Anti-inflammatory regulatory T cells have lately attracted attention as part of the immune response to Mycobacterium tuberculosis infection, where they counterbalance the protective but pro-inflammatory immune response mediated by Th17 cells and especially by the better-known Th1 cells. In chronic infectious diseases there is a delicate balance between pro- and anti-inflammatory responses. While Th1 and Th17 are needed in order to control infection by Mycobacterium tuberculosis, the inflammatory onset can ultimately become detrimental for the host. In this review, we assess current information on the controversy over whether counterbalancing regulatory T cells are promoting pathogen growth or protecting the host.

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Regulatory T Cells in Mycobacterium tuberculosis Infection

Mannan-binding lectin-associated serine protease-1 (MASP-1) mediates immune responses against Aeromonas hydrophila in vitro and in vivo in grass carp.

Tuberculosis remains a global health threat of alarming proportions, resulting in 1.5 million deaths worldwide. The only available licensed vaccine, BCG, does not confer lifelong protection against active TB. To date, development of an effective vaccine against TB has proven to be elusive, and devising newer approaches for improved vaccination outcomes is an essential goal. Insights gained over the last several years have revealed multiple mechanisms of immune manipulation by Mtb in infected macrophages and dendritic cells that support disease progression and block development of protective immunity. This review provides an assessment of the known immunoregulatory mechanisms altered by Mtb, and how new interventions may reverse these effects. Examples include blocking of inhibitory immune cell co-receptor checkpoints (e.g. PD-1). Conversely, immune mechanisms that strengthen immune cell effector functions may be enhanced by interventions, including stimulatory immune cell co-receptors (e.g., OX40). Modification of the activity of key cell “immunometabolism” signaling pathway molecules, including mTOR, GSK3β, wnt/β-catenin, AMPK and sirtuins, related epigenetic changes, and preventing induction of immune regulatory cells (e.g., Tregs, MDSCs) are powerful new approaches to improve vaccine responses. Interventions to favorably modulate these components have been studied primarily in oncology to induce efficient anti-tumor immune responses, often by potentiation of cancer vaccines. These agents include antibodies and a rapidly increasing number of small molecule drug classes that have contributed to the dramatic immune-based advances in treatment of cancer and other diseases. Because immune responses to malignancies and to Mtb share many similar mechanisms, studies to improve TB vaccine responses using interventions based on “immuno-oncology” are needed to guide possible repurposing. Understanding regulation of immune cell functions appropriated by Mtb to promote the imbalance between protective and pathogenic immune responses may guide development of innovative drug-based adjunct approaches to substantially enhance the clinical efficacy of TB vaccines.

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Adjunct Strategies for Tuberculosis Vaccines: Modulating Key Immune Cell Regulatory Mechanisms to Potentiate Vaccination.

IFNL3-adjuvanted HCV DNA vaccine reduces regulatory T cell frequency and increases virus-specific T cell responses.

Novel compounds and more efficient treatment options are urgently needed for the treatment of cystic echinococcosis (CE), which is caused by Echinococcus granulosus. The decoction of Sophora moorcroftiana (Fabaceae) has been used to treat parasitosis for years in traditional Tibetan medicine. The aim of this study was to screen insecticidal water-soluble alkaloids from S. moorcroftiana seeds and evaluate the therapeutic effects against CE and the immune response induced by the alkaloidal fraction. Low polarity compounds (E2-a) were isolated from water-soluble alkaloid (E2) and matrine and sophocarpine were identified as major components. The E2-a fraction was more effective against protoscoleces than other constituents from S. moorcroftiana. After 20 weeks of secondary infection with protoscoleces, mice were orally treated with E2-a (100 mg/kg/day) for 6 weeks to evaluate therapeutic and immunoregulatory activities. Compared with the untreated group, E2-a treatment induced a significant reduction in cyst weight (mean 2.93 g) (p < 0.05) and an impaired ultrastructural modification of the cyst. Interestingly, the application of E2-a resulted in a significant increased frequency of CD3+CD4+ T-cell subsets and decreased frequency of CD3+PD-1+ T-cell subsets, compared with protoscolece-infected mice without treatment. The E2-a fraction of S. moorcroftiana can inhibit the cyst development of CE and boost the specific immune response by reducing the expression of PD-1 and accelerate the cytokine secretion of antigen-specific T-cells. All data suggest the E2-a fraction from S. moorcroftiana seeds may be used as a new potential therapeutic option against E. granulosus infection.

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Therapeutic and immunoregulatory effects of water-soluble alkaloids E2-a from Sophora moorcroftiana seeds as a novel potential agent against echinococcosis in experimentally protoscolex-infected mice.

