regulators. Gomez and I. Smith, unpublished results , required sigma E under both stressed and unstressed conditions, and recent experiments have shown that RNAP-sigma E can transcribe sigB Rodrigue et al.

This question is currently being investigated. As is the case with many ECF sigma factors, sigma E activity is downregulated by an anti-sigma factor, RseA, that is encoded by a gene, Rv, adjacent to sigE Rodrigue et al. The possible role of RseA in virulence is not known and is also being studied. Sigma H is another member of the ECF family of sigma factors, like sigma E, and is very similar to the sigma R of Streptomyces species.

Sigma R responds to certain types of oxidative stress, such as diamide treatment, that oxidize protein-SH groups, which then form intramolecular disulfide bonds Its promoter recognition activity is blocked by binding of an anti-sigma factor, RsrA, that is encoded by a gene adjacent to sigR.

On oxidative diamide stress, key SH groups in RsrA become oxidized and its binding to sigma R is disrupted Sigma R is then able to transcribe several genes such as its own structural gene sigR and the trx operon, encoding thioredoxin and thioredoxin reductase, which can reduce proteins that were oxidized by diamide treatment.

Thioredoxin and its reductase function to return the system to the unstressed state, since the newly reduced RsrA can again bind to sigma R Subsequently, this gene was inactivated in three laboratories , , The phenotype of the sigH mutant is as expected from the Streptomyces experiments and the earlier M.

A combination of DNA array analyses and individual gene expression assays showed that there are no genes that require sigma H during unstressed growth , but genes similar to those transcribed by the Streptomyces RNAP-sigma R, including those encoding thioredoxin reductase and two thioredoxins, are dependent on sigma H for their expression after diamide stress , , Many of these M. Transcription assays have shown that some of these genes are transcribed by mycobacterial RNAP-sigma H The virulence phenotype of the sigH mutant is subtle in that its growth in macrophages and mice is normal in terms of bacterial load , , but there are differences in lung histopathology, including fewer granulomas and a generally delayed pulmonary inflammatory response As is the case for Streptomyces , M.

Biochemical experiments have shown that the purified M. As discussed earlier in this review, bacteria have multiple two-component systems, each responding to different stimuli, and several laboratories have made mutations in M. PhoP shows high similarity to the PhoP response regulator of S. On this basis, phoP was disrupted in a clinical M. The mutant grows poorly in mouse macrophages and is severely attenuated in mouse organs, where it has an SGIV phenotype.

These results have been confirmed and extended as phoP has been disrupted in M. In vitro experiments have shown that the M. Genes controlled by PhoP are not known yet, including those important for virulence, and this is currently being investigated. PrrA is one of the 13 annotated response regulators in the M. It had been previously shown that this gene was upregulated during M. The growth of the prrA mutant in mouse primary macrophages was slightly lower than that of the wild-type M.

In agreement with these observations, the use of GFP reporter fusions with the prrA promoter showed that this gene was transiently induced in macrophages, with peak levels of gene expression 4 h after infection and with levels declining after that time. The significance of PrrA to virulence is not clear, given the very subtle attenuation phenotype.

Rv is another M. The mutant had an unusal phenotype in that it grew better than the wild type in murine macrophages and human MDMs. However, it did not persist in the lungs and livers of infected mice, growing initially and being cleared after days, respectively, showing a delayed PER phenotype.

Virulence phenotypes of other two-component gene mutations have been measured, e. No macrophage phenotype was observed, and these genes were not induced in macrophages In agreement with these results, 10 of the 13 two-component response regulator genes in M.

Included in this group were mutants with disruptions in regX and trcS. Other two-component systems in M. Another response regulator, DosR Rvc , controls the global response to oxidative stress and low oxygen response, including the expression of the anoxia-induced hspX gene as well as its own expression A proteomic analysis of M. Thus, DosR is important for the mycobacterial response to various environmental stresses, and a recent report shows that disruption of the M.

While a mutation in M. In addition to sigma factors and response regulators, bacteria use other types of transcriptional regulators to control the expression of large groups of genes. As discussed above, there are many ORFs that are annotated as transcriptional regulators in the M. Among the rarely characterized M. Other transcriptional regulators have been described that are potentially important for virulence, like RelA , since relA mutant shows defects in long-term survival in vitro while its macrophage growth is normal.

