Reactivation Of Latent Tuberculosis Research Articles

Influence of diabetes mellitus on immunity to human tuberculosis.

Type 2 diabetes mellitus(DM) is a major risk factor for the development of active pulmonary tuberculosis (TB), with development of DM pandemic in countries where TB is also endemic. Understanding the impact of DM on TB and the determinants of co-morbidity is essential in responding to this growing public health problem with improved therapeutic approaches. Despite the clinical and public health significance posed by the dual burden of TB and DM, little is known about the immunological and biochemical mechanisms of susceptibility. One possible mechanism is that an impaired immune response in patients with DM facilitates either primary infection with Mycobacterium tuberculosis or reactivation of latent TB. Diabetes is associated with immune dysfunction and alterations in the components of the immune system, including altered levels of specific cytokines and chemokines. Some effects of DM on adaptive immunity that are potentially relevant to TB defence have been identified in humans. In this review, we summarize current findings regarding the alterations in the innate and adaptive immune responses and immunological mechanisms of susceptibility of patients with DM to M. tuberculosis infection and disease.

Vitamin D deficiency among smear positive pulmonary tuberculosis patients and their tuberculosis negative household contacts in Northwest Ethiopia: a case\u2013control study

BackgroundVitamin D is a fat-soluble vitamin that increases the immunity against tuberculosis (TB), decreases the re-activation of latent TB and reduces the severity of active TB disease. Epidemiological studies on the prevalence of vitamin D deficiency, and its association with TB showed inconsistent results in different countries. This study was aimed to determine the prevalence of vitamin D deficiency and its association with TB in Northwest Ethiopia.MethodsA case–control study was conducted among smear positive pulmonary tuberculosis patients and their household contacts without symptoms suggestive of TB. Study participants were recruited at 11 TB diagnostic health facilities in North and South Gondar zones of Amhara region between May 2013 and April 2015. The spot-morning-spot sputum samples and 5 ml blood sample were collected prior to commencing TB treatment for the diagnosis of TB and serum vitamin D assay, respectively. The diagnosis of TB was performed using smear microscopy and GeneXpert. Serum vitamin D level was analyzed using VIDAS 25 OH Vitamin D Total testing kits (Biomerieux, Marcy I’Etoile, France) on mini VIDAS automated immunoassay platform. Vitamin D status was interpreted as deficient (<20 ng/ml), insufficient (20–29 ng/ml), sufficient (30–100 ng/ml) and potential toxicity (>100 ng/ml).ResultsOf the total study participants, 134 (46.2%) were vitamin D deficient, and only 56 (19.3%) had sufficient vitamin D level. A total of 59 (61.5%) TB patients and 75 (38.7%) non TB controls were vitamin D deficient. Results of multivariate logistic regression analyses showed a significantly higher vitamin D deficiency among tuberculosis cases (p < 0.001), females (p = 0.002), and urban residents (p < 0.001) than their respective comparison groups. Moreover, age groups of 35–44 (p = 0.001), 45–54 (p = 0.003) and ≥55 (p = 0.001) years had significantly higher vitamin D deficiency compared with age group <15 years.ConclusionsVitamin D deficiency is highly prevalent among TB patients and non TB controls in Ethiopia where there is year round abundant sunshine. Study participants with tuberculosis, females, older age groups, and urban residents had significantly higher prevalence of vitamin D deficiency. These findings warrant further studies to investigate the role of vitamin D supplementation in the prevention and treatment of tuberculosis in high TB burden countries like Ethiopia.

Quiz: Acute Kidney Injury in a Patient on a TNF-α Blocking Agent

Quiz: Acute Kidney Injury in a Patient on a TNF-α Blocking Agent

Health system challenges: An obstacle to the success of isoniazid preventive therapy.

