Diametric Role of the Latency-Associated Protein Acr1 of Mycobacterium tuberculosis in Modulating the Functionality of Pre- and Post-maturational Stages of Dendritic Cells

Abstract

It is instrumental for the Mycobacterium tuberculosis (Mtb) to persist within its host in dormancy. Mtb represses most of its metabolic machinery during latency, but upregulates the expression of latency-associated protein alpha-crystallin protein (Acr1). Therefore, it is imperative to understand how throughout dormancy, Mtb employs Acr1 to regulate the host immunity. This study reveals that Acr1 exhibits divergent effect on the pre- and post-maturation stages of dendritic cells (DCs). In the current study, we demonstrate that early encounter of bone marrow cells with Acr1 while differentiating into DCs (AcrDCpre), leads to impairment in their maturation. In contrast, when exposed to Acr1 after maturation (AcrDCpost), DCs show augmentation in their activity, secretion of TNF-α, IL-12, IL-6, and activation of T cells. Additionally, AcrDCpost promoted the polarization of naïve CD4 T cells to Th1 cells and Th17 cells and restricted the intracellular growth of Mtb. Furthermore, these DCs upregulated the expression of CCR7 and exhibited enhanced migratory capabilities. The discrete impact of Acr1 on DCs is mediated through a mechanism involving STAT-1, SOCS-3, ERK, TLR-4, and NF-κB signaling pathways. This study reveals the unprecedented role of Acr1 in distinctly modulating the function of DCs at different stages of maturation.

A multiple T cell epitope comprising DNA vaccine boosts the protective efficacy of Bacillus Calmette–Guérin (BCG) against Mycobacterium tuberculosis

“…It has been previously reported that the Acr1 protein provides enhanced protective efficacy when overexpressed in BCG [31]. However, Acr1 impairs the maturation and functionality of DCs and supports the intracellular survival of Mtb [22,32]. Similarly, Rv2626c protein has been shown to protect against Mtb, as well as modulate the functionality of macrophages and assist in the escape of pathogen [33,34].…”

“…Mtb is known to modulate APCs to prevent the activation and expression of MHC and co-stimulatory molecules [20][21][22]. Therefore, we wanted to examine the immune status of APCs in the lungs upon C6 administration from Mtb infected mice.…”

Mycobacterium tuberculosis: Rewiring host cell signaling to promote infection

“…For example, the latency-associated protein Acr1 was found to impair the maturation of DCs. 59 Additionally, the mycobacterial serine hydrolase Hip1 reduced surface expression of MHC class II and the costimulatory molecules CD40 and CD86, as well as a number of pro-inflammatory cytokines. 60 Several groups have also reported that infection of DCs with M. tuberculosis reduces their expression integrins and chemokine receptors, 61,62 therefore hindering their migration to lymph nodes and delaying the onset of adaptive immunity.…”

“…Besides interfering with autophagy, M. tuberculosis has been reported in in vitro studies to manipulate antigen presentation by several other means. For example, the latency‐associated protein Acr1 was found to impair the maturation of DCs . Additionally, the mycobacterial serine hydrolase Hip1 reduced surface expression of MHC class II and the costimulatory molecules CD40 and CD86, as well as a number of pro‐inflammatory cytokines .…”

Reinforcing the Functionality of Mononuclear Phagocyte System to Control Tuberculosis

“…TLR-4 senses HSP60/65 and 38-kDa Mtb antigen inducing protective TNF-α production ( 78 ). In addition, another Mtb small heat shock protein X also recognized as α-crystallin-1 can specifically modulate the function of DCs at different maturation stages ( 79 , 80 ). TLR-4 activation is known to induce macro-autophagy by recruitment of Beclin-1.…”