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Tuberculosis (TB) kills more people than any other single infectious disease globally. Despite decades of research, there is no vaccine to prevent TB transmission. Bacille Calmette-Guérin (BCG) vaccine, developed a century ago, is effective against childhood (disseminated and miliary) TB. However, its protective efficacy against pulmonary TB varies from 0 to 80% in different populations. One of the main reasons for the lack of an effective vaccine against TB is the lack of complete understanding about correlates of protective immunity on which to base vaccine design and development. However, some household contacts who are extensively exposed to Mtb infection remain persistently negative to tuberculin skin test and interferon-gamma assay. These individuals, called 'resisters', clear Mtb infection early before the development of acquired immunity. The immunological basis of early Mtb clearance is yet to be established; however, innate lymphocytes such as monocytes/macrophages, dendritic cells, neutrophils and natural killer cells, and innate-like T cells such as mucosal-associated invariant T cells, invariant natural killer (NK) T cells and gamma-delta (γδ) T cells, have been implicated in this early protection. In recent years, NK cells have attracted increasing attention because of their role in controlling Mtb infection. Emerging data from animal and epidemiological studies indicate that NK cells play a significant role in the fight against Mtb. NK cells express various surface markers to recognize and kill both Mtb and Mtb-infected cells. This review presents recent advances in our understanding of NK cells in the fight against Mtb early during infection, with emphasis on cohort studies., (© 2020 British Society for Immunology.)

Induction of Th1 (cell-mediated) immunity and associated production of IFN-γ by CD4+ T cells has been widely used as a marker of protective immunity against tuberculosis (TB). This is based on two assumptions. The first is the widely accepted view that Mycobacterium tuberculosis ( Mtb ), the causative agent of TB is an obligate intracellular pathogen, and the second is based on the Th1/Th2 paradigm, which posits that polarization of CD4+ T cells into type1 (cell-mediated) and type 2 (humoral) is central for proper induction of protective immunity against pathogens. However, almost all licensed vaccines currently in use are primarily anti-body based whether intracellular or extra-cellular. In addition, converging data from both animal models and humans indicate that the production of IFN-γ alone is not sufficient to confer protection against TB. In addition, a substantial body of the literature suggests that, in addition to Th1 cells, antibody classes and sub-classes are protective against TB. In a recent study, we have shown that there is a synergy between IFN-γ (cell-mediated) and IgA (humoral) in human population in an endemic setting. In this review, current data from both animal and human studies that support mixed Th1 and Th2 responses that are protective against Mtb and other pathogens are presented.

One-third of the world population is estimated to have Mycobacterium tuberculosis infection. Accurate and timely identification of infected individuals is critical for treatment and control. The current diagnostic methods lack the desired sensitivity and specificity, require sophisticated equipment and skilled workforce or take weeks to yield results. Diagnosis of extrapulmonary TB, TB-HIV co-infection, childhood TB and sputum smear-negative pulmonary TB pose serious challenges. Interest in developing serodiagnostic methods is increasing because detection of antibody is rapid, simple and relatively inexpensive, and does not require a living cell for detection. Three types of tests, namely screening tests to overcome diagnostic delay, specific tests for diagnosis of extrapulmonary TB and other bacteriologically negative cases, and tests for vaccine-induced immunity need critical consideration. Several factors must be considered to develop serodiagnostic methods for TB. Antigen recognition by infected individuals is highly heterogeneous due to stage of disease, differences in HLA types, strain of the bacilli, health of the patient and bacillary load. With advances in molecular biological techniques, a number of novel antigens have been identified. Some of these antigens have proven valuable in detecting specific antibodies in some of the most challenging TB patients. The best example is a fusion protein containing several M. tuberculosis proteins (e.g. CFP-10, MTB8, MTB48, MTB81 and the 38-kDa protein) which showed encouraging results in detecting antibodies in sera of patients, including TB-HIV co-infection. This review presents progress made in the serodiagnosis of TB during the last decade.

