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Although the bovine tuberculosis (TB) agent, Mycobacterium bovis , may infect humans and cause disease, long-term epidemiological data indicate that humans represent a spill-over host in which infection with M. bovis is not self-maintaining. Indeed, human-to-human transmission of M. bovis strains and other members of the animal lineage of the tubercle bacilli is very rare. Here, we report on three mutations affecting the two-component virulence regulation system PhoP/PhoR (PhoPR) in M. bovis and in the closely linked Mycobacterium africanum lineage 6 (L6) that likely account for this discrepancy. Genetic transfer of these mutations into the human TB agent, Mycobacterium tuberculosis , resulted in down-regulation of the PhoP regulon, with loss of biologically active lipids, reduced secretion of the 6-kDa early antigenic target (ESAT-6), and lower virulence. Remarkably, the deleterious effects of the phoPR mutations were partly compensated by a deletion, specific to the animal-adapted and M. africanum L6 lineages, that restores ESAT-6 secretion by a PhoPR-independent mechanism. Similarly, we also observed that insertion of an IS 6110 element upstream of the phoPR locus may completely revert the phoPR-bovis –associated fitness loss, which is the case for an exceptional M. bovis human outbreak strain from Spain. Our findings ultimately explain the long-term epidemiological data, suggesting that M. bovis and related phoPR -mutated strains pose a lower risk for progression to overt human TB, with major impact on the evolutionary history of TB.

Mycobacterium bovis bacille Calmette-Guérin (BCG), an experimental vaccine designed to protect cattle from bovine tuberculosis, was administered for the first time to a newborn baby in Paris in 1921. Over the past century, BCG has saved tens of millions of lives and has been given to more humans than any other vaccine. It remains the sole tuberculosis vaccine licensed for use in humans. BCG provides long-lasting strong protection against miliary and meningeal tuberculosis in children, but it is less effective for the prevention of pulmonary tuberculosis, especially in adults. Evidence mainly from the past two decades suggests that BCG has non-specific benefits against non-tuberculous infections in newborn babies and in older adults, and offers immunotherapeutic benefit in certain malignancies such as non-muscle invasive bladder cancer. However, as a live attenuated vaccine, BCG can cause localised or disseminated infections in immunocompromised hosts, which can also occur following intravesical installation of BCG for the treatment of bladder cancer. The legacy of BCG includes fundamental discoveries about tuberculosis-specific and non-specific immunity and the demonstration that tuberculosis is a vaccine-preventable disease, providing a foundation for new vaccines to hasten tuberculosis elimination.

Tuberculosis (TB), caused by Mycobacterium tuberculosis complex (MTBC) pathogens, remains a global health threat. While bacterial genetic adaptations during host infection are poorly understood, phase variation in genomic homopolymeric tracts (HT) may drive pathogenicity evolution. Here, we demonstrate that M. bovis exploits HT insertion mutations in the fumarate reductase-encoding frd operon to subvert host immunometabolism. In macrophages, wild-type M. bovis secretes FRD-catalyzed succinate, stabilizing hypoxia-inducible factor-1α (HIF-1α) to drive glycolytic reprogramming and IL-1β production. This activates IL-1R-dependent Th1 immunity, restraining bacterial replication. Conversely, M. bovis frd HT insertion mutants impair succinate secretion, suppressing HIF-1α/IL-1β signaling and redirecting immunity toward pathogenic Th17 responses that promote neutrophil infiltration and tissue necrosis. Mice infection models reveal that M. bovis frd mutants exhibit enhanced pathogenicity, with higher pulmonary bacterial burdens. IL-1R blockade phenocopies frd HT insertion mutation effects, exacerbating lung pathology. Crucially, conserved frd HT polymorphisms in clinical M. tb isolates suggest shared immune evasion strategies across MTBC pathogens. Our work uncovers the bacterial gene phase variation mechanism of hijacking the succinate/HIF-1α/IL-1β axis to operate host immunity, providing a framework for targeting host metabolic checkpoints in TB therapy. In this work, authors show that Mycobacterium bovis exploits frd operon phase variation to hijack host immunity. By disrupting bacterial succinate production, identified mutations steer immunity toward harmful Th17 responses instead of protective Th1, worsening disease.