The researchers identified infection with HIV as the strongest risk factor in the reactivation of latent tuberculosis (TB) infection or progression to active disease. Isoniazid preventive therapy (IPT) is one of the interventions recommended by the World Health Organization and the South African (SA) National Department of Health to prevent progression to active TB disease in people living with HIV. Adherence to IPT is therefore the responsibility of healthcare clients and clinicians. To describe the incidence of TB among clients who received IPT, rates of completing and not completing IPT among those who started it, and the reasons for non-completion. A quantitative, non-experimental, descriptive retrospective cohort study was undertaken. The clinic records of 104 HIV-positive adults receiving care at a clinic in SA who started IPT between 1 July 2010 and 30 November 2011 were analysed. Sixty-six of 104 study respondents (63.5%) completed the IPT course. None of the respondents who completed IPT was diagnosed with TB, and 86.8% of the respondents who did not complete the programme did so because of the poor quality of healthcare they received, and not by their own choice. The study results strengthened the findings of similar local and international studies that IPT is advantageous in the prevention of TB. The finding that so many patients did not complete the programme as a result of drug dispensing or prescription problems is alarming, and revealed a major shortcoming in the healthcare system.

Gene therapy based in antimicrobial peptides and proinflammatory cytokine prevents reactivation of experimental latent tuberculosis.

Mycobacterium tuberculosis (Mtb) latent infection can lead to reactivation. The design of new strategies to prevent it is an important subject. B6D2F1 mice were infected intratracheally with a low dose of Mtb H37Rv to induce chronic infection. After 7 months, mice were treated with one dose of recombinant adenoviruses encoding TNFα, β defensin-3 and LL37. Immunosupression was induced 1 month later with corticosterone. In comparison with the control group, mice treated with adenoviruses showed significantly less bacterial load and pneumonia, the adenoviruses encoding TNFα and LL37 being the most efficient. Gene therapy based in a proinflammatory cytokine or antimicrobial peptides is a potentially useful system to prevent reactivation of latent tuberculosis.

CD4+ T-cell–independent mechanisms suppress reactivation of latent tuberculosis in a macaque model of HIV coinfection

The synergy between Mycobacterium tuberculosis (Mtb) and HIV in coinfected patients has profoundly impacted global mortality because of tuberculosis (TB) and AIDS. HIV significantly increases rates of reactivation of latent TB infection (LTBI) to active disease, with the decline in CD4(+) T cells believed to be the major causality. In this study, nonhuman primates were coinfected with Mtb and simian immunodeficiency virus (SIV), recapitulating human coinfection. A majority of animals exhibited rapid reactivation of Mtb replication, progressing to disseminated TB and increased SIV-associated pathology. Although a severe loss of pulmonary CD4(+) T cells was observed in all coinfected macaques, a subpopulation of the animals was still able to prevent reactivation and maintain LTBI. Investigation of pulmonary immune responses and pathology in this cohort demonstrated that increased CD8(+) memory T-cell proliferation, higher granzyme B production, and expanded B-cell follicles correlated with protection from reactivation. Our findings reveal mechanisms that control SIV- and TB-associated pathology. These CD4-independent protective immune responses warrant further studies in HIV coinfected humans able to control their TB infection. Moreover, these findings will provide insight into natural immunity to Mtb and will guide development of novel vaccine strategies and immunotherapies.

How Should We Manage Latent Tuberculosis Infection in Patients Receiving Anti-TNF-α Drugs: Literature Review

Context: The introduction of new drugs that specifically antagonize tumor necrosis factor alpha (anti-TNF-α) has provided an effective treatment in a wide variety of autoimmune diseases. Nevertheless, the possibility of the reactivation of latent TB (Tuberculosis) infection (LTBI) among these patients is a considerable challenge. The aim of this paper is to evaluate LTBI diagnostic tools in patients who are candidates for anti-TNF-α therapy emphasizing how to manage these patients. Evidence Acquisition: A systematic web-based search was conducted in MEDLINE, Cochrane Library Database, and UpToDate® resources using the key words “anti-TNF-α” and “latent tuberculosis” up to March 2015. Two reviewers extracted and summarized the data and suggested protocols for the diagnosis and management of LTBI in patients receiving TNF-α inhibitors. Results: There were somewhat different approaches proposed by various researchers regarding the subject. While no recommendation was found to be unique to include all patients in all situations, the data emphasize the importance of ruling out TB infection before deciding to start an anti-TNF-α drug. Conclusions: Special high-risk groups, including patients with LTBI, should be treated before receiving TNF-α inhibitors. The tuberculin skin test (TST) is a somewhat cost-effective test for the diagnosis of LTBI. However, its usefulness with respect to false results should be re-evaluated in this situation.