The world is confronted with major tuberculosis (TB) outbreaks at a time when the protection of bacillus Calmette-Guérin (BCG) vaccine has become inconsistent and controversial. Major TB outbreaks are caused by a group of genetically similar strains of Mycobacterium tuberculosis (Mtb) strains, including the Beijing family genotypes. The Beijing family genotypes exhibit important pathogenic features such high virulence, multi-drug resistance and exogenous reinfection. These family strains have developed mechanisms that modulate/suppress immune responses by the host, such as inhibition of apoptosis of infected macrophages, diminished production of interleukin (IL)-2, interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha and elevated levels of IL-10 and IL-18. They demonstrate distinct expression of proteins, such as several species of alpha-crystallin (a known Mtb virulence factor), but decreased expression of some antigens such as heat shock protein of 65 kDa, phosphate transport subunit S and a 47-kDa protein. In addition, the Beijing family strains specifically produce a highly bioactive lipid (a polyketide synthase)-derived phenolic glycolipid. This altered expression of proteins/glycolipids may be important factors underlying the success of the Beijing family strains. The Beijing family strains are speculated to have originated from South-east Asia, where BCG vaccination has been used for more than 60 years. The hypothesis that mass BCG vaccination may have been a selective factor that favoured genotypic and phenotypic characteristic acquired by the Beijing family strains is discussed.

Mycobacterium tuberculosis (Mtb) early secreted protein antigen 6 (ESAT-6) and culture filtrate protein 10 (CFP-10) are among candidate vaccines against tuberculosis (TB). Results of experimental animal models show that these antigens are associated with induction of strong T cell immunity [interferon (IFN)-γ production], while others report that these proteins as virulent factors involved in pathogenicity of Mtb infection. However, the role of ESAT-6/CFP-10 during natural Mtb infections in humans has not been established. In this paper we present results of a longitudinal study from an Mtb-infected human population from an endemic setting. Whole blood assay was used to determine levels of IFN-γ, tumour necrosis factor (TNF)-α and interleukin (IL)-10 against rESAT-6/CFP-10 in TB patients, household contacts and community controls. The levels of IFN-γ, TNF-α and IL-10 against rESAT-6/CFP-10 at baseline were significantly higher in patients and community controls than in household contacts. In patients, no significant difference was observed in the level of these cytokines before and after chemotherapy whereas, in contacts, the level of these cytokines increased significantly and progressively over time. The study shows that the levels of IFN-γ, TNF-α and IL-10 against rESAT-6/CFP-10 are depressed during Mtb infection or exposure but are elevated during clinical TB. Our findings from a study of naturally infected human population suggest that IFN-γ, TNF-α and IL-10 against rESAT-6/CFP-10 are markers for clinical TB but not for protective immunity. [ABSTRACT FROM AUTHOR]

