System-wide identification of myeloid markers of TB disease and HIV-induced reactivation in the macaque model of Mtb infection and Mtb/SIV co-infection

Abstract

Mycobacterium tuberculosis (Mtb) has developed specialized mechanisms to parasitize its host cell, the macrophage. These mechanisms allow it to overcome killing by oxidative burst and persist in the wake of an inflammatory response. Mtb infection in the majority of those exposed is controlled in an asymptomatic form referred to as latent tuberculosis infection (LTBI). HIV is a well-known catalyst of reactivation of LTBI to active TB infection (ATB). Through the use of nonhuman primates (NHPs) co-infected with Mtb and Simian Immunodeficiency Virus (Mtb/SIV), we are able to simulate human progression of TB/AIDS comorbidity. The advantage of NHP models is that they recapitulate the breadth of human TB outcomes, including immune control of infection, and loss of this control due to SIV co-infection. Identifying correlates of immune control of infection is important for both vaccine and therapeutics development. Using macaques infected with Mtb or Mtb/SIV and with different clinical outcomes we attempted to identify signatures between those that progress to active infection after SIV challenge (reactivators) and those that control the infection (non-reactivators). We particularly focused on pathways relevant to myeloid origin cells such as macrophages, as these innate immunocytes have an important contribution to the initial control or the lack thereof, following Mtb infection. Using bacterial burden, C-reactive protein (CRP), and other clinical indicators of disease severity as a guide, we were able to establish gene signatures of host disease state and progression. In addition to gene signatures, clustering algorithms were used to differentiate between host disease states and identify relationships between genes. This allowed us to identify clusters of genes which exhibited differential expression profiles between the three groups of macaques: ATB, LTBI and Mtb/SIV. The gene signatures were associated with pathways relevant to apoptosis, ATP production, phagocytosis, cell migration, and Type I interferon (IFN), which are related to macrophage function. Our results suggest novel macrophage functions that may play roles in the control of Mtb infection with and without co-infection with SIV. These results particularly point towards an interplay between Type I IFN signaling and IFN-γ signaling, and the resulting impact on lung macrophages as an important determinant of progression to TB.

Mycobacterium tuberculosis-THP-1 like macrophages protein-protein interaction map revealed through dual RNA-seq analysis and a computational approach

“…For example, several genes were found to be up-regulated within the host cells, playing a major role during the infection such as SECTM1, LYPD4 and HSPA6 . SECTM1 is a protein involved in immune processes [20, 21]. In addition, HSPA6, a poorly known protein serving as a positive regulator in Enterovirus-A71, was also found to be induced [22].…”

Discovering common pathogenetic processes between COVID-19 and tuberculosis by bioinformatics and system biology approach

“…ISG15 can collaborate with IL-12 to stimulate T and NK cells to produce IFN-g, which regulates Mycobacterium tuberculosis infection through an extracellular cytokine-like pathway (Bogunovic et al, 2012;Kimmey et al, 2017). Mx1 has noteworthy antiviral effects on hematopoietic cells, alongside its recognized antiviral activity on nonhematopoietic cells (Spitaels et al, 2019;Gough et al, 2022). OASL induces amyloid fibrillation in RIPK3, promoting virus-induced necrosis (Lee et al, 2023).…”