Increased levels of interferon‐γ primed by culture filtrate proteins antigen and CpG‐ODN immunization do not confer significant protection against Mycobacterium tuberculosis infection

Abstract

Summary The results of various animal model studies of tuberculosis (TB) suggest that culture filtrate proteins (CFPs), which are antigens secreted by Mycobacterium tuberculosis, are largely responsible for improvements in TB vaccines. The great obstacle to developing protein subunit vaccines is that adjuvants are required in order to stimulate relevant protective immune responses. Acting as immune adjuvants, CpG‐oligodeoxynucleotides (CpG‐ODNs) promote the activation of Th1 cells and of pro‐inflammatory cytokines. To evaluate the adjuvant role of CpG‐ODNs in conferring enhanced immunogenic capacity and protection against M. tuberculosis, we immunized mice with CFP antigen combined with synthetic CpG‐ODNs (CFP/CpG) or with incomplete Freund's adjuvant (IFA) (CFP/IFA). Immunization with CFP/CpG induced a T helper 1 (Th1)‐biased response accompanied by a higher immunoglobulin G2a (IgG2a) antibody/IgG1 antibody ratio, elevated production of interferon‐γ (IFN‐γ) by spleen cells and in lungs. However, CFP/IFA‐immunized mice presented higher levels of IgG1 antibodies, as well as increased production of IFN‐γ, interleukin (IL)‐5, and IL‐10 by spleen cells, together with lower levels of IFN‐γ in the lungs. Despite the stronger Th1 response seen in both groups, believed to be necessary for protection against TB, only mice immunized with CFP/IFA were protected after M. tuberculosis infection. Lung histology revealed that lung parenchyma were better preserved in CFP/IFA‐immunized mice, which also presented intense lymphocyte recruitment to the lesion, whereas CFP/CpG‐immunized mice presented severe pulmonary injury accompanied by necrosis. Based on the data presented, we discuss the widely accepted paradigm that high levels of IFN‐γ are directly correlated with protection against experimental TB.

Variantes en los factores de transcripción para IFN, TBET, STAT1, STAT4 y HLX y el riesgo de desarrollar tuberculosis pulmonar en un estudio de casos y controles de una población colombiana

“…This impaired IFNγ production could be associated with an inability to clear the bacterial load and the consequent progress of the disease and its pathology. This assumption is consistent with evidence suggesting that IFNγ expression correlates with protective immunity against TB (6,8,9); however, according to other studies, high levels of IFNγ protein post-infection represents a risk factor for developing active TB (16)(17)(18)(19)(20). These data suggest that the mechanisms that control the excessive inflammatory responses during Mtb infection may have a critical role in the immunopathology of TB.…”

HBHA vaccination may require both Th1 and Th17 immune responses to protect mice against tuberculosis

“…However, we did not detect significant differences in the production of these cytokines at the time of sacrifice between animals immunized with nano-HBHA-CpG vs HBHA-DDA/MPL (data not shown). The link between CpG and IL-17 production is complex, and conflicting reports are found in the literature, showing either a positive or a negative association [43][44][45][46][47][48][49]. However, these studies used different protocols of administration, which may have impacted on the nature of the different antigenpresenting cell populations present at the site of immunization [50].…”

Cationic Liposomes Formulated with Synthetic Mycobacterial Cordfactor (CAF01): A Versatile Adjuvant for Vaccines with Different Immunological Requirements

“…It is therefore striking that the three lead adjuvants for TB subunit vaccines AS01 (Mtb72F) [35] , IC31 (Ag85B-ESAT-6 and Ag85B-TB10.4) [36] , [37] and CAF01 all share the same basic combination of a delivery vehicle and a Th1-inducing immunomodulator. In contrast, single immunomodulators like CpG [38] or MPL [39] as well as delivery vehicles administered without immunomodulators e.g. liposomes or niosomes [40] do not confer significant protection against TB infection.…”