Community-wide transmission of a strain of Mycobacterium tuberculosis that causes reduced lung pathology in mice

Abstract

Since 1992, Mycobacterium tuberculosis strain PG004 has been responsible for a large outbreak of tuberculosis in one northern Californian community. There are no epidemiological or host factors to explain this outbreak. PG004 was therefore analysed for biological characteristics that might explain its widespread distribution. BABL/c mice were infected intravenously with PG004, non-PG004 M. tuberculosis strains CCC20 and CCC23 isolated from patients in the same community, and the laboratory strain H37Rv. The susceptibility of PG004 to reactive nitrogen intermediates (RNIs) was compared with that of H37Rv. Because of the reported association of phenolic glycolipid production with mouse virulence, a junction sequence in the polyketide synthase gene cluster (pks15/1) was compared among strains. It was found that the most virulent strain, based on mouse mortality, was not the outbreak strain PG004, but the non-outbreak strain CCC20. This strain had an intact pks15/1 sequence identical to that of another non-outbreak strain, CCC23, which caused death in only one out of ten mice in 300 days of follow-up. The outbreak strain PG004 had a frameshift mutation in the pks15/1 sequence identical to the sequence of H37Rv, and it was no more resistant to RNIs than H37Rv. The most distinguishing feature of PG004 was its failure to produce well-organized, coalescing granulomas in mouse lungs. The lack of organized granulomas and reduced pathology may prevent restriction of PG004 in the lungs and allow it to spread into alveolar air spaces and escape the host to transmit to others. Humans with reduced lung pathology may remain undiagnosed and untreated in the community longer than those with severe disease. The over-representation of an M. tuberculosis strain in a community, therefore, may be more associated with strains that cause reduced rather than severe lung pathology.

Differential Virulence and Disease Progression following Mycobacterium tuberculosis Complex Infection of the Common Marmoset (Callithrix jacchus)

“…Scale bars were 1 mm (G to I), 0.2 mm (A, B, and D to F), and 0.5 mm (C). ment and extrapulmonary disease in patients infected with these strains, and there is precedent for this phenomenon in mice (61). Both the M. africanum and the Beijing strains showed increased extrapulmonary dissemination of disease to the spleen and liver, while NHPs infected with CDC 1551 showed the slowest rate of disease progression and more limited extrapulmonary dissemination.…”

Genetic Diversity in Mycobacterium tuberculosis Clinical Isolates and Resulting Outcomes of Tuberculosis Infection and Disease

“…However, further studies have shown that this surface lipid is not present in all hypervirulent Beijing strains (99). For example, a comparison of an outbreak Beijing strain to a nonoutbreak Beijing strain in California identified a 7-bp frameshift mutation on the pks gene in the outbreak strain, while the nonoutbreak strain had an intact pks gene cluster that is typical of other virulent Beijing strains (19).…”