The Ag85B protein of Mycobacterium tuberculosis may turn a protective immune response induced by Ag85B-DNA vaccine into a potent but non-protective Th₁immune response in mice

Abstract

Clarifying how an initial protective immune response to tuberculosis may later loose its efficacy is essential to understand tuberculosis pathology and to develop novel vaccines. In mice, a primary vaccination with Ag85B-encoding plasmid DNA (DNA-85B) was protective against Mycobacterium tuberculosis (MTB) infection and associated with Ag85B-specific CD4+ T cells producing IFN-gamma and controlling intramacrophagic MTB growth. Surprisingly, this protection was eliminated by Ag85B protein boosting. Loss of protection was associated with a overwhelming CD4+ T cell proliferation and IFN-gamma production in response to Ag85B protein, despite restraint of Th1 response by CD8+ T cell-dependent mechanisms and activation of CD4+ T cell-dependent IL-10 secretion. Importantly, these Ag85B-responding CD4+ T cells lost the ability to produce IFN-gamma and control MTB intramacrophagic growth in coculture with MTB-infected macrophages, suggesting that the protein-dependent expansion of non-protective CD4+ T cells determined dilution or loss of the protective Ag85B-specific CD4+ induced by DNA-85B vaccination. These data emphasize the need of exerting some caution in adopting aggressive DNA-priming, protein-booster schedules for MTB vaccines. They also suggest that Ag85B protein secreted during MTB infection could be involved in the instability of protective anti-tuberculosis immune response, and actually concur to disease progression.

T-bet acts as a powerful adjuvant in Ag85B DNA‑based vaccination against tuberculosis

“…Thus, in this study, we evaluated the protective responses of DNA vaccines in the spleens and lungs following MTB infection. Vaccinated mice were infected with 1x10 5 CFU of the MTB H37Rv strain. Approximately 3 months later the bacillary burden in the spleens and lungs was detected, and it was identified that the bacterial burdens in Ag85B/T-bet-vaccinated mice were lower than in the empty vector mice.…”

“…Three months after the last immunization, different groups of mice were challenged intravenously at the tail vein with 1x10 5 CFU of the MTB H37Rv strain. The mice spleens and lungs were dissected on weeks 1, 2, 4 and 8.…”

“…It has also been demonstrated to induce a powerful Th1-type immune response in mice as well as in humans, and to induce Th1-type cells to produce interleukin (IL)-2, tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). A number of studies have demonstrated a significant protective effect in the lungs of mice immunized with Ag85B (6,7), while there are only a few studies contradicting the efficacy of the Ag85B vaccine (5,8,9). Thus, in order to further identify the immunoprotective force of DNA vaccines against TB, the appropriate immune adjuvant is required.…”

“…In previous years, the secreted MTB protein, Ag85B, has been the main focus of intensive research. Ag85B, a 30-kDa fibronectin-binding protein with mycolyl-transferase activity, is a major protein secreted by all Mycobacterium species belonging to the Ag85B family and is a potent immunoprotective antigen (5). It has also been demonstrated to induce a powerful Th1-type immune response in mice as well as in humans, and to induce Th1-type cells to produce interleukin (IL)-2, tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ).…”

Ub Combination Enhanced Cellular Immune Response Elicited by HSP65 DNA Vaccine against <i>Mycobacterium tuberculosis</i>

“…However, the efficacy of DNA vaccines is limited due to problems related to delivery, animal species and degradation of plasmid DNA, resulting in modest cellular and humoral immune responses. In the past years, DNA vaccines also have been studied against tuberculosis in animal models [11][12][13][14][15][16]. These DNA vaccines encoding Ag85A/B/C, ESAT-6, MPT64, PST1/2/3, 38 kDa or HSP70, when used individually or in combination, have conferred inferior or similar to protection against M. TB challenge than that of BCG.…”