Safety of secukinumab in the treatment of psoriasis

ABSTRACTIntroduction: Secukinumab is a human monoclonal antibody that selectively targets and neutralizes interleukin (IL)-17A, a cytokine that is normally involved in mucocutaneous defense against extracellular organisms and is abnormally expressed in psoriasis. In 2015, secukinumab was the first IL-17A inhibitor approved for the treatment of moderate-to-severe psoriasis.Areas covered: This review evaluates the safety profile of secukinumab for the treatment of moderate-to-severe psoriasis and its role in the clinical landscape. A literature search was performed for articles published through February 2016; additional data from a pooled safety analysis of 10 Phase II and III secukinumab studies were reviewed.Expert opinion: Collectively, these studies show that secukinumab demonstrates a highly favorable safety profile, especially compared with commonly used psoriasis treatments such as methotrexate and TNF-α blockers. More specifically, secukinumab carries no increased risks for end-organ toxicities, serious infection, multiple sclerosis, reactivation of latent tuberculosis or hepatitis B, leukemia/lymphoma, and nonmelanoma skin cancer. Mucocutaneous candidiasis is a common side effect and occurs at a rate of 3.55/100 subject-years with secukinumab 300 mg, yet these infections usually do not interfere with maintenance of secukinumab therapy. The combination of proven efficacy and safety make secukinumab an excellent new treatment choice for individuals with moderate-to-severe psoriasis.

Understanding HIV-Mycobacteria synergism through comparative proteomics of intra-phagosomal mycobacteria during mono- and HIV co-infection.

Mycobacterium tuberculosis (Mtb) is the most common co-infection in HIV patients and a serious co-epidemic. Apart from increasing the risk of reactivation of latent tuberculosis (TB), HIV infection also permits opportunistic infection of environmental non-pathogenic mycobacteria. To gain insights into mycobacterial survival inside host macrophages and identify mycobacterial proteins or processes that influence HIV propagation during co-infection, we employed proteomics approach to identify differentially expressed intracellular mycobacterial proteins during mono- and HIV co-infection of human THP-1 derived macrophage cell lines. Of the 92 proteins identified, 30 proteins were upregulated during mycobacterial mono-infection and 40 proteins during HIV-mycobacteria co-infection. We observed down-regulation of toxin-antitoxin (TA) modules, up-regulation of cation transporters, Type VII (Esx) secretion systems, proteins involved in cell wall lipid or protein metabolism, glyoxalate pathway and branched chain amino-acid synthesis during co-infection. The bearings of these mycobacterial factors or processes on HIV propagation during co-infection, as inferred from the proteomics data, were validated using deletion mutants of mycobacteria. The analyses revealed mycobacterial factors that possibly via modulating the host environment, increased viral titers during co-infection. The study provides new leads for investigations towards hitherto unknown molecular mechanisms explaining HIV-mycobacteria synergism, helping address diagnostics and treatment challenges for effective co-epidemic management.

B cell responses in older adults with latent tuberculosis: Considerations for vaccine development.