Regulatory T cells (Tregs), which could be down-regulated by IL-28B, were reported to suppress T-cell-mediated immunity. The aim of this study was to investigate the role of IL-28B on the immune responses and protective efficacy of a tuberculosis (TB) subunit vaccine. First, a recombinant adenoviral vector expressing mouse IL-28B (rAd-mIL-28B) was constructed; then C57BL/6 mice were immunized with subunit vaccine ESAT6-Ag85B-Mpt64(190-198)-Mtb8.4-HspX (EAMMH) and rAd-mIL-28B together thrice or primed with Mycobacterium bovis bacillus Calmette-Gue'rin (BCG) and boosted by EAMMH and rAd-mIL-28B twice. At last the immune responses were evaluated, and the mice primed with BCG and boosted by subunit vaccines were challenged with virulent Mycobacterium tuberculosis H37Rv to evaluate the protective efficacy. The results showed that rAd-mIL-28B treatment significantly down-regulated the frequency of Tregs at 4 weeks after the last immunization but did not increase the Th1-type immune responses. Moreover, in the regimen of BCG priming and EAMMH boosting, rAd-mIL-28B treatment did not increase the antigen-specific cellular and humoral immune responses, and consequently did not reduce the bacteria load following H37Rv challenge. Instead, it induced more serious pathology reaction. In conclusion, IL-28B down-regulates Tregs following EAMMH vaccination but does not improve the protective immune responses.

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IL-28B down-regulates regulatory T cells but does not improve the protective immunity following tuberculosis subunit vaccine immunization

Tuberculosis, caused by Mycobacterium tuberculosis, affects the functions of the lung and causes high morbidity and mortality rates worldwide. MASP-2 is an executioner enzyme, which plays an essential role in the activation of lectin pathway. In our previous studies, the MASP-2 played a dual role in promoting the progress of lesions in BCG-infected rabbit skin models. However, the really effects of MASP-2 on tuberculosis are unknown. The aim of this study was to investigate the effects of MASP-2 in granuloma formation with BCG-infected mice. Compared to the control group, rAd-hMASP-2 treated group showed increasing in survival rate of BCG-infected mice (P = 0.042), and decreasing of bacteria loads (P = 0.005) in the lung tissue. MASP-2 displayed a protective efficacy in BCG-infected mice, which promoted the activation and recruitment of macrophages and lymphocytes to the granuloma. Moreover, the data obtained from the ELISA and RT-PCR demonstrated that mRNA expression for IL-6, CCL12, CCL2 and cytokines of IFN-γ, TNF-α in lung were significantly elevated by treatment of rAd-hMASP-2. Those findings provided an evidence that MASP-2 may be as a newly immunomodulatory in targeting granuloma formation, which displayed a potential protective role in control of tuberculosis.

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Effects of hMASP-2 on the formation of BCG infection-induced granuloma in the lungs of BALB/c mice.

Effects of MBL-associated serine protease-2 (MASP-2) on liquefaction and ulceration in rabbit skin model of tuberculosis.

The in-depth study of fungal secondary metabolites (SMs) over the past few years has led to the discovery of a vast number of novel fungal SMs, some of which possess good biological activity. However, because of the limitations of the traditional natural product mining methods, the discovery of new SMs has become increasingly difficult. In recent years, with the rapid development of gene sequencing technology and bioinformatics, new breakthroughs have been made in the study of fungal SMs, and more fungal biosynthetic gene clusters of SMs have been discovered, which shows that the fungi still have a considerable potential to produce SMs. How to study these gene clusters to obtain a large number of unknown SMs has been a research hotspot. With the continuous breakthrough of molecular biology technology, gene manipulation has reached a mature stage. Methods such as gene knockout and heterologous expression techniques have been widely used in the study of fungal SM biosynthesis and have achieved good effects. In this review, the representative studies on the biosynthesis of fungal SMs by gene knockout and heterologous expression under the fungal genome mining in the last three years were summarized. The techniques and methods used in these studies were also briefly discussed. In addition, the prospect of synthetic biology in the future under this research background was proposed.

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Application of Gene Knockout and Heterologous Expression Strategy in Fungal Secondary Metabolites Biosynthesis

The invention provides an immunologic adjuvant. The immunologic adjuvant is composed of cationic liposome dimethyl trihexadecyl alkylammonium (DDA), PolyI: C and cholesterol. According to the immunologic adjuvant provided by the invention, a novel vaccine adjuvant DDA+PolyI: C+cholesterol (DPC for short) is constructed by combining cholesterol with DDA and polyI: C through screening reagents capable of enhancing the stability of the adjuvants and giving consideration to both immunocompetence and clinical application of a vaccine, thus improving the stabilities of the adjuvants DDA and polyI: C, and the particle size is less than that of DDA+PolyI: C (DP for short), thus facilitating the performances of later-period development and production; the immunologic adjuvant is combined with fusion protein LT70 to construct a tuberculosis subunit vaccine LT-70-DPC, and the overall protection effect is found to be higher than those of BCG and LT70-DP.

Xiaoling Lu

Papers

IL-28B down-regulates regulatory T cells but does not improve the protective immunity following tuberculosis subunit vaccine immunization

Effects of hMASP-2 on the formation of BCG infection-induced granuloma in the lungs of BALB/c mice.

Effects of MBL-associated serine protease-2 (MASP-2) on liquefaction and ulceration in rabbit skin model of tuberculosis.

Application of Gene Knockout and Heterologous Expression Strategy in Fungal Secondary Metabolites Biosynthesis

Immunologic adjuvant and vaccine containing immunologic adjuvant