Drug treatment of tuberculosis diminishes but does not abolish the protection against secondary M. tuberculosis challenge

Abstract Early human studies found that individuals with latent M. tuberculosis (Mtb) infection are less likely to develop active tuberculosis (TB) compared to naïve individuals with similar levels of exposure. Using Mtb-barcoded libraries (Lib A - first infection; Lib B - second infection), we showed that an existing Mtb infection in cynomolgus macaques protects against the establishment and progression of a second Mtb challenge. Studies suggest that humans treated for active TB are at higher risk for developing disease following reinfection. Therefore we hypothesized that drug treatment would compromise the protection against a second Mtb infection. To test this hypothesis, we treated macaques infected with Lib A with anti-TB drugs for three months before infecting with Lib B. As a control, a group of macaques were infected with both Lib A and B following the same timeline but without drug treatment. In both groups, the number of granulomas arising from the second infection (Lib B) was significantly fewer than the number of granulomas from the first infection (Lib A). Comparing with the naïve group from our previous study, both drug and non-drug treated groups had significantly fewer live bacteria in the Lib B granulomas albeit the drug treated group had >10x higher bacterial burden than the untreated group. The Lib B granulomas in both groups were smaller and less inflammed (determined by PET CT) compared to granulomas from the naïve animals. No difference in the T cell response in Lib B granulomas was found in both drug and non-drug treated groups. These data suggest that the protection conferred by the first infection to the secondary Mtb challenge remains intact and that bacteria from the second infection were rapidly controlled regardless of treatment.