Maurizio Vacca
Email Address
micvacc@nus.edu.sg
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Publication Harnessing the Immunomodulatory Properties of Bacterial Ghosts to Boost the Anti-mycobacterial Protective Immunity(Frontiers Media S.A., 2019) Lim, J.; Koh, V.H.Q.; Cho, S.S.L.; Periaswamy, B.; Choi, D.P.S.; Vacca, M.; De Sessions, P.F.; Kudela, P.; Lubitz, W.; Pastorin, G.; Alonso, S.; MICROBIOLOGY AND IMMUNOLOGY; PHARMACYTuberculosis (TB) pathogenesis is characterized by inadequate immune cell activation and delayed T cell response in the host. Recent immunotherapeutic efforts have been directed at stimulating innate immunity and enhancing interactions between antigen presenting cells and T cells subsets to improve the protective immunity against TB. In this study, we investigated the immunostimulatory properties of bacterial ghosts (BG) as a novel approach to potentiate the host immunity against mycobacterial infection. BG are intact cytoplasm-free Escherichia coli envelopes and have been developed as bacterial vaccines and adjuvant/delivery system in cancer immunotherapy. However, BG have yet to be exploited as immunopotentiators in the context of infectious diseases. Here, we showed that BG are potent inducers of dendritic cells (DC), which led to enhanced T cell proliferation and differentiation into effector cells. BG also induced macrophage activation, which was associated with enhanced nitric oxide production, a key anti-mycobacterial weapon. We further demonstrated that the immunostimulatory capability of BG far exceeds that of LPS and involves both TLR4-dependent and independent pathways. Consistently, BG treatment, but not LPS treatment, reduced the bacterial burden in infected mice, which correlated with increased influx of innate and adaptive effector immune cells and increased production of key cytokines in the lungs. Finally and importantly, enhanced bacilli killing was seen in mice co-administered with BG and second-line TB drugs bedaquiline and delamanid. Overall, this work paves the way for BG as potent immunostimulators that may be harnessed to improve mycobacteria killing at the site of infection. © Copyright © 2019 Lim, Koh, Cho, Periaswamy, Choi, Vacca, De Sessions, Kudela, Lubitz, Pastorin and Alonso.Publication Calcineurin B in CD4+ T Cells prevents autoimmune colitis by negatively regulating the JAK/STAT pathway(2018) Mencarelli, A; Vacca, M; Khameneh, H.J; Acerbi, E; Tay, A; Zolezzi, F; Poidinger, M; Mortellaro, A; BIOLOGY; MICROBIOLOGY AND IMMUNOLOGY; DUKE-NUS MEDICAL SCHOOLCalcineurin (Cn) is a protein phosphatase that regulates the activation of the nuclear factor of activated T-cells (NFAT) family of transcription factors, which are key regulators of T-cell development and function. Here, we generated a conditional Cnb1 mouse model in which Cnb1 was specifically deleted in CD4+ T cells (Cnb1CD4 mice) to delineate the role of the Cn-NFAT pathway in immune homeostasis of the intestine. The Cnb1CD4 mice developed severe, spontaneous colitis characterized at the molecular level by an increased T helper-1-cell response but an unaltered regulatory T-cell compartment. Antibiotic treatment ameliorated the intestinal inflammation observed in Cnb1CD4 mice, suggesting that the microbiota contributes to the onset of colitis. CD4+ T cells isolated from Cnb1CD4 mice produced high levels of IFN? due to increased activation of the JAK2/STAT4 pathway induced by IL-12. Our data highlight that Cn signaling in CD4+ T cells is critical for intestinal immune homeostasis in part by inhibiting IL-12 responsiveness of CD4+ T cells. © 2018 Mencarelli, Vacca, Khameneh, Acerbi, Tay, Zolezzi, Poidinger and Mortellaro.Publication NLRP10 enhances CD4+ T-cell-mediated IFN? response via regulation of dendritic cell-derived IL-12 release(2017) Vacca, M; Böhme, J; Zambetti, L.P; Khameneh, H.J; Paleja, B.S; Laudisi, F; Ho, A.W.S; Neo, K; Leong, K.W.K; Marzuki, M; Lee, B; Poidinger, M; Santambrogio, L; Tsenova, L; Zolezzi, F; de Libero, G; Singhal, A; Mortellaro, A; BIOLOGY; MICROBIOLOGY AND IMMUNOLOGYNLRP10 is a nucleotide-binding oligomerization domain-like receptor that functions as an intracellular pattern recognition receptor for microbial products. Here, we generated a Nlrp10-/- mouse to delineate the role of NLRP10 in the host immune response and found that Nlrp10-/- dendritic cells (DCs) elicited sub-optimal IFN? production by antigen-specific CD4+ T cells compared to wild-type (WT) DCs. In response to T-cell encounter, CD40 ligation or Toll-like receptor 9 stimulation, Nlrp10-/- DCs produced low levels of IL-12, due to a substantial decrease in NF-?B activation. Defective IL-12 production was also evident in vivo and affected IFN? production by CD4+ T cells. Upon Mycobacterium tuberculosis (Mtb) infection, Nlrp10-/- mice displayed diminished T helper 1-cell responses and increased bacterial growth compared to WT mice. These data indicate that NLRP10-mediated IL-12 production by DCs is critical for IFN? induction in T cells and contributes to promote the host defense against Mtb. © 2017 Vacca, Böhme, Zambetti, Khameneh, Paleja, Laudisi, Ho, Neo, Leong, Marzuki, Lee, Poidinger, Santambrogio, Tsenova, Zolezzi, De Libero, Singhal and Mortellaro.