<i>Mycobacterium tuberculosis</i>H37Rv:ΔRD1 Is More Virulent than<i>M. bovis</i>Bacille Calmette‐Guérin in Long‐Term Murine Infection

Sherman, David R.; Guinn, Kristi M.; Hickey, Mark J.; Mathur, Sanjeev Kumar; Zakel, Kelly L.; Smith, Sherilyn

doi:10.1086/421472

Cited by 49 publications

(37 citation statements)

References 15 publications

(34 reference statements)

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“…Importantly, BCG::RD1 displays increased virulence which, however, does not attain that of M. tuberculosis H37Rv. This result is in accordance with the very recent observation that M. tuberculosis H37Rv deleted for the whole RD1 region is more virulent than BCG in long-term mouse infection (21), pointing out the contribution of other M. tuberculosis-specific genes or genomic regions in virulence. This increased growth of BCG::RD1 seems to be intimately linked to in vivo conditions since no difference in growth rate was observed in vitro for BCG::RD1 compared with BCG in the conditions tested.…”

Section: Discussionsupporting

confidence: 92%

Influence of ESAT-6 Secretion System 1 (RD1) of Mycobacterium tuberculosis on the Interaction between Mycobacteria and the Host Immune System

Majlessi

Brodin²,

Brosch³

et al. 2005

The Journal of Immunology

126

119

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The chromosomal locus encoding the early secreted antigenic target, 6 kDa (ESAT-6) secretion system 1 of Mycobacterium tuberculosis, also referred to as “region of difference 1 (RD1),” is absent from Mycobacterium bovis bacillus Calmette-Guérin (BCG). In this study, using low-dose aerosol infection in mice, we demonstrate that BCG complemented with RD1 (BCG::RD1) displays markedly increased virulence which albeit does not attain that of M. tuberculosis H37Rv. Nevertheless, phenotypic and functional analyses of immune cells at the site of infection show that the capacity of BCG::RD1 to initiate recruitment/activation of immune cells is comparable to that of fully virulent H37Rv. Indeed, in contrast to the parental BCG, BCG::RD1 mimics H37Rv and induces substantial influx of activated (CD44highCD45RB−CD62L−) or effector (CD45RB−CD27−) T cells and of activated CD11c+CD11bhigh cells to the lungs of aerosol-infected mice. For the first time, using in vivo analysis of transcriptome of inflammatory cytokines and chemokines of lung interstitial CD11c+ cells, we show that in a low-dose aerosol infection model, BCG::RD1 triggered an activation/inflammation program comparable to that induced by H37Rv while parental BCG, due to its overattenuation, did not initiate the activation program in lung interstitial CD11c+ cells. Thus, products encoded by the ESAT-6 secretion system 1 of M. tuberculosis profoundly modify the interaction between mycobacteria and the host innate and adaptive immune system. These modifications can explain the previously described improved protective capacity of BCG::RD1 vaccine candidate against M. tuberculosis challenge.

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Section: Discussionsupporting

confidence: 92%

Influence of ESAT-6 Secretion System 1 (RD1) of Mycobacterium tuberculosis on the Interaction between Mycobacteria and the Host Immune System

Majlessi

Brodin²,

Brosch³

et al. 2005

The Journal of Immunology

126

119

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“…This has led to the hypothesis that the ongoing evolution of BCG has resulted in the loss of regions involved in virulence and has caused the vaccine to become overattenuated (21). Despite the plethora of genomic data, the phenotypic consequence of mutations in BCG strains has not been convincingly demonstrated beyond the original loss of the RD1 region (18,24,34). Intriguingly, Raghavan and colleagues demonstrated that the transcription of genes within the RD2 region is influenced by the RD1-associated secreted virulence factor EspR, presenting a conceptual link between the deletion of these two elements from BCG (26).…”