Bacille Calmette-Guérin (BCG), developed a century ago, is the only licensed tuberculosis (TB) vaccine in use to date. The protective efficacy of BCG against TB varies with no apparent protection in some population, and mechanisms of its immune protection is poorly known, and yet BCG is the most widely used vaccine, with more than 4 billion BCG-vaccinated children globally. BCG is probably the only licensed vaccine currently in use believed to mediate immune protection through the production of interferon (IFN)-γ by CD4 T cells, which in turn activates macrophages to kill Mycobacterium tuberculosis ( Mtb). Currently, a number of new TB candidate vaccines are in different phases of clinical trial. The majority of these new vaccines are either recombinant forms of BCG or prime boosters of BCG (rBCG) and their immunogenicity is tested using BCG as a benchmark by measuring specific IFN-γ produced by CD4+ T cells as a protective immune marker. However, some recent studies that examined mechanisms of immune protection of BCG in animals and humans have reported a lack of correlation between IFN-γ production by CD4 cells and BCG-induced immune protection. These studies point to the fact that there is a missing link in our understanding of TB immunology. Conversely, there is emerging evidence that other T cell subsets (gammadelta, γδ), CD8+ T cells and natural killer (NK) cells may play a vital role in immune protection against Mtb infection and BCG-induced immune protection. γδ T cells and NK cells, which were considered to be part of the innate immunity in the past, have been shown to develop immunological memory upon re-encounter with the same pathogen. In this paper, the controversy over the role of IFN-γ as a marker for protective immunity against TB, and emerging data on the role of γδ T cells, CD8+ and NK cells in TB immunology, will be presented. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) caused by Mycobacterium tuberculosis ( Mtb) is one of the most important infectious diseases globally. Immune effector mechanisms that lead to protection or development of clinical disease are not fully known. It is generally accepted that cell-mediated immunity (CMI) plays a pivotal role in controlling Mtb infection, whereas antibody responses are believed to have no protective role. This generalization is based mainly on early classical experiments that lacked standard protocols, and the T helper type 1 (Th1)/Th2 paradigm. According to the Th1/Th2 paradigm Th1 cells protect the host from intracellular pathogens, whereas Th2 cells protect form extracellular pathogens. During the last two decades, the Th1/Th2 paradigm has dominated not only our understanding of immunity to infectious pathogens but also our approach to vaccine design. However, the last few years have seen major discrepancies in this model. Convincing evidence for the protective role of antibodies against several intracellular pathogens has been established. Studies of B cell-deficient mice, severe combined immunodeficiency (SCID) mice, passive immunization using monoclonal (mAb) and polyclonal antibodies and immune responses against specific mycobacterial antigens in experimental animals reveal that, in addition to a significant immunomodulatory effect on CMI, antibodies play an essential protective role against mycobacterial infections. In this review, our current understanding of the essential role of antibodies during Mtb infections, limitations of the Th1/Th2 model and the unfolding interdependence and mutual regulatory relationships between the humoral and CMI will be presented and discussed. [ABSTRACT FROM AUTHOR]

Recently, mouse models for latent (LTB) and slowly progressive primary tuberculosis (SPTB) have been established. However, cytokine profiles during the two models are not well established. Using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) we studied the expression levels of interleukin (IL)-2, IL-4, IL-10, IL-12, IL-15, interferon (IFN)-γ and tumour necrosis factor (TNF)-α during the course of LTB and SPTB in the lungs and spleens of B6D2F1Bom mice infected with the H37Rv strain of Mycobacterium tuberculosis ( Mtb). The results show that, except for IL-4, cytokine expression levels were significantly higher during SPTB than LTB in both the lungs and spleens. During LTB, all the cytokines (except IL-2 in the lungs) had higher expression levels during the initial period of infection both in the lungs and spleens. During SPTB, the expression levels of IL-15 increased significantly from phases 1 to 3 in the lungs. The expression levels of IL-10, IL-12 and IFN-γ increased significantly from 2 to 3 in the lungs. IL-10 and IL-15 increased significantly from phases 2 to 3, whereas that of TNF-α decreased significantly and progressively from phases 1 to 3 in the spleens. Over-expression of proinflammatory cytokines during active disease has been well documented, but factor(s) underlying such over-expression is not known. In the present study, there was a progressive and significant increase in the expression levels of IL-15, together with Th1 cytokines (IL-12 and IFN-γ) during SPTB but a significant decrease during LTB. IL-15 is known to up-regulate the production of proinflammatory cytokines, IL-1β, IL-8, IL-12, IL-17, IFN-γ and TNF-α and has an inhibitory effect on activation-induced cell death. IL-15 is known to be involved in many proinflammatory disease states such as rheumatoid arthritis, sarcoidosis, inflammatory bowel diseases, autoimmune diabetes, etc. Our results, together with the above observations, suggest that IL-15 may play an important role in mediating active disease during Mtb infection. [ABSTRACT FROM AUTHOR]