Modern clinical Mycobacterium tuberculosis strains leverage type I IFN pathway for a pro-inflammatory response in the host

Abstract

12Host phagocytes respond to infections by innate defense mechanisms through metabolic 13 shuffling in order to restrict the invading pathogen. However, this very plasticity of the host 14 provides an ideal platform for pathogen mediated manipulation. By employing the macrophage 15 model of Mtb infection, we identify an important strategy employed by modern clinical lineages 16 in regulating the host immune-metabolism axis. The potent ability of these strains to specifically 17 elicit a strong and early macrophage type I IFN response (in contrast to the protracted response 18 to ancient Mtb), was dependent on an increased ability to localize in acidified phagosomes; this 19 higher transit via acidified compartments is important for stimulation of the DNA dependent 20 signaling in infected macrophages. The augmented IFN signaling provided a positive regulatory 21 loop for enhanced expression of the cellular oxysterol-CH25H which in turn facilitated higher 22 107 108 Fig.1: Modern lineages have evolved to induce a significantly higher type I IFN response 109 A-C) Relative luciferase activity in naïve and stimulated THP1 dual macrophages: Infected with Mtb 110 Erdman at a MOI-5 (A), or with Mtb strains belonging to different lineages [L1-4] at a MOI-5 (B), 2 111 independent isolates of each lineage are represented as open and closed circles, T83 Vietnamese L1 112 subtype Mtb is shown as inverted triangle, or with Mtb L1 [grey bars; 1-N72, 2-N73] and L3 [black bars; 113 3-N4, 4-N24] at different MOIs (C). At the indicated time points, culture supernatants were harvested and 114 tested for luciferase expression. Values represent average ratios + SE of RLU in infected and control 115 samples from triplicate wells of two independent experiments [N=2].116 D-F) Relative expression in macrophages infected with N24 [L3] or N73 [L1] at a MOI-5. D) IFNβ

Mycobacterium tuberculosis (Mtb) lipid mediated lysosomal rewiring in infected macrophages modulates intracellular Mtb trafficking and survival

“…The precise contributions of lysosomal rewiring to Mtb trafficking and survival during in vivo infections require further studies. Similarly, it will be interesting to extend these studies to clinical isolates of Mtb, which differ in SL-1 gene expression and lipid levels (82)(83)(84). Some strains of the "ancestral" Clade 2 show reduced expression of genes in the SL-1 biosynthetic pathway (85), whereas a recent report shows an Mtb strain belonging to the ancestral lineage with a point mutation in the papA2 gene, which confers it a loss of SL-1 phenotype (86).…”

The antidepressant sertraline provides a novel host directed therapy module for augmenting TB therapy

“…The effect of the combination was again better in controlling bacterial numbers in spleens of treated mice wherein HR did not reduce CFU in contrast to the 6-8-fold lower bacterial numbers with the combination. We and several other groups have identified type I IFN as an early response of host macrophages to infection with Mtb strains (41,42,49,66). With recent evidences implicating type I IFN as a pathogen beneficial response, we hypothesized that attenuating this axis would prove beneficial in controlling bacteria in macrophages.…”

“…Macrophages respond to Mtb infection by elaborating an array of signaling cascades and effector functions with the nucleic acid driven type I IFN response as an active and dominant response to during infection (42,(44)(45)(46)(47)(48)(49). We questioned the benefit to Mtb in actively stimulating this response and hypothesized that suppressing this response in cells would alter macrophage infection dynamics.…”

“…We hypothesized that neutralizing a prominent pathogen-beneficial response would indirectly supplement host immunity facilitating better pathogen control. The early, robust, type I IFN response of phagocytes to intracellular bacterial infections including Mtb, is often associated with a detrimental effect on host immune activation and survival (39)(40)(41)(42). We sought to offset this response by using sertraline (SRT) -a previously identified antagonist of poly I:C mediated type I IFN signaling, in macrophages and evaluate Mtb infection dynamics (43).…”

Robust lysosomal rewiring in Mtb infected macrophages mediated by Mtb lipids restricts the intracellular bacterial survival

“…Despite these differences, our data shows that altered lysosomal homeostasis, mediated in part by SL-1, is central to both human and mouse infection models. Clinical isolates of Mtb exhibit clade specific virulence patterns with strong correlations of their phylogenetic relationships with gene expression profiles and host inflammatory responses (Portevin et al, 2011; Reiling et al, 2013; Shankaran et al, 2019). Some strains of the ‘ancestral’ Clade 2 show reduced expression of genes in the SL-1 biosynthetic pathway (Homolka et al, 2010), while a recent report shows an Mtb strain belonging to the ancestral lineage L1 having a point mutation in the pap A2 gene, which confers it a loss of SL-1 phenotype (Panchal et al, 2019).…”