Mycobacterium tuberculosis PtpA is a secreted effector protein that dephosphorylates several proteins in the host cell cytoplasm, such as p-JNK, p-p38, and p-VPS33B, leading to suppression of host innate immunity. Here we show that, in addition, PtpA enters the nucleus of host cells and regulates the expression of host genes, some of which are known to be involved in host innate immunity or in cell proliferation and migration (such as GADD45A ). PtpA can bind directly to the promoter region of GADD45A in vitro. Both phosphatase activity and DNA-binding ability of PtpA are important in suppressing host innate immune responses. Furthermore, PtpA-expressing Mycobacterium bovis BCG promotes proliferation and migration of human lung adenoma A549 cells in vitro and in a mouse xenograft model. Further research is needed to test whether mycobacteria, via PtpA, might affect cell proliferation or migration in humans. Mycobacterium tuberculosis secretes a protein, PtpA, that dephosphorylates proteins in the host cell cytoplasm, weakening immune responses. Here, the authors show that PtpA also enters the nucleus, affects the expression of several host genes, and promotes proliferation and migration of a cancer cell line.

Quantifying pathogen transmission in multi-host systems is difficult, as exemplified in bovine tuberculosis (bTB) systems, but is crucial for control. The agent of bTB, , persists in cattle populations worldwide, often where potential wildlife reservoirs exist. However, the relative contribution of different host species to bTB persistence is generally unknown. In Britain, the role of badgers in infection persistence in cattle is highly contentious, despite decades of research and control efforts. We applied Bayesian phylogenetic and machine-learning approaches to bacterial genome data to quantify the roles of badgers and cattle in infection dynamics in the presence of data biases. Our results suggest that transmission occurs more frequently from badgers to cattle than (10.4x in the most likely model) and that within-species transmission occurs at higher rates than between-species transmission for both. If representative, our results suggest that control operations should target both cattle and badgers.

The ongoing severe acute respiratory sickness coronavirus 2 (SARS‐CoV‐2) pandemic has resulted in more than 3,600,000 detected cases of COVID‐19 illness and nearly 260,000 deaths worldwide as of May 6, 2020. Recently, BCG vaccination was shown to correlate with reduced COVID‐19 case fatality rates (preprint: Miller et al , 2020; preprint: Sala & Miyakawa, 2020; https://www.jsatonotes.com/2020/03/if-i-were-north-americaneuropeanaustral.html ). The most recent data from publicly available resources also indicate that both COVID‐19 incidence and total deaths are strongly associated with the presence or absence of national mandatory BCG vaccination programs. As seen in Table 1, seven of eight countries with very low numbers of total deaths (< 40 per 1 million population) adopted a mandatory BCG vaccination program using one of a set of 6 separate BCG strains (Table 1). In contrast, COVID‐19 mortality was markedly higher in countries where BCG vaccination is not widely administered or is given only to high‐risk groups. COVID‐19 mortality was also higher in countries where widespread BCG vaccination was discontinued more than 20 years ago and in countries that used the BCG Denmark strain regularly or temporarily. This raises the question of whether BCG vaccination and reduced COVID‐19 mortality are causally related. An additional question is why different BCG strains may be variably associated with mortality. Graphical Abstract Is there more to BCG vaccination and reduced COVID‐19 case fatality rates than a mere correlation? Masayuki Miyasaka comments on this timely but intriguing question and provide some interesting points to consider.

