Course of murine tuberculosis and response to first-line therapy depends on route of infection and inoculum size.
BACKGROUND
In the search for new anti-tuberculosis drugs, numerous potential drugs are being screened in vitro. In animal models, promising new anti-tuberculosis drugs are assessed in terms of toxic side effects and comparative therapeutic efficacy. Mice are frequently used and experimental infections are established in different ways.


OBJECTIVE
To investigate to what extent the route of Mycobacterium tuberculosis inoculation is a determinant in the pathogenesis of tuberculosis (TB) and the therapeutic outcome. Results will contribute to insight into the translational value of TB models used for preclinical studies.


METHODS
TB in mice was established through intratracheal or intravenous mycobacterial inoculation. The efficacy of a 26-week treatment regimen was evaluated, including assessment of relapse of infection 13 weeks post-treatment.


RESULTS
It was shown that the course of TB and the therapeutic response, in terms of histopathological characteristics and mycobacterial load, in lungs and extra- pulmonary organs is substantially different and dependent on the route of infection applied and the inoculum size used.


CONCLUSIONS
When evaluating the comparative therapeutic potential of novel anti-tuberculosis drugs or drug treatment schedules investigated in different studies, it should be noted that the route of infection applied and the inoculum size used influence the course of murine TB and the therapeutic response to the standard first- line anti-tuberculosis drug regimen.
Erasmus MC, Department of Medical Microbiology and Infectious Diseases, University Medical Centre Rotterdam, Rotterdam, The Netherlands. j.desteenwinkel@erasmusmc.nl
J E M
JE
de Steenwinkel
M T
MT
ten Kate
G J
GJ
de Knegt
H A
HA
Verbrugh
A
A
van Belkum
R
R
Hernandez-Pando
I A J M
IA
Bakker-Woudenberg
D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005260:Female; D019570:Inhalation Exposure; D007275:Injections, Intravenous; D008099:Liver / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development / Q000472:pathogenicity; D012008:Recurrence; D015203:Reproducibility of Results; D013154:Spleen / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D013997:Time Factors; D014376:Tuberculosis / Q000175:diagnosis / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy / Q000382:microbiology
D000995:Antitubercular Agents