Reactivation of latent tuberculosis (LTBI) is more common among the aging population and may contribute to increased transmission in long-term health care facilities. Difficulties in detecting LTBI due to potential blunting of the tuberculin skin test (TST), and the lowered ability of the elderly to tolerate the course of antibiotics, underscore the need for an effective vaccine. Immuno-senescence reduces the capacity of vaccines to induce sufficient levels of protective immunity against many pathogens, further increasing the susceptibility of the elderly to infectious diseases. We sought to evaluate the response of B cells to Mycobacterium tuberculosis (Mtb) in residents of long-term care facilities to determine the feasibility of using a vaccine to control infection and transmission from reactivated LTBI. Our results demonstrate that although B cell responses were higher in subjects with LTBI, Mtb antigens could stimulate B cell activation and differentiation in vitro in TST negative subjects. B cells from elderly subjects expressed high basal levels of Toll-like receptor (TLR)2 and TLR4 and responded strongly to Mtb ligands with some activation pathways dependent on TLR2. B cells derived from blood, tonsil and spleen from younger subjects responded similarly and to the same magnitude. These results suggest that B cell responses are robust in the elderly and modifications to a TB vaccine, such as TLR2 ligand-based adjuvants, may help increase immune responses to a protective level.

DNA vaccination boosts Bacillus Calmette–Guérin protection against mycobacterial infection in zebrafish

Despite the widespread use of the current Bacillus Calmette–Guérin (BCG) vaccine, tuberculosis is still a major cause of morbidity and mortality worldwide. Vaccination with BCG does not prevent a Mycobacterium tuberculosis infection, nor does it inhibit the reactivation of latent tuberculosis. Here, we show that adult zebrafish are modestly and variably protected from a mycobacterial infection by BCG vaccination. An intraperitoneal (i.p.) BCG vaccination was associated with enhanced survival upon a high-dose (20,000 bacteria) Mycobacterium marinum infection. In addition, BCG-vaccinated fish were more able to restrict a low-dose (30 bacteria) intraperitoneal infection with M. marinum, as indicated by lower bacterial loads at six weeks post infection (wpi). However, the vaccination could not completely prevent an infection. A qRT-PCR analysis comparing BCG-vaccinated and unvaccinated fish upon a mycobacterial infection indicated that the induction of Tumor necrosis factor (TNF) was more modest in vaccinated fish. The partial protection gained by BCG could be boosted by a DNA vaccine combining Ag85B, ESAT6 and a resuscitation-related gene RpfE, suggesting that this combination of antigens could be useful for a future BCG booster vaccine. We conclude that zebrafish is a useful early-phase preclinical model for studying subunit vaccines designed for boosting the effects of BCG.

Profiling the Proteome of Mycobacterium tuberculosis during Dormancy and Reactivation

Tuberculosis, caused by Mycobacterium tuberculosis, still remains a major global health problem. The main obstacle in eradicating this disease is the ability of this pathogen to remain dormant in macrophages, and then reactivate later under immuno-compromised conditions. The physiology of hypoxic nonreplicating M. tuberculosis is well-studied using many in vitro dormancy models. However, the physiological changes that take place during the shift from dormancy to aerobic growth (reactivation) have rarely been subjected to a detailed investigation. In this study, we developed an in vitro reactivation system by re-aerating the virulent laboratory strain of M. tuberculosis that was made dormant employing Wayne's dormancy model, and compared the proteome profiles of dormant and reactivated bacteria using label-free one-dimensional LC/MS/MS analysis. The proteome of dormant bacteria was analyzed at nonreplicating persistent stage 1 (NRP1) and stage 2 (NRP2), whereas that of reactivated bacteria was analyzed at 6 and 24 h post re-aeration. Proteome of normoxially grown bacteria served as the reference. In total, 1871 proteins comprising 47% of the M. tuberculosis proteome were identified, and many of them were observed to be expressed differentially or uniquely during dormancy and reactivation. The number of proteins detected at different stages of dormancy (764 at NRP1, 691 at NRP2) and reactivation (768 at R6 and 983 at R24) was very low compared with that of the control (1663). The number of unique proteins identified during normoxia, NRP1, NRP2, R6, and R24 were 597, 66, 56, 73, and 94, respectively. We analyzed various biological functions during these conditions. Fluctuation in the relative quantities of proteins involved in energy metabolism during dormancy and reactivation was the most significant observation we made in this study. Proteins that are up-regulated or uniquely expressed during reactivation from dormancy offer to be attractive targets for therapeutic intervention to prevent reactivation of latent tuberculosis.

