Mycobacterial Lipoprotein Z Triggers Efficient Innate and Adaptive Immunity for Protection Against Mycobacterium tuberculosis Infection

Abstract

Mycobacterial lipoproteins are considered to be involved in both virulence and immunoregulatory processes during Mycobacterium tuberculosis (M.tb) infection. In our previous investigations on the immunoreactivity of more than 30 M.tb proteins in active TB patients, we identified mycobacterial lipoprotein Z (LppZ) as one of the most immune dominant antigens. How LppZ triggers immune responses is still unclear. In this study, we analyzed LppZ-mediated innate and adaptive immunity using a murine air pouch model and an M.tb infection model, respectively. We found that LppZ could not only recruit inflammatory cells but also induce the production of proinflammatory cytokines inside the pouches. LppZ could also induce strong Th1 responses following immunization and confer protection against challenge with M.tb virulent strain H37Rv at a similar level to BCG vaccination but with less pathological damage in the lungs. Furthermore, we revealed the presence of LppZ-specific functional CD4+ T cells in the lungs of the challenged mice that were capable of secreting double or triple cytokines, including IFN-γ, IL-2, and TNF-α. Our study thus demonstrates that LppZ is of strong immunogenicity during M.tb infection in both humans and mice and has the ability to trigger effective innate and cellular immunity. Considering the limitations of candidate antigens in the pipeline of TB vaccine development, LppZ-mediated immune protection against M.tb challenge in the mouse model implies its potential application in vaccine development.

Age-Related Immunoreactivity Profiles to Diverse Mycobacterial Antigens in BCG-Vaccinated Chinese Population

“…Different immunological patterns were revealed under either M.tb infection or neonatal BCG vaccination among E6C10 -, E6C10 + HDs and TB cohorts. Consistent with previous studies (11,12,14,15), Rv3006 is of high immunogenicity upon M.tb infection, with the most IFN-g specific SFUs in TB patients (Figure S1B). However, BCG vaccination does not induce strong immunoreactivity to Rv3006 in E6C10and E6C10 + adults (Figure S1B).…”

“…Rv3006 (also known as lipoprotein Z, LppZ) is both a cell-wall component and a secreting protein (13). Studies from our own and other groups demonstrate that it is of high immunogenicity during M.tb infection triggering both innate and adaptive immunity (11,12,14,15). Rv3841 (also known as BfrB, a ferritin-like protein) is reported to be an iron-storage protein (16).…”

Recombinant BCG With Bacterial Signaling Molecule Cyclic di-AMP as Endogenous Adjuvant Induces Elevated Immune Responses After Mycobacterium tuberculosis Infection

“…As an intracellular bacterium, Mtb primarily survives and multiplies in macrophages after infection, and the cellular immune response mediated by T cells is crucial and dominates the elimination process of Mtb (45–48). Helper T (Th) cells produce cytokines, especially Th1 type cytokines, which are thought to play a major protective role in anti-Mtb infection (49).…”

“…Elevated c-di-AMP in rBCG-DisA had changed the immunogenicity of BCG from our results, but the enhancement may be not sufficient to be distinguished with the immune responses induced by BCG alone. The Mtb infection model could be established by intravenous (54–56), aerosol (25, 48), or intranasal (47, 57) infection routes. In this study, we used intravenous infection of mice as a model for evaluation study, which resulted in much higher bacteria loads than human tuberculosis.…”

Network-Based Integrated Analysis of Transcriptomic Studies in Dissecting Gene Signatures for LPS-Induced Acute Lung Injury

“…MAPK3 is a negative moderator of DC and is necessary for the induction of T cell anergy towards an inflammatory phenotype [ 37 ]. Tumor necrosis factor receptor–associated factor 6 ( TRAF6 ) is a decisive adaptor regulating Toll-like receptors (TLRs), whose polyubiquitination leads to mediate pro-inflammatory cytokines production in ALI [ 38 ]. Moreover, necroptosis, a cell death form modulated by the RIPK1-RIPK3-MLKL signaling, has been implicated in the close relationship between necroptosis and ALI/ARDS [ 39 , 40 ].…”