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

Tuberculosis, caused by the intracellular pathogen Mycobacterium tuberculosis, is the world's leading cause of death in humans from a single infectious agent A safe and effective vaccine against this scourge is urgently needed This study demonstrates that immunization with the 30-kDa major secretory protein, alone or in combination with other abundant extracellular proteins of M tuberculosis, induces strong cell-mediated immune responses and substantial protective immunity against aerosol challenge with virulent M tuberculosis bacilli in the highly susceptible guinea pig model of pulmonary tuberculosis Protection is manifested by decreased clinical illness including decreased weight loss, reduced mortality, and decreased growth of M tuberculosis in the lungs and spleens of immunized animals compared with sham-immunized controls This study demonstrates that purified major extracellular proteins of M tuberculosis are candidate components of a subunit vaccine against tuberculosis and provides compelling support for the concept that extracellular proteins of intracellular pathogens are key immunoprotective molecules

https://www.pnas.org/content/pnas/92/5/1530.full.pdf

Protective immunity against tuberculosis induced by vaccination with major extracellular proteins of Mycobacterium tuberculosis.

An experimental vaccine that was based on secreted proteins of Mycobacterium tuberculosis was investigated in a mouse model of tuberculosis. I used a short-term culture filtrate (ST-CF) containing proteins secreted from actively replicating bacteria grown under defined culture conditions. The immunogenicity of the ST-CF was investigated in combination with different adjuvants, and peak proliferative responses were observed when ST-CF was administered with the surface-active agent dimethyldioctadecylammonium chloride. The immunity induced by this vaccine was dose dependent, and, in the optimal concentration, the vaccine induced a potent T-helper 1 response which efficiently protected the animals against a subsequent challenge with virulent M. tuberculosis. Antigenic targets for the T cells generated were mapped by employing narrow-molecular-weight fractions of ST-CF. The experimental vaccine primed a broadly defined T-cell repertoire directed to multiple secreted antigens present in ST-CF. A vaccination with viable Mycobacterium bovis bacillus Calmette-Guerin (BCG), in contrast, induced a restricted T-cell reactivity directed to two secreted protein fractions with molecular masses of 5 to 12 and 25 to 35 kDa. The protective efficacy of the ST-CF vaccine was compared with that of a BCG standard vaccine, and both induced a highly significant protection of equal magnitude. The vaccination with ST-CF gave rise to a population of long-lived CD4 cells which could be isolated 22 weeks after the vaccination and could adoptively transfer acquired resistance to T-cell-deficient recipients. My results confirm the hypothesis that M. tuberculosis cells release protective antigens during growth. The high efficacy of a subunit vaccine observed in the present study is discussed as a possible alternative to a live recombinant vaccine carrier.

https://iai.asm.org/content/iai/62/6/2536.full.pdf

Effective vaccination of mice against Mycobacterium tuberculosis infection with a soluble mixture of secreted mycobacterial proteins.

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.

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.

Some aspects of the early development of tuberculous infection were compared in vaccinated and nonvaccinated guinea pigs after low dose, respiratory challenge with Mycobacterium tuberculosis H37Rv. Changes with time of the logarithm of the number of viable mycobacteria recovered from the lungs of animals from both groups sacrificed at several intervals between zero and 35 days after challenge described a sigmoid curve with three phases: a lag phase, a phase of logarithmic growth, and a stationary or decline phase. The influence of vaccination on the rate of accumulation of the challenge organism was not detected before 10 to 14 days after infection. The significance of these results is discussed with reference to the important role a critical amount of antigen can play in any test system in which acquired cellular immunity is studied.

Host-Parasite Relationships in Experimental Airborne Tuberculosis

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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.

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

Host-Parasite Relationships in Experimental Airborne Tuberculosis