Tuberculosis
Shilpa Vasishta
Jared E. Coe
Daniel A. Burack
William R. Jacobs Jr.
<p> </p>
<p style="margin: 0in 0in 8pt; line-height: normal; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto;"><span style="color: black; font-family: 'Verdana',sans-serif; font-size: 10.5pt; mso-fareast-font-family: 'Times New Roman'; mso-bidi-font-family: 'Times New Roman';">The current research interests of my lab include 1) generating complete sets of precise null barcoded deletion mutants of <em>Mycobacterium</em> <em>tuberculosis</em> to screen for virulence and drug persistence in mouse and non-human primate models, 2) understanding persistence-the capacity of subpopulations of <em>M. tuberculosis</em> to resist killing assaults by bactericidal drugs or immune effectors, 3) use of a novel recombinant herpes vector to make novel influenza, Tuberculosis, Dengue, and EEEV vaccines that specifically elicit antibodies that mediate antibody dependent cell mediated cytotoxicity, and 4) develop new luciferase reporter phage point of care diagnostics.</span></p>
<ul>
<li>The Exterminators <a href="https://www.esquire.com/news-politics/a3918/exterminators1207/" target="_blank" rel="noopener">https://www.esquire.com/news-politics/a3918/exterminators1207/</a></li&…;
<li>Presidential Lecture <a href="https://www.youtube.com/watch?v=sBsUUW3UrSw" target="_blank" rel="noopener">https://www.youtube.com/watch?v=sBsUUW3UrSw</a></li>
<li>National Academy of Sciences Profile <a href="http://www.nasonline.org/member-directory/members/20030248.html">http:/…;
</ul>
<p class="MsoNormal" style="line-height: 15.6pt;"><span style="font-size: 9.0pt;">Dr. Jacobs is pioneering the use of molecular genetics to control tuberculosis (TB), which kills nearly two million people a year. His research is identifying the genes that make<span> </span><em>Mycobacterium tuberculosis</em><span> </span>(MTB) - the bacteria that causes TB - virulent, identifying new drug targets and engineering weakened strains that can be used as live vaccines. Dr. Jacobs was the first scientist to introduce foreign DNA into MTB, a technique now regularly used by TB investigators around the world.</span></p>
<p class="MsoNormal" style="line-height: 15.6pt;"><span style="font-size: 9.0pt;">Dr. Jacobs recently discovered two new ways of killing the bacteria that cause TB, a finding that could also lead to a therapy to prevent drug-resistant TB strains from developing. He also devised an onsite lab test that not only can quickly diagnose TB but can also distinguish treatable TB strains from those that are drug resistant—a process that ordinarily takes months. Dr. Jacobs is participating in a groundbreaking partnership between HHMI and the University of KwaZulu-Natal (UKZN) in South Africa; the partners are establishing an international research center that will contribute to the worldwide effort to control the TB-HIV co-epidemic and will train a new generation of scientists in Africa.</span></p>
<ol>
<li>Tiwari S, Casey R, Goulding CW, Hingley-Wilson S, Jacobs WR Jr. (2019) Infect and Inject: How Mycobacterium tuberculosis Exploits Its Major Virulence-Associated Type VII Secretion System, ESX-1. Microbiol Spectr. PMID: 31172908</li>
<li>Porcelli, S.S, Jacobs WR Jr. (2019). Eacting Edward Jenner's Revenge: The quest for a new tuberculosis vaccine. Sci Trasl Med. PMID: 31043569</li>
<li>Vilcheze C, Jacobs WR Jr. (2019). The Isonizid Paradigm of Killing, Resistance, and Persistence in Mycobcaterium Tuberculosis. J Mol Biol. PMID: 30797860</li>