Tuberculosis (TB), caused by the intracellular bacterium (Mtb), remains a major health threat. A live, attenuated mycobacterium known as Bacille Calmette-Guérin (BCG), derived from the causative agent of cattle TB, , has been in clinical use as a vaccine for 90 years. The current incidence of TB demonstrates that BCG fails to protect sufficiently against pulmonary TB, the major disease manifestation and source of dissemination. The protective efficacy of BCG is on average 50% but varies substantially with geographical location and is poorer in those with previous exposure to mycobacteria. BCG can also cause adverse reactions in immunocompromised individuals. However, BCG has contributed to reduced infant TB mortality by protecting against extrapulmonary TB. In addition, BCG has been associated with reduced general childhood mortality by stimulating immune responses. In order to improve the efficacy of BCG, two major strategies have been employed. The first involves the development of recombinant live mycobacterial vaccines with improved efficacy and safety. The second strategy is to boost BCG with subunit vaccines containing Mtb antigens. This article reviews recombinant BCG strains that have been tested against TB in animal models. This includes BCG strains that have been engineered to induce increased immune responses by the insertion of genes for Mtb antigens, mammalian cytokines, or host resistance factors, the insertion of bacterial toxin-derived adjuvants, and the manipulation of bacterial genes in order to increase antigen presentation and immune activation. Subunit vaccines for boosting BCG are also briefly discussed.

•BCG zmp1 mutants confer increased protection in a guinea pig model of TB as compared to BCG.•The improved protective efficacy of zmp1 deletion mutants is independent on the BCG sub-strain.•BCG zmp1 deletion mutants demonstrate an improved safety profile in a SCID mouse model.•BCG zmp1 mutants are promising candidates for further vaccine development due to their protective efficacy and safety profile. Having demonstrated previously that deletion of zinc metalloprotease zmp1 in Mycobacterium bovis BCG increased immunogenicity of BCG vaccines, we here investigated the protective efficacy of BCG zmp1 deletion mutants in a guinea pig model of tuberculosis infection. zmp1 deletion mutants of BCG provided enhanced protection by reducing the bacterial load of tubercle bacilli in the lungs of infected guinea pigs. The increased efficacy of BCG due to zmp1 deletion was demonstrated in both BCG Pasteur and BCG Denmark indicating that the improved protection by zmp1 deletion is independent from the BCG sub-strain. In addition, unmarked BCG Δzmp1 mutant strains showed a better safety profile in a CB-17 SCID mouse survival model than the parental BCG strains. Together, these results support the further development of BCG Δzmp1 for use in clinical trials.

How Mycobacterium tuberculosis (Mtb) rewires macrophage energy metabolism to facilitate survival is poorly characterized. Here, we used extracellular flux analysis to simultaneously measure the rates of glycolysis and respiration in real time. Mtb infection induced a quiescent energy phenotype in human monocyte-derived macrophages and decelerated flux through glycolysis and the TCA cycle. In contrast, infection with the vaccine strain, M. bovis BCG, or dead Mtb induced glycolytic phenotypes with greater flux. Furthermore, Mtb reduced the mitochondrial dependency on glucose and increased the mitochondrial dependency on fatty acids, shifting this dependency from endogenous fatty acids in uninfected cells to exogenous fatty acids in infected macrophages. We demonstrate how quantifiable bioenergetic parameters of the host can be used to accurately measure and track disease, which will enable rapid quantifiable assessment of drug and vaccine efficacy. Our findings uncover new paradigms for understanding the bioenergetic basis of host metabolic reprogramming by Mtb.

Mycobacterium bovis Bacillus Calmette–Guérin (BCG) has long been used as a vaccine against tuberculosis and bladder cancer. BCG is also an effective adjuvant; it has long been known that its cell wall acts as an adjuvant. Recent research has revealed that various lipids and glycolipids are involved in the induction of innate immunity as ligands for C-type lectin receptors. However, the effects of the components of BCG used as adjuvants are not comparable to those of live BCG. On the other hand, since live bacteria are essential for the protective effect of BCG, a hypothesis has been proposed that proteins actively secreted by living bacteria are responsible for important immune responses, and various secreted proteins have been characterized. However, this hypothesis has not yet been verified. In this review, we discuss the purification, identification, and characterization of BCG-secreted proteins, namely culture filtrate proteins (CFP), and mention new possibilities for CFP.