Number of viable virulent human-type (H37Rv) tubercle bacilli in the lungs of unvaccinated or BCG-vaccinated C57BL/6 mice at each interval following quantitative airborne infection. (C57BL/6 is a relatively resistant strain of mouse.) The vaccinated mice received 10⁶ viable BCG tubercle bacilli subcutaneously 6 weeks before they were challenged by aerosol with H37Rv. Other strains of mice may respond somewhat differently (45). Note that the initial logarithmic growth phase was followed by a plateau and is similar to that of the guinea pigs represented in Fig. 3 and to that of the rabbits represented in Fig. 4. Note also that the H37Rv bacillary titers reached higher levels in nonvaccinated mice and guinea pigs than in rabbits. Vaccination of mice lowers mycobacterial titers, because an effective immune response occurs faster. However, vaccination does not arrest the disease in mice (or in guinea pigs). (Courtesy of Ian M. Orme, Colorado State University, Fort Collins, CO; reproduced with permission.)

Number of viable human- or bovine-type tubercle bacilli in the lungs of Lurie's natively resistant and susceptible inbred rabbits at each interval following quantitative airborne infection (1, 33, 64). Commercially available New Zealand White rabbits resemble Lurie's resistant strain of rabbits (24, 25, 33, 35, 37, 44, 71). This graph makes several points: (i) higher bacillary titers occur with the bovine type than with the human type, because the bovine type is much more virulent for rabbits; (ii) higher bacillary titers occur with Lurie's susceptible rabbits, because they have less native and acquired immunity; (iii) many human-type tubercle bacilli (but not many of the more-virulent bovine type) are destroyed soon after they are inhaled by the resident pulmonary alveolar macrophages (AM); (iv) the AM of the resistant rabbits destroy more human-type tubercle bacilli than the AM of the susceptible rabbits; (v) the multiplications of the highly virulent bovine-type and the less-virulent human-type bacilli in both susceptible and resistant rabbits are the same during the logarithmic growth phase (i.e., both types of bacilli grow equally well in nonactivated macrophages); and (vi) acquired (adaptive) immunity has less effect on reducing bacillary numbers when the infecting strain is more virulent. Human-type tubercle bacilli are more virulent for mice and guinea pigs than they are for rabbits. Therefore, TB vaccines would be less beneficial for mice and guinea pigs than would TB vaccines for rabbits. Also, TB vaccines in mice and guinea pigs would have less ability to detect differences in two or more proposed vaccines than would TB vaccines (tested by tubercle counting) in rabbits. This graph shows the increase in the number of viable bacilli relative to the initial number deposited in the pulmonary alveoli, which is the number zero in the graph. (The inhaled dose of the human type was roughly 100 times the inhaled dose of the bovine type because of differences in their virulences.) Additional rabbits would be needed to obtain the standard errors for each time point. However, these results are consistent with the tubercle count data on these same rabbit races (1, 64, 69). The number of human- and bovine-type tubercle bacilli in the lungs of the resistant rabbits failed to decrease during the period illustrated, because liquefaction and cavity formation occurred (with the extracellular multiplication of the bacilli) (64). Liquefaction usually did not occur in the susceptible rabbits (64), probably because their macrophages develop lower levels of hydrolytic enzymes (see reference 34). (Reproduced from reference 1 with permission of the American Thoracic Society. Copyright © American Thoracic Society.)

Formalin-fixed lungs of a commercial New Zealand White rabbit that inhaled about 33,000 virulent human-type tubercle bacilli (H37Rv) 5 weeks previously. Upon dissection, these lungs contained 131 grossly visible primary tubercles with no apparent grossly visible secondary tubercles. The “ratio” (i.e., the number of tubercle bacilli estimated to be inhaled divided by the number of grossly visible primary tubercles produced) was 250. In other words, in this rabbit, 250 viable H37Rv tubercle bacilli must be inhaled to produce each visible primary pulmonary tubercle. Effective BCG (and other effective vaccines for tuberculosis) should increase this ratio at least 5-fold (35, 68). Small areas of caseous necrosis are visible in many of the tubercles. On the left, this photograph shows the ventral surface of the right upper lobe, right middle lobe, and azygous lobe. On the right, the photograph shows the ventral surface of the left upper lobe and left lower lobe. The right lower lobe (RLL) had been removed for culture. This RLL contained 23 grossly visible tubercles and 1.35 × 10⁵ culturable tubercle bacilli. Magnification, ×1.04. (Reproduced from reference 31 with permission of the publisher.)

Number of viable virulent human-type tubercle bacilli (H37Rv) in the lungs of BCG-vaccinated or control guinea pigs at each interval following quantitative airborne infection. Note that the in vivo bacillary growth curves for guinea pigs resemble those found for mice (Fig. 2) and for rabbits (Fig. 4). (Other experiments showed that the stationary phase in guinea pigs continues at least 18 weeks [2]). BCG-vaccinated guinea pigs are tuberculin positive before challenge. Therefore, the logarithmic growth stage ends sooner, and the number of viable tubercle bacilli is markedly reduced. In the vaccinated host, the disease is less severe, and the animals live longer. However, they usually die of the disease, because they do not develop effective CMI. The guinea pigs were immunized intradermally with live BCG 6 weeks before the aerosol challenge. Note also that BCG vaccination of guinea pigs lowers the bacillary titers 2 to 3 logs, whereas BCG in mice (Fig. 2) lowers these titers only 1 log (see also reference 49). BCG makes the guinea pigs strongly tuberculin positive but produces only a weak DTH in mice. This comparison further supports the principle that tissue-damaging DTH is an important immunological host defense against the intracellular multiplication of tubercle bacilli. However, Fig. 2 and 3 are not strictly comparable, because the mice represented in Fig. 2 inhaled more tubercle bacilli than the guinea pigs represented in Fig. 3. (Reproduced from reference 95 with permission of the American Thoracic Society. Copyright © American Thoracic Society.)