Section: Discussionmentioning

confidence: 99%

Region of Difference 2 Contributes to Virulence ofMycobacterium tuberculosis

et al. 2011

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Mycobacterium bovis BCG strains are live, attenuated vaccines generated through decades of in vitro passage. Because in vitro growth does not select for interaction with the host, it has been hypothesized that genetic loci lost from BCG code for virulence determinants that are dispensable for growth in the laboratory, as exemplified by Region of Difference 1 (RD1), which was lost during the original derivation of BCG between 1908 and 1921. Region of Difference 2 (RD2) was lost during the ongoing propagation of BCG between 1927 and 1931, a time that coincides with reports of the ongoing attenuation of the vaccine. In this study, RD2 has been disrupted in M. tuberculosis H37Rv to test whether its loss contributed to the further attenuation of BCG. The deletion of RD2 did not affect in vitro growth; in contrast, the mutant manifested a decrease in pulmonary and splenic bacterial burdens and reduced pathology in C57BL/6 mice at early time points. This attenuated phenotype was complemented by reintroducing the genes Rv1979c to Rv1982 (including mpt64) but not Rv1985c to Rv1986. In RAW 264.7 macrophages, H37Rv:⌬RD2 showed a decreased proliferation and impaired modulation of the host innate immune response; both observations were complemented with Rv1979c to Rv1982. To test the effect of RD2 disruption on innate immunity, Rag ؊/؊ mice were infected; H37Rv:⌬RD2 had increased survival times compared those of H37Rv. These findings support the notion that the safety profile of certain BCG vaccines stems from multiple attenuating mutations, with the RD2 deletion resulting in a less-virulent organism through the impaired bacterial manipulation of the host innate immune response.Tuberculosis (TB) has been, and continues to be, one of the most widespread bacterial infections worldwide (www.who.int /tb/publications/global_report/2009/). On an individual level, the management of TB cases can be achieved in settings where prompt microbiologic diagnosis and appropriate treatment are provided. However, on a global public health level, this approach has had limited success, indicating a need to consider alternative strategies for TB control, including immunization.For nearly a century, Mycobacterium bovis BCG strains have been used as vaccines against TB. The efficacy observed in a number of different BCG trials has provided proof-of-principle data that TB should, in theory, be a disease that is preventable through vaccination. However, variable estimates of efficacy have diminished the enthusiasm for BCG immunization. While the effectiveness of BCG vaccines has been the subject of controversy, their safety profile generally has not been disputed; about 1 in 100,000 vaccinees suffers disseminated BCG disease, and those with BCG-osis typically have severe immunologic defects, either genetic (e.g., SCID) or acquired (e.g., AIDS) (4, 5, 37). Thus, BCG vaccines provide an example of a profound attenuation, enabling researchers to uncover virulence determinants that are present in M. tuberculosis and virulent M. bovis but absent from BCG...

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“…42 This suggests that additional genetic lesions contribute to the attenuation of BCG. Whole genome sequence comparison reveals 2,223 single nucleotide polymorphisms (SNPs) between BCG-Pasteur 1173P2 and M. tb H37Rv, and 736 SNPs between BCG-Pasteur and M. bovis AF2122/97.…”

Section: Bcg: a Brief Historymentioning

confidence: 99%

BCG Vaccines: Their mechanisms of attenuation and impact on safety and protective efficacy

Liu

Tran²,

Leung³

et al. 2009

Human Vaccines

123

117

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by MDR strains that are also resistant to a fluoroquinolone and at least one second-line injectable agent (amikacin, kanamycin and/or capreomycin), caught the world's attention after an outbreak in KwaZulu-Natal, South Africa, where 52 of 53 infected patients died. 2 HIV co-infection was a contributing factor in most of these deaths, and indeed, a deadly association between HIV and TB has been known almost since the start of the HIV-epidemic. Of the 1.7 million people who died from TB in 2006, an estimated 200,000 were co-infected with HIV. 1 Because of these situations, effective approaches alternative to antibiotics are urgently needed for the control of TB.Bacille Calmette-Guérin (BCG), an attenuated strain of Mycobacterium bovis (M. bovis), is currently the only available vaccine against TB. Since 1974, BCG vaccination has been included in the WHO Expanded Program on Immunization. 3 It is estimated that more than 3 billion individuals have been immunized with BCG and over 100 million doses of BCG are administered annually, making it the most widely used vaccine in humans. 3 Meta-analysis studies have confirmed that BCG protects children, providing >80% efficacy against severe forms of TB, including tuberculous meningitis and miliary TB. 4,5 In contrast, evidence for protection against pulmonary TB in adolescents and adults remains contentious as efficacy estimates from clinical trials, observational case control studies and contact studies range from 0 to 80%. 6,7 The reasons for the variable protective efficacy are unknown but several hypotheses have been proposed, including differences among the vaccine strains used in clinical studies, exposure of trial populations to environmental mycobacteria, nutritional or genetic differences in human populations, differences in trial methods, and variations among clinical M. tb strains. 8-13 These explanations are not mutually exclusive and all may contribute to the heterogeneity in vaccine efficacy.A key aspect of this issue may concern the nature of BCG attenuation. Although it is generally considered safe and has been used as a human vaccine since the 1920s, the mechanisms of BCG attenuation remain largely unknown. This is further complicated by the fact that BCG is not a single strain, but instead comprises a number of substrains that exhibit phenotypic and biochemical differences. 14 BCG strains also exhibit differences in residual virulence level. [15][16][17] However, side effects were often attributed to variations in the viability of vaccines during preparation procedures (e.g., freezedrying). 14 In other words, the observed differential virulence among Mycobacterium bovis Bacille Calmette-Guérin (BCG) was developed as an attenuated live vaccine for tuberculosis control nearly a century ago. Despite being the most widely used vaccine in human history, the mechanisms of attenuation of BCG remain poorly understood. BCG is not a single organism, but comprises a number of substrains that differ in genotypes and phenotypes. The impacts of these differences on BCG...

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Mycobacterium tuberculosisH37Rv:ΔRD1 Is More Virulent thanM. bovisBacille Calmette‐Guérin in Long‐Term Murine Infection

Cited by 49 publications

References 15 publications

Influence of ESAT-6 Secretion System 1 (RD1) of Mycobacterium tuberculosis on the Interaction between Mycobacteria and the Host Immune System

Influence of ESAT-6 Secretion System 1 (RD1) of Mycobacterium tuberculosis on the Interaction between Mycobacteria and the Host Immune System

Region of Difference 2 Contributes to Virulence ofMycobacterium tuberculosis

BCG Vaccines: Their mechanisms of attenuation and impact on safety and protective efficacy

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