The impact of immunosuppressive therapy on QuantiFERON and tuberculin skin test for screening of latent tuberculosis in patients with inflammatory bowel disease scheduled for anti-TNF therapy

Objective. Patients with inflammatory bowel disease (IBD) should be routinely screened for latent tuberculosis (LTB) before starting anti-TNF therapy in order to prevent reactivation of LTB. Besides tuberculin skin test (TST), QuantiFERON-TB Gold In-Tube (QFT-G-IT) has gained wide acceptance as a screening strategy for LTB in IBD, although it may be negatively influenced by the prior use of immunomodulators (IMM) such as azathioprine or methotrexate. This study aimed to assess the impact of IMM on the TST and the QFT-G-IT for LTB screening in IBD patients scheduled for anti-TNF therapy. Material and methods. This observational, prospective, single-center study included consecutive IBD patients scheduled for anti-TNF therapy undergoing on the same day both TST and QFT-G-IT for screening of LTB, between 2008 and 2010. Patients with a prior history of known or suspicious (L)TB receiving (prophylactic) anti-TB therapy were excluded. Results. Seventy-five patients were finally included; 28 were treated with thiopurines (IMM group), while 47 (control group) received either 5-aminosalicylic acid (n = 41) or no therapy (newly diagnosed patients, n = 6). Overall, TST and QFT-G-IT were positive in 14 (18.7%) and 16 (21.3%) patients, respectively. There was no statistically significant difference between the two groups regarding the TST (p = 0.761) and QFT-G-IT (0.572) positivity. The overall concordance between the two tests was moderate (kappa = 0.584), being substantial in the IMM group (kappa = 0.700) and moderate in the control group (kappa = 0.498). Conclusion. These preliminary results suggest that IMM may not have a significant impact on either QFT-G-IT or TST, although larger, prospective studies are certainly warranted.

Prime-boost vaccination strategy with bacillus Calmette-Guérin (BCG) and liposomized alpha-crystalline protein 1 reinvigorates BCG potency.

Bacillus Calmette-Guérin (BCG) remains the only available and most widely administered vaccine against Mycobacterium tuberculosis (Mtb), yet it fails to protect vaccinated individuals either from primary infection or reactivation of latent tuberculosis (TB). Despite BCG's variable efficacy against TB, the fact remains that BCG imparts protection in children against the disease, indicating that BCG possesses a wide protective antigenic repertoire. However, its failure to impart protection in adulthood can be linked to its failure to generate long-lived memory response and elicitation of an inadequate immune response against latency-associated antigens. Therefore, to improve the protective efficacy of BCG, a novel vaccination strategy is required. Consequently, in the present study, we have exploited the vaccination potential of liposomized α-crystalline 1 (Acr1L), a latency-associated antigen to induce enduring protective immunity against Mtb in BCG-primed animals. It is noteworthy that an increase in the multi-functional [interferon (IFN)-γ(hi) /tumour necrosis factor (TNF)-α(hi) ] CD4 and CD8 T cells were observed in BCG-primed and Acr1L-boosted (BCG-Acr1L) animals, compared to BCG alone. Further, substantial expansion of both central memory (CD44(hi) /CD62L(hi) ) and effector memory (CD44(hi) /CD62L(lo) ) populations of CD4 and CD8 T cells was noted. Importantly, BCG-Acr1L exhibited significantly better protection than BCG, as evidenced by a reduction in the bacterial burden and histopathological data of the lungs. In essence, BCG-Acr1L could be a potent future vaccination strategy to reinvigorate BCG potency.

