Epidemiologic consequences of microvariation in Mycobacterium tuberculosis.
BACKGROUND
Evidence from genotype-phenotype studies suggests that genetic diversity in pathogens have clinically relevant manifestations that can impact outcome of infection and epidemiologic success. We studied 5 closely related Mycobacterium tuberculosis strains that collectively caused extensive disease (n = 862), particularly among US-born tuberculosis patients.


METHODS
Representative isolates were selected using population-based genotyping data from New York City and New Jersey. Growth and cytokine/chemokine response were measured in infected human monocytes. Survival was determined in aerosol-infected guinea pigs.


RESULTS
Multiple genotyping methods and phylogenetically informative synonymous single nucleotide polymorphisms showed that all strains were related by descent. In axenic culture, all strains grew similarly. However, infection of monocytes revealed 2 growth phenotypes, slower (doubling ∼55 hours) and faster (∼25 hours). The faster growing strains elicited more tumor necrosis factor α and interleukin 1β than the slower growing strains, even after heat killing, and caused accelerated death of infected guinea pigs (∼9 weeks vs 24 weeks) associated with increased lung inflammation/pathology. Epidemiologically, the faster growing strains were associated with human immunodeficiency virus and more limited in spread, possibly related to their inherent ability to induce a strong protective innate immune response in immune competent hosts.


CONCLUSIONS
Natural variation, with detectable phenotypic changes, among closely related clinical isolates of M. tuberculosis may alter epidemiologic patterns in human populations.
Public Health Research Institute, Newark, NJ, USA.
Barun
B
Mathema
Natalia
N
Kurepina
Guibin
G
Yang
Elena
E
Shashkina
Claudia
C
Manca
Carolina
C
Mehaffy
Helle
H
Bielefeldt-Ohmann
Shama
S
Ahuja
Dorothy A
DA
Fallows
Angelo
A
Izzo
Pablo
P
Bifani
Karen
K
Dobos
Gilla
G
Kaplan
Barry N
BN
Kreiswirth
D000328:Adult; D000818:Animals; D061245:Axenic Culture; D016207:Cytokines / Q000378:metabolism; D019143:Evolution, Molecular; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006168:Guinea Pigs; D006801:Humans; D007113:Immunity, Innate; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000145:classification / Q000235:genetics* / Q000302:isolation & purification*; D009515:New Jersey / Q000453:epidemiology; D009519:New York City / Q000453:epidemiology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D014376:Tuberculosis / Q000453:epidemiology* / Q000382:microbiology
D016207:Cytokines