https://academicworks.medicine.hofstra.edu/cgi/viewcontent.cgi?article=1534&context=articles

HMGB1 in Health and Disease

The oral traditions of medicine and public health have it that malnutrition is an important risk factor for the development of tuberculosis (TB). Malnutrition profoundly affects cell-mediated immunity (CMI), and CMI is the principle host defense against TB. It makes biological sense. Although most health professionals readily accept this principle, much of this belief is based on uncontrolled observations such as disaster situations or on backwards logic from the cachexia common among TB patients. In fact, the evidence in humans is surprisingly thin from the perspective of scientific rigor. And few data, if any, quantify the extent of the relative or attributable risk of TB due to malnutrition. Moreover, until recently, data from experimental animals were based on animal models that were largely not relevant to human TB infection and disease. This article reviews the scientific data supporting the contention that malnutrition is an important risk factor for TB concentrating on observations in humans and on experimental animal studies based on a highly relevant animal model. If it is true, malnutrition may account for a greater population attributable risk of TB than HIV infection, and certainly a much more correctable one.

The relationship between malnutrition and tuberculosis: evidence from studies in humans and experimental animals

Understanding the physical characteristics of the local microenvironment in which Mycobacterium tuberculosis resides is an important goal that may allow the targeting of metabolic processes to shorten drug regimens. Pimonidazole hydrochloride (Hypoxyprobe) is an imaging agent that is bioreductively activated only under hypoxic conditions in mammalian tissue. We employed this probe to evaluate the oxygen tension in tuberculous granulomas in four animal models of disease: mouse, guinea pig, rabbit, and nonhuman primate. Following infusion of pimonidazole into animals with established infections, lung tissues from the guinea pig, rabbit, and nonhuman primate showed discrete areas of pimonidazole adduct formation surrounding necrotic and caseous regions of pulmonary granulomas by immunohistochemical staining. This labeling could be substantially reduced by housing the animal under an atmosphere of 95% O2. Direct measurement of tissue oxygen partial pressure by surgical insertion of a fiber optic oxygen probe into granulomas in the lungs of living infected rabbits demonstrated that even small (3-mm) pulmonary lesions were severely hypoxic (1.6 ± 0.7 mm Hg). Finally, metronidazole, which has potent bactericidal activity in vitro only under low-oxygen culture conditions, was highly effective at reducing total-lung bacterial burdens in infected rabbits. Thus, three independent lines of evidence support the hypothesis that hypoxic microenvironments are an important feature of some lesions in these animal models of tuberculosis.

https://iai.asm.org/content/iai/76/6/2333.full.pdf

Tuberculous granulomas are hypoxic in guinea pigs, rabbits, and nonhuman primates.

Bacille Calmette-Guerin (BCG) vaccination for the prevention of tuberculosis has been used in humans since 1921. Furthermore, for > 60 years it has been possible to separate BCG strains (defined here as a BCG vaccine maintained in a particular laboratory and used in a particular trial or set of trials) on the basis of in vitro and in vivo tests. Investigators have concluded that differences in the BCG strains used in efficacy trials on humans may be responsible for the wide range in levels of protection from tuberculosis reported in those trials. We review the development of the separate strains used in the trials included in a recent meta-analysis and examine data for and against the protective efficacy of different BCG strains. The difficulties in correlating results of in vitro and in vivo tests with protective efficacy in humans are discussed. The limited data available from human studies suggest that the BCG strain used for vaccination is not a significant determinant of the overall efficacy in the prevention of tuberculosis.

Relationship Between Bacille Calmette-Guerin (BCG) Strains and the Efficacy of BCG Vaccine in the Prevention of Tuberculosis

Mycobacterium tuberculosis has a penetrance of its host population that would be the envy of most human pathogens. About one-third of the human population would have a positive skin test for the infection and is thus thought to harbor the bacterium. Globally, 22 “high-burden” countries account for more than 80% of the active tuberculosis cases in the world, which shows the inequitable distribution of the disease. There is no effective vaccine against infection, and current drug therapies are fraught with problems, predominantly because of the protracted nature of the treatment and the increasing occurrence of drug resistance. Here we focus on the biology of the host-pathogen interaction and discuss new and evolving strategies for intervention.