<li>O'Donnell MR, Larsen MH, Brown TS, Jain P, Munsamy V, Wolf A, Uccellini L, Karim F, D'Olivera T, Mathema B, Jacobs WR, Pym A. (2019). Early Detection of emergent drug resistant tuberculosis (XDR-TB) by flow cytometry-based phenotyping and whole genome sequencing. Antimicrob Agents Chemother. PMCID: PMC6437479</li>
<li>Shen L., Frencher J., Huang D., Wang W., Yang E., Chen C.Y., Zhang Z., Wang R., Qaqish A., Larsen M.H., Shen H., Porcelli S.A., Jacobs W.R., Jr., Chen Z.W. (2019). Immunization of <span style="color: #333333; text-transform: none; text-indent: 0px; letter-spacing: normal; font-family: 'Open Sans', HelveticaNeue, 'Helvetica Neue', Helvetica, Arial, sans-serif; font-size: 15px; font-style: normal; font-weight: 400; word-spacing: 0px; float: none; display: inline !important; white-space: normal; orphans: 2; widows: 2; background-color: #ffffff; font-variant-ligatures: normal; font-variant-caps: normal; -webkit-text-stroke-width: 0px; text-decoration-style: initial; text-decoration-color: initial;">Vγ2Vδ2</span> T cells programs sustained effector memory responses that control tuberculosis in nonhuman primates. Proc Natl Acad Sci U.S.A. 116 (13): 6371-6378. PMID: 30850538</li>
<li>Johndrow CT, Goldberg MF, Johnson AJ, Ng TW, Kunnath-Velayudhan S, Lauvau G, Kaplan DH, Gossel GH, Kadolsky UD, Yates AJ, Chan J, Jacobs WR Jr, Porcelli SA. (2018). Suppresion of Th1 Priming by TLR2 Agonists during Cutaneous Immunization is Mediated by Recruited CCR2+ Monocytes. J Immunol. 201(12):3604-3616. PMID: 30455402</li>
<li>Bhatt K, Machado H, Osorio NS, Sousa J, Cardoso F, Magalhaes C, Chen B, Chen M, Kim J, Singh A, Ferreira CM, Castro AG, Torrado E, Jacobs WR Jr, Bhatt A, Saraiva M. (2018). A Nonribosomal Peptide Synthase Gene Driving Virulence in <em>Mycobacterium tuberculosis</em>. mSphere. 3(5). PMCID: PMC6211224</li>
<li>Tiwari S, vanTonder AJ, Vilcheze C, Mendes V, Thomas SE, Malek A, Chen B, Chen M, Kim J, Blundell TL, Parkhill J, Weinrick B, Berney M, Jacobs WR Jr. (2018). Arginine-deprived-induced ozidative damage sterilizes <em>Mycobacterium tuberculosis</em>. PNAS. 115(39):9779-9784. PMCID: PMC6166831</li>
<li>Kennedy SC, Johnson AJ, Bharrham S, Linderstam Arlehamn CS, XU J, Garforth SJ, Chan J, Jacobs WR Jr, Settle A, Almo SC, Porcelli SA. (2018). Identification of Mycobacterial Ribosomal Proteins as Targets for CD4+ T Cells that Enhance Protective Immunity in Tuberculosis. Infection and Immunity. 86(9). PMCID: PMC6105890</li>
<li>Vilcheze C, Copelan J, Keiser, Weisbrod T, Washington J, Jain P, Malek A, Weinrick B, Jacobs WR Jr. (2018). Rational Design of Biosafety Level 2-Approved, Multidrug-Resistant Strains of Mycobacterium tuberculosis through Nutrient Auxothrophy. MBio. 9(3). PMCID: PMC5974470</li>
<li>Harbut MB, Yang B, Liu R, Yano T, Vilcheze C, Cheng B, Lockner J, Guo H, Yu C, Franzblau SG, Petrassi HM, Jacobs WR Jr., Rubin H, Chatterjee AK, Wang F. (2018). Small Molecules Targeting <em>Mycobacterium tuberculosis</em> Type II NADH Dehydrogenase Exhibit Antimycobacterial Activity. Angew Chem Int Ed Engl. 57(13):3478-3482. PMCID: PMC6066186</li>
<li>Vilcheze C, Weinrick B, Leung LW, Jacobs WR Jr. (2018). Plasticity of Mycobacterium tuberculosis NADH dehydrogenases and their role in virulence. PNAS. 115(7):1599-1604. PMCID: PMC5816213</li>
<li>Vilcheze C, Kim J, Jacobs WR Jr. (2018). Vitamin C potentiates the killing of <em>Mycobacterium tuberculosis</em> by the first-line tuberculosis drugs isoniazid and rifampicin in mice. Antimicrob Agents Chemother. PMCID: PMC5826150</li>
<li>Burn, C., Ramsey, N., Garforth, S.J., Almo, S., Jacobs, W.R., Jr. and Herold, B.C. (2018). An HSV-2 single-cycle candidate vaccine deleted in glycoprotein D, DeltagD-2, protects male mice from lethal skin challenge with clinical isