Abstract
Tuberculosis relapse following drug treatment of active disease is an important global public health problem due to the poorer clinical outcomes and increased risk of drug resistance development. Concurrent infection with HIV, including in those receiving anti-retroviral therapy (ART), is an important risk factor for relapse and expansion of drug resistant Mycobacterium tuberculosis (Mtb) isolates. A greater understanding of the HIV-associated factors driving TB relapse is important for development of interventions that support immune containment and complement drug therapy. We employed the humanized mouse to develop a new model of post-chemotherapy TB relapse in the setting of HIV infection. Paucibacillary TB infection was observed following treatment with Rifampin and Isoniazid and subsequent infection with HIV-1 was associated with increased Mtb burden in the post-drug phase. Organized granulomas were observed during development of acute TB and appeared to resolve following TB drug therapy. At relapse, granulomatous pathology in the lung was infrequent and mycobacteria were most often observed in the interstitium and at sites of diffuse inflammation. Compared to animals with HIV mono-infection, higher viral replication was observed in the lung and liver, but not in the periphery, of animals with post-drug TB relapse. The results demonstrate a potential role for the humanized mouse as an experimental model of TB relapse in the setting of HIV. Long term, the model could facilitate discovery of disease mechanisms and development of clinical interventions.
Highlights
Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) infection is the leading cause of infectious disease-related mortality, with the World Health Organization estimating 10 million cases of TB and 1.45 million deaths in 2018 (WHO, 2019)
We further adapted this in vivo system to model TB relapse in a Cornell-like model of disease (Radaeva et al, 2005) in order to permit exploration of the effects of HIV co-infection on relapse
Following 8 weeks of Mtb infection, the lungs of human immune system (HIS) mice were characterized by large areas of granulomatous inflammation including some areas of necrosis and caseous necrosis (Figure 1B)
Summary
Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) infection is the leading cause of infectious disease-related mortality, with the World Health Organization estimating 10 million cases of TB and 1.45 million deaths in 2018 (WHO, 2019). Model of TB Relapse Following HIV Co-infection range from latent infection to active TB occur frequently (Dooley et al, 2011; Rockwood et al, 2016; McIvor et al, 2017) and play an important role in the global TB burden (Chao and Rubin, 2010; Mirsaeidi and Sadikot, 2018). In those with bacteriological evidence of cure following drug therapy, recurrent TB can occur due to endogenous reactivation (relapse) or re-infection. The emergence of multi (MDR)- and extensively (XDR)-drug resistant isolates in a growing number of geographical regions is an important factor contributing to the global health crisis of TB (WHO, 2019)
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