Systems biology approaches to investigate the role of granulomas in TB-HIV coinfection

Abstract

The risk of active tuberculosis disease is 15-21 times higher in those coinfected with human immunodeficiency virus-1 (HIV) compared to tuberculosis alone, and tuberculosis is the leading cause of death in HIV+ individuals. Mechanisms driving synergy between Mycobacterium tuberculosis (Mtb) and HIV during coinfection include: disruption of cytokine balances, impairment of innate and adaptive immune cell functionality, and Mtb-induced increase in HIV viral loads. Tuberculosis granulomas are the interface of host-pathogen interactions. Thus, granuloma-based research elucidating the role and relative impact of coinfection mechanisms within Mtb granulomas could inform cohesive treatments that target both pathogens simultaneously. We review known interactions between Mtb and HIV, and discuss how the structure, function and development of the granuloma microenvironment create a positive feedback loop favoring pathogen expansion and interaction. We also identify key outstanding questions and highlight how coupling computational modeling with in vitro and in vivo efforts could accelerate Mtb-HIV coinfection discoveries.

Keywords: HIV - human immunodeficiency virus; TB-HIV coinfection; granuloma; systems biology; tuberculosis.

Figure 1

HIV changes the structure and function of the granuloma in pre-existing LTBI allowing for bacterial growth and dissemination. (A) Cellular level changes: An example granuloma classified as contained (bacteria localized) made up of CD4+ and CD8+ T cells, B cells, macrophages, and neutrophils that transforms into a disseminating granuloma upon HIV infection. The granuloma is rich in HIV susceptible cells (CXCR4 and CCR5 cells) that can help accelerate CD4+ T cell destruction. Granulomas during coinfection have been shown to contain higher CD8+ T cells and have higher rates of macrophage turnover. These cellular changes at the granuloma level ultimately alter the function of the granuloma which can lead to increased bacterial load and dissemination. (B) Molecular mechanism #1: HIV has been shown to have detrimental impacts on the functionality of CD4+ T cells and therefore the balance between pro-and anti-inflammatory cytokines produced by the local immune cells is thrown into dysregulation. The change in the cytokine milieu can facilitate granuloma dissolution. (C) Molecular mechanism #2: The immune response to Mtb results in an increase in inflammation and T cell recruitment to the site of infection. This Mtb-induced inflammation and availability of HIV susceptible cells within the granuloma (CXCR4 and CCR5 cells) have been implicated in the increased viral loads and increased viral diversity found in coinfection. An increase in viral load would lead to local destruction of the cells in the granuloma therefore aiding bacterial dissemination.

Figure 2

Pre-existing HIV impacts innate immune functions that can impact Mtb granuloma development and progression. HIV can alter the phagocytosis abilities of dendritic cells and macrophages limiting their ability to kill intracellular Mtb. HIV also interferes with antigen processing and presentation required to activate T cells. The result is disorganized granulomas with high bacterial load, high viral load, and high dissemination rates.