Tuberculosis chemoprophylaxis in rheumatoid arthritic patients receiving tumor necrosis factor inhibitors or conventional therapy

IntroductionPatients with rheumatoid arthritis (RA) have increased susceptibility to infection. The risk of acquiring infection including tuberculosis (TB) in RA may be increased in patients receiving any immuno-suppressive medication including anti-TNF therapy, which is used successfully for treating patients with rheumatoid arthritis. The aim of this work was to assess the risk of TB in RA patients on anti-TNF therapy compared to conventional disease modifying anti rheumatic drugs when screening for latent TB and TB chemoprophylaxis was applied. Patients and methodsThis study conducted on (235) RA patients indicated for either conventional therapy or anti-TNF therapy from 1-1-2010 to 1-10-2013. Assessment was done before RA treatment and included medical history, clinical examination, plain chest X-ray, HRCT chest QuantiFERON®-TB Gold in-tube (QFT-GIT) test and microbiologic investigations for tuberculosis when indicated. All patients with positive QFT-GIT received chemoprophylactic treatment for TB. ResultsThe studied rheumatoid arthritic patients were divided into two groups; group (A) included (105) RA patients on conventional disease modifying anti rheumatic drugs (DMARDs) with mean age (51±12) and group (B) included (130) RA patients on anti-TNF therapy with mean age (48±13). This study showed no significant increase of tuberculosis among patients on anti-TNF therapy (group B) compared to patients on (DMARDs) (group A). Chemo-prophylaxis in patients on anti-TNF therapy leads to prevention of reactivation of latent TB. ConclusionThere was no significant increased risk for tuberculosis among RA patients receiving anti-TNF therapy when screening and chemoprophylaxis was applied, so screening of RA patients before anti-TNF therapy for latent tuberculosis and TB chemoprophylaxis should be done.

Role of casual contacts in the recent transmission of tuberculosis in settings with high disease burden

Tuberculosis (TB) remains a major cause of morbidity and mortality worldwide. It is expected that combining multiple molecular methods will further help in focusing contact investigations. We performed a population-based molecular epidemiological study in six sites in China between 1 June 2009 and 31 December 2010. A genotyping method combining 7-loci MIRU-VNTR and IS6110-based RFLP was employed to determine predictors of recent transmission. A second interview was performed with the clustered patients to identify potential epidemiological links. The molecular clustering analysis revealed that 187 isolates (15.3%) were clustered by sharing identical VNTR-IS6110 combined patterns, with an estimated recent transmission index being 8.9%. None of these patients reported having contacts with other members within the same cluster. Nineteen of 121 reported having a history of contact with a TB case within 2 years before the current TB diagnosis. Additionally, geographical correlation was established for 19 cases in nine clusters, while only one possible epidemiological link was established in secondary interview. The results underscore the role of casual contact or reactivation of latent TB as a driving factor maintaining the current endemicity in rural China, with high disease burdens of tuberculosis.

Adverse effects of TNF inhibitors in SpA: are they different from RA?

Tumor necrosis factor (TNF) inhibitors were the first biologic drugs prescribed for the treatment of spondyloarthritis (SpA) and rheumatoid arthritis (RA). Although they provide significant improvement of signs and symptoms, TNF inhibitors need to be used frequently for a long period of time. The analysis of the follow-up of the largest national biologics registries has shown that the most important adverse effect of TNF inhibitors is infection, which is significantly higher than the non-biologic treatment group; reactivation of latent tuberculosis is three to four times more frequent in patients using monoclonal antibodies than soluble receptors. The only cancer site more frequent to be associated with TNF inhibitors in RA and SpA is the non-melanoma skin cancer. Paradoxical reactions do occur during anti-TNF treatment mainly in SpA, such as new manifestations or flares of acute uveitis, new onset of psoriasis, such as palmoplantar pustulosis, or new onset or flares of inflammatory bowel disease, which occurs especially during etanercept treatment.