However, there have been no published reports describing the relA mutant phenotype in animal models. The synthesis of M. Investigations were carried out to see whether the M. Biochemical studies showed that purified M.

Thus, M. While the M. The reason for this attenuation is not known, but it was suggested that the higher levels of HSPs in the mutant may cause increased host immunosurveillence followed by more efficient killing of the pathogen In addition to potential roles in immunosurveillance, M.

Recombinant M. It has recently been shown that M. This suggests a role for GroES in Pott's disease, the extrapulmonary form of TB discussed earlier in this review that is marked by the weakening and resorption of spinal vertebrae. WhiB was originally described in S. There are seven members of the WhiB family in M. For this reason, studies of mycobacterial WhiB orthologs have been performed, initially with M.

The same whiB3 mutation was made in M. This attenuation phenotype is similar to that observed in the original M.

This result indicates significant differences in virulence mechanisms of these two members of the M. Genome comparisons of M. Also not known is the role in virulence of other members of the M. A promoter trap search has identified whiB2 Rvc as being differentially expressed in the lungs of M.

As shown in this review, much work has been performed in the search for M. Various targets have been identified, e. More work has to be performed so that that every potential gene is systematically inactivated in the M. Ideally, the mariner transposon system can be modified to incorporate signature tagging so that many potential mutants can be tested in vivo at the same time.

In addition to this global search, there are more specific approaches that can be undertaken. For example, as mentioned earlier in this review review, some M. The numerous comparative genomic sequencing projects being conducted now may identify potential genes that are responsible for these phenotypes, and these could then be individually characterized.

As previously discussed, all M. Of the nine genes in the deleted region, only Rv, encoding Esat6 has been implicated in virulence, since a mutant with a disruption in this gene is attenuated for virulence It is not known whether any of the other genes in the RD1 region are also important for M. As an intracellular pathogen, M. In the same way, the infected phagocytic cell and surrounding tissue respond in a global sense to the presence of an intruding pathogen.

As discussed earlier in this review, DNA arrays have been used to study the global expression of genes in wild-type and mutant M. Proteomic techniques have also been used to measure the levels of large numbers of bacterial proteins when M.

The purpose of this section is to discuss how new global methods are currently being used and could be used in the near future to study the interactions between M. There have been some descriptions of host responses when macrophages are allowed to phagocytose M. However, these macrophage responses have generally been limited to the expression of a small number of genes or the levels of a few proteins, and as discussed earlier in this review, there are often widely discordant results from different laboratories.

Recently, DNA array analyses have been used to study host gene expression during M. This study also used primary macrophages from mutant mice, providing significant information on mechanisms of the host response to infection.

To more completely describe the M. As an example of this combined approach, mutations in the M. Thus, global expression profiling with DNA arrays can now be used to identify the M. This was recently done with wild-type S. At the same time, it will be possible to globally compare the expression of macrophage genes during the infection with wild-type M. However, since these regulators presumably control many genes that are differentially expressed during macrophage infection, it may not be possible to determine initially the identity of the bacterial effector molecules important for virulence that are missing in the mutants.

Thus, it will be important also to characterize the M. Since mutations in some M. In these experiments, one could compare the effect of the presence or absence of a molecule like the kDa protein on host gene expression during M. The results of such studies, in which effector molecules are presented to the macrophage in their normal context or are not presented, should clarify their roles in virulence. For want of a better term, this section discusses M. As discussed above, one of the early stages in progression of TB is the formation of a granuloma as monocytes and lymphocytes are recruited to the site of the original infection in the lung, ultimately surrounding and isolating the infectious bacteria, if the infection is controlled.

Thus, it is important to study M. Generally, most experiments have been done in animal models, and at various stages in infection, infected organs, e. There have not been many studies involving systems that are not as complex as the whole infected animal but that allow the interaction between infected macrophages and lymphocytes.

Several attempts have been made to bridge the gap between simple ex vivo macrophage and in vivo animal model experiments, and two examples are cited. A whole-blood assay has been used to study early stages in M. The advantages of this system are that monocytes and lymphocytes present in blood can interact as they do ordinarily and that M. Another system assembles cellular components thought to be involved in early M.

Minus Related Pages. How TB Spreads. TB Risk Factors. TB Terms. Exposure to TB.