/pdf/tuberculosis-what-we-don-t-know-can-and-does-hurt-us-184mdway7v.pdf

Tuberculosis: What We Don’t Know Can, and Does, Hurt Us

Host-parasite relationships in experimental airborne tuberculosis. 3. Relevance of microbial enumeration to acquired resistance in guinea pigs.

Host-parasite relationships in experimental airborne tuberculosis. IV. Early events in the course of infection in vaccinated and nonvaccinated guinea pigs.

New approaches consisting of 'multistage' vaccines against (TB) are emerging that combine early antigenic proteins with latency-associated antigens. In this study, HspX was tested for its potential to elicit both short- and long-term protective immune responses. HspX is a logical component in vaccine strategies targeting protective immune responses against primary infection, as well as against reactivation of latent infection, because as previously shown, it is produced during latency, and as our studies show, it elicits protection within 30 days of infection. Recent studies have shown that the current TB vaccine, bacilli Calmette-Guerin (BCG), does not induce strong interferon-γ T-cell responses to latency-associated antigens like HspX, which may be in part why BCG fails to protect against reactivation disease. We therefore tested HspX protein alone as a prophylactic vaccine and as a boost to BCG vaccination, and found that HspX purified from M. tuberculosis cell lysates protected mice against aerosol challenge and improved the protective efficacy of BCG when used as a booster vaccine. Native HspX was highly immunogenic and protective, in a dose-dependent manner, in both short- and long-term infection models. Based on these promising findings, HspX was produced as a recombinant protein in E. coli, as this would enable facile purification; however, recombinant HspX (rHspX) alone consistently failed to protect against aerosol challenge. Incubation of rHspX with mycobacterial cell lysate and re-purification following incubation restored the capacity of the protein to confer protection. These data suggest the possibility that the native form may chaperone an immunogenic and protective antigen that is mycobacteria-specific.

https://onlinelibrary.wiley.com/doi/pdf/10.1038/icb.2012.34

HspX-mediated protection against tuberculosis depends on its chaperoning of a mycobacterial molecule.

The results of research on the immunogenicity of experimental mycobacterial vaccines are characterized by a remarkable lack of agreement about which substances are most immunogenic. The disagreement has usually been attributed to the differences in the methods of preparing the vaccines. An alternative hypothesis is that the conflicting results are a product of the different methods used to assess the potency of the vaccines.To determine if the method by which a vaccine is tested is a major factor contributing to the disagreement, an experiment was conducted in which a series of five different vaccines was distributed to each of nine participating laboratories. Each investigator evaluated the potency of the vaccines in one or more animal models of his own choosing. This in effect held the method of vaccine preparation constant while permitting all other variables to change.The ranking of the five vaccines was random, thus demonstrating that the method by which a vaccine is tested influences the apparent potency of a vaccine. These results cast doubt on the conclusions about the relative potency of tuberculosis vaccines evaluated by different methods.

A co-operative evaluation of test systems used to assay tuberculosis vaccines.

HLA-B-associated transcript 3 (BAT3), also known as Scythe or BAG6, is a nuclear protein implicated in the control of apoptosis and natural killer (NK) cell-dendritic cell (DC) interaction. We demonstrate that BAT3 modulates the immune response by regulating the function of macrophages. BAT3 is released by macrophages in vitro and it down-regulates nitric oxide and proinflammatory cytokines release in IFN-γ and LPS stimulated macrophages. Furthermore, Mycobacterium tuberculosis-derived protein ESAT-6 (Rv3875) induced transient increase in the expression and release of BAT3 in macrophages. We show that induction of apoptosis by ESAT-6 is dependent on the cleavage of BAT3 by caspase-3 and proteasomal degradation. Our results also indicate that BAT3 regulates ESAT-6-induced apoptosis by interacting with anti-apoptotic protein BCL-2. Taken together, the data suggest that BAT3 plays a role in the early immune response to M. tuberculosis infection and may be a key protein associated with the fate of antigen presenting cells during infection.

/pdf/bat3-regulates-mycobacterium-tuberculosis-protein-esat-6-o5se8avwj3.pdf

BAT3 regulates Mycobacterium tuberculosis protein ESAT-6-mediated apoptosis of macrophages.

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