Tuberculose disséminée survenant après traitement de la maladie de Crohn par infliximab : à propos d’un cas

Anti-tumor necrosis factor (TNF) therapy has been the major advance in the treatment of inflammatory bowel disease, especially Crohn's disease. But there is a higher risk of infections, especially tuberculosis (TB), in patients treated with anti-TNFα. The authors report a case of disseminated tuberculosis with the following features: pulmonary tuberculosis, left supra clavicular cervical and meditational lymphadenopathy, bilateral pleural effusion, peritoneal and splenic involvement. This disseminated tuberculosis was observed in a 39-year-old woman who was treated by infliximab for refractory Crohn's disease. The evolution with antituberculosis drugs was fatal, the death of the patient was due to hepatic encephalitis. The physicians should always be aware in the use of TNF-alpha blockers according to guidelines. Its recommended to realize a complete pretherapeutic assessment and it is necessary to follow-up the patients to detect possible reactivation of latent tuberculosis.

Identification of biomarkers for tuberculosis susceptibility via integrated analysis of gene expression and longitudinal clinical data.

Tuberculosis (TB) is an infectious disease caused by the bacteria Mycobacterium tuberculosis (Mtb) that affects millions of people worldwide. The majority of individuals who are exposed to Mtb develop latent infections, in which an immunological response to Mtb antigens is present but there is no clinical evidence of disease. Because currently available tests cannot differentiate latent individuals who are at low risk from those who are highly susceptible to developing active disease, there is considerable interest in the identification of diagnostic biomarkers that can predict reactivation of latent TB. We present results from our analysis of a controlled longitudinal experiment in which a group of rhesus macaques were exposed to a low dose of Mtb to study their progression to latent infection or active disease. Subsets of the animals were then euthanized at scheduled time points, and granulomas taken from their lungs were assayed for gene expression using microarrays. The clinical profiles associated with the animals following Mtb exposure revealed considerable variability, and we developed models for the disease trajectory for each subject using a Bayesian hierarchical B-spline approach. Disease severity estimates were derived from these fitted curves and included as covariates in linear models to identify genes significantly associated with disease progression. Our results demonstrate that the incorporation of clinical data increases the value of information extracted from the expression profiles and contributes to the identification of predictive biomarkers for TB susceptibility.

METHODOLOGICAL APPROACHES TO MYCOBACTERIUM TUBERCULOSIS GENOTYPING FOR EVOLUTIONARY AND EPIDEMIOLOGICAL RESEARCH

Abstract. Current genome evolution of Mycobacterium tuberculosis is marked by virtual absence of the lateral gene transfer leading to the clonal population of this species consisting of separate genetic families. Standard typing method of M. tuberculosis (IS6110-RFLP, spoligo- and VNTR-typing) are based on variation of mobile and repetitive elements and provide sufficient strain discrimination for epidemiological purposes such as, estimation of recent transmission versus reactivation of latent tuberculosis, laboratory contamination, mixed infection. At the same time, rapid evolution of some markers may lead to emergence of identical profiles in the non-related strains (homoplasy) due to convergent evolution. Use of different independent markers may help solve this problem. Regularly updated databases are available for global and local analysis and are also important for standardised terminology and designation of the genotypes. Some of the M. tuberculosis genetic families continue to circulate in the limited areas while other families have become omnipresent due to their likely increased transmissibility and pathogeneicity (e.g., Beijing and LAM). The most frequently isolated Russian subvariant Beijing B0/W148 is marked by significantly higher population growth compared to the Russian Beijing population as a whole and hence may be defined as a successful clone in Russia. Recent years revealed higher than previously thought level of genome variation in M. tuberculosis even between related isolates. The whole-genome sequencing may become a useful typing method if its cost is reduced to be similar to that of the traditional typing methods. Accumulation of the data on old and new markers, development and use of new algorithms of their analysis will help to refine our knowledge about evolution of M. tuberculosis and its families, will provide better tools for epidemiological monitoring of the circulating strains on local and global scale.