Room: Roger Guindon Hall, Room 4113 (Office), 4115 (Lab)
Office: 613-562-5800 ext. 8163
Work E-mail: email@example.com
The Sun Lab is currently recruiting researchers at all levels (undergraduate, graduate and postdoctoral). To apply, please send your CV to firstname.lastname@example.org
The central research focus of the Sun laboratory is to improve our understanding of the host-pathogen interactions during infection by Mycobacterium tuberculosis (Mtb), which will pave the way towards advancing host-directed therapy to treat tuberculosis (TB). To achieve this goal, my lab combines leading techniques in molecular and cell biology with novel persistent infection models and kinome analysis.
Mtb has co-evolved with humans for over forty thousand years and to date remains a global health threat. Ten million people develop active tuberculosis every year resulting in over 1.5 million deaths annually, establishing it as the leading cause of infectious disease-related death worldwide. Antimicrobial chemotherapy has long been the standard choice for the relatively successful treatment of active TB, but the emergence of multidrug-resistant TB creates new challenges, in particular as successful development of clinically approved drugs has been virtually non-existent. In line with this, alternative adjunctive therapies are needed to combat TB.
Host-directed therapies (HDT) is one such promising alternative as this strategy will circumvent development of antibiotic resistance, induce host immunity enabled killing of latent Mtb that are known to have increased tolerance to antibiotics, and avoid the need for drugs to penetrate the uniquely impermeable Mtb cell membrane. The successful development of HDT will depend on a clear understanding of the underlying host macrophage signaling networks hijacked during Mtb infection. The concept of HDT seeks to either (1) boost host immunity by enhancing the ability of host macrophage to kill invading Mtb, or (2) denying Mtb from a required host pathway necessary for its survival. To this end, my lab has discovered the host Protein Phosphatase, Mg2+/Mn2+-dependent 1A (PPM1A) as a new target exploited by Mtb to persist intracellularly by deactivating antibacterial programs in the macrophage.
PPM1A signaling pathway
We have demonstrated that elevated PPM1A levels rendered macrophages “immune paralyzed” and attenuated both the innate antibacterial and antiviral immune response. Consistent with this, we showed that Mtb-induced PPM1A upregulation blocked the ability of Mtb-infected macrophages to undergo apoptosis, a critical innate immune mechanism that facilitates intracellular bacterial killing and priming of the adaptive immune response. Importantly, in proof of concept studies, we showed that targeting the PPM1A signaling network restores the ability of Mtb-infected macrophages to undergo apoptosis, leading to selective apoptotic killing of infected macrophages, which enhances the ability of existing anti-Mtb drugs to kill Mtb in a “release and kill” strategy. As such, targeting of the PPM1A signaling pathway is a promising new strategy to develop HDT for tuberculosis.
Current research topics:
- Regulation of PPM1A in macrophages during Mtb infection
- Characterization of the PPM1A signaling network in macrophage apoptosis
- Targeting the PPM1A signaling network to improve killing of Mtb
- Role of PPM1A in monocyte-to-macrophage differentiation
- Role of PPM1A in antibacterial/antiviral response pathways
- Schaaf K, Smith SR, Duverger A, Wagner F, Wolschendorf F, Westfall AO, Kutsch O and Sun J. (2017) Mycobacterium tuberculosis exploits the PPM1A signaling pathway to block host macrophage apoptosis. Sci Rep, 7:42101.
- Schaaf K, Smith SR, Hayley V, Kutsch O and Sun J. (2017) High-throughput assay to evaluate drug efficacy against macrophage passaged Mycobacterium tuberculosis. J Vis Exp, (121).
- Shah S, Dalecki AG, Malalasekera A, Crawford C, Michalek S, Kutsch O, Sun J, Bossman S and Wolschendorf F. (2016) 8-hydroxyquinolines are boosting-agents of copper related toxicity in Mycobacterium tuberculosis. Antimicrob Agents Chemother, 60(10):5765-76.
- Schaaf K, Hayley V, Wolschendorf F, Speer A, Niederweis M, Kutsch O and Sun J. (2016) A macrophage infection model to predict drug efficacy against Mycobacterium tuberculosis. Assay Drug Dev Technol, 14(6):345-54.
- Sun J*, Schaaf K, Duverger A, Wolschendorf F, Speer A, Wagner F, Niederweis M and Kutsch O. (2016) Protein Phosphatase, Mg2+/Mn2+-dependent 1A controls the innate antiviral and antibacterial response of macrophages during HIV-1 and Mycobacterium tuberculosis infection. Oncotarget, 7(13):15394-15409. *co-corresponding author
- Sun J, Siroy A, Lokareddy RK, Speer A, Doornbos KS, Cingolani G, Niederweis M. (2015) The Tuberculosis Necrotizing Toxin kills macrophages by hydrolyzing NAD+. Nature Struct Mol Biol, 22(9):672-8.
- Speer A, Sun J, Danilchanka O, Meikle V, Rowland JL, Walter K, Buck BR, Pavlenok M, Holscher C, Ehrt S, Niederweis M. (2015) Surface hydrolysis of sphingomyelin by the outer membrane protein Rv0888 supports replication of Mycobacterium tuberculosis in macrophages. Mol Microbiol, 97(5):881-97.
- Danilchanka O, Sun J, Pavlenok M, Maueröder C, Speer A, Siroy A, Marrero J, Trujillo C, Mayhew DL, Doornbos KS, Muñoz LE, Herrmann M, Ehrt S, Berens C, Niederweis M. (2014) An outer membrane channel protein of Mycobacterium tuberculosis with exotoxin activity. Proc Natl Acad Sci U S A, 6;111(18):6750-5.
- Sun J, Singh V, Lau A, Stokes RW, Obregón-Henao A, Orme IM, Wong D, Av-Gay Y, Hmama Z. (2013) Mycobacterium tuberculosis nucleoside diphosphate kinase inactivates small GTPases leading to evasion of innate immunity. PLoS Pathog, 9(7):e1003499.
- Wong D, Bach H, Sun J, Hmama Z, Av-Gay Y. (2011) Mycobacterium tuberculosis protein tyrosine phosphatase (PtpA) excludes host vacuolar-H+-ATPase to inhibit phagosome acidification. Proc Natl Acad Sci U S A, 108(48):19371-6.
- Sun J, Wang X, Lau A, Liao TY, Bucci C, Hmama Z. (2010) Mycobacterial nucleoside diphosphate kinase blocks phagosome maturation in murine RAW 264.7 macrophages. PLoS ONE, 5(1), e8769.
- Sun J, Lau A, Wang X, Liao TY, Zoubeidi A, Hmama Z. (2009) A broad-range of recombination cloning vectors in mycobacteria. Plasmid, 62(3), 158-65.
- Sun J, Deghmane AE, Bucci C, Hmama Z. (2009). Detection of Activated Rab7 GTPase with an Immobilized RILP Probe. Methods Mol Biol, 531, 57-69.
- Sun J, Deghmane AE, Soualhine H, Hong T, Bucci C, Solodkin A, Hmama Z. (2007) Mycobacterium bovis BCG disrupts the interaction of Rab7 with RILP contributing to inhibition of phagosome maturation. J Leuk Biol, 82(6), 1437-1445.
- Soualhine H, Deghmane AE, Sun J, Mak K, Talal A, Av-Gay Y, Hmama Z. (2007) Mycobacterium bovis bacillus Calmette-Guérin secreting active cathepsin S stimulates expression of mature MHC class II molecules and antigen presentation in human macrophages. J Immunol, 15;179(8):5137-45.
- Bach H, Sun J, Hmama Z, Av-Gay Y. (2006) Mycobacterium avium subsp. paratuberculosis PtpA is an endogenous tyrosine phosphatase secreted during infection. Infect Immun, 74(12):6540-6.