Abstract
Infection with Mycobacterium tuberculosis (Mtb) is the leading cause of death in human immunodeficiency virus (HIV)+ individuals, particularly in Sub-Saharan Africa. Management of this deadly co-infection is a significant global health challenge that is exacerbated by the lack of efficient vaccines against both Mtb and HIV, as well as the lack of reliable and robust animal models for Mtb/HIV co-infection. Here we describe a tractable and reproducible mouse model to study the reactivation dynamics of latent Mtb infection following the loss of CD4+ T cells as it occurs in HIV-co-infected individuals. Whereas intradermally (i.d.) infected C57BL/6 mice contained Mtb within the local draining lymph nodes, depletion of CD4+ cells led to progressive systemic spread of the bacteria and induction of lung pathology. To interrogate whether reactivation of Mtb after CD4+ T cell depletion can be reversed, we employed interleukin (IL)-2/anti-IL-2 complex-mediated cell boost approaches. Although populations of non-CD4 lymphocytes, such as CD8+ memory T cells, natural killer (NK) cells and double-negative (DN) T cells significantly expanded after IL-2/anti-IL-2 complex treatment, progressive development of bacteremia and pathologic lung alterations could not be prevented. These data suggest that the failure to reverse Mtb reactivation is likely not due to anergy of the expanded cell subsets and rather indicates a limited potential for IL-2-complex-based therapies in the management of Mtb/HIV co-infection.
Highlights
Infections with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), are the major cause of death in human immunodeficiency virus (HIV)+ individuals, accounting for approximately 25% of all HIV-related fatalities [1]
Given that CD4+ T cells were efficiently depleted in spleen, lung and lymph node (LN) in anti-CD4 monoclonal antibody (mAb)-treated animals (Fig 1B), we reasoned that this model resembles progression from latent TB infection (LTBI) to active TB in human HIV/Mtb co-infection
We show that i.d. infection of B6 mice with Mtb resulted in LTBI restricted to ear-draining LNs
Summary
Infections with Mtb, the causative agent of tuberculosis (TB), are the major cause of death in human immunodeficiency virus (HIV)+ individuals, accounting for approximately 25% of all HIV-related fatalities [1]. TB and HIV/AIDS account for more than 2 million deaths per year [1, 2] and HIV+ individuals are 30 times more likely to develop active TB than HIV−. Both pathogens profoundly impact on the human immune system and the gradual decline of CD4+ T cells, the hallmark of HIV infection, is believed to be a major contributing factor in the progression to active TB disease and premature death [3]. A Mouse Model for Reactivation of Latent Tuberculosis collection and analysis, decision to publish, or preparation of the manuscript
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