Abstract
Mycobacterium tuberculosis (M. tb), the intracellular pathogen causing tuberculosis, has developed mechanisms that endow infectivity and allow it to modulate host immune response for its survival. Genomic and proteomic analyses of non-pathogenic and pathogenic mycobacteria showed presence of genes and proteins that are specific to M. tb. In silico studies predicted that M.tb Rv1954A is a hypothetical secretory protein that exhibits intrinsically disordered regions and possess B cell/T cell epitopes. Treatment of macrophages with Rv1954A led to TLR4-mediated activation with concomitant increase in secretion of pro-inflammatory cytokines, IL-12 and TNF-α. In vitro studies showed that rRv1954A protein or Rv1954A knock-in M. smegmatis (Ms_Rv1954A) activates macrophages by enhancing the expression of CD80 and CD86. An upregulation in the expression of CD40 and MHC I/II was noted in the presence of Rv1954A, pointing to its role in enhancing the association of APCs with T cells and in the modulation of antigen presentation, respectively. Ms_Rv1954A showed increased infectivity, induction of ROS and RNS, and apoptosis in RAW264.7 macrophage cells. Rv1954A imparted protection against oxidative and nitrosative stress, thereby enhancing the survival of Ms_Rv1954A inside macrophages. Mice immunized with Ms_Rv1954A showed that splenomegaly and primed splenocytes restimulated with Rv1954A elicited a Th1 response. Infection of Ms_Rv1954A in mice through intratracheal instillation leads to enhanced infiltration of lymphocytes in the lungs without formation of granuloma. While Rv1954A is immunogenic, it did not cause adverse pathology. Purified Rv1954A or Rv1954A knock-in M. smegmatis (Ms_Rv1954A) elicited a nearly two-fold higher titer of IgG response in mice, and PTB patients possess a higher IgG titer against Rv1954A, also pointing to its utility as a diagnostic marker for TB. The observed modulation of innate and adaptive immunity renders Rv1954A a vital protein in the pathophysiology of this pathogen.
Highlights
Mycobacterium tuberculosis (M. tb), the causative agent of tuberculosis (TB), persists as a latent form in nearly 30% of the global population who may serve as reservoir for inadvertent transmission of disease and develop active TB during immunocompromised conditions
A comparative study of the M. tb Rv1954A putative protein with a database comprising all the known protein sequences showed that it is absent in other species of mycobacteria except BCG
The Rv1954A protein is secretory in nature, which was predicted by PredictProtein software (Supplementary Figure S2A)
Summary
Mycobacterium tuberculosis (M. tb), the causative agent of tuberculosis (TB), persists as a latent form in nearly 30% of the global population who may serve as reservoir for inadvertent transmission of disease and develop active TB during immunocompromised conditions. M. tb has evolved mechanisms that enable it to avoid phago-lysosomal fusion and allow the pathogen to remain in a nonreplicating state within the macrophages, thereby dodging immunosurveillance (Bussi and Gutierrez, 2019). This is achieved by an arsenal of infectivity factors that modulate the host defense strategies. M. tb modulates the activity of the macrophage by dampening the secretion of pro-inflammatory cytokines, which in turn suppress the antibacterial activity of other immune cells. Apart from immune modulation, M. tb proteins impair the activity of antigen-presenting cells (APCs) by either suppressing the expression of co-stimulatory molecules or impairing the activity of antigen-presenting molecules (Noss et al, 2000; Hickman et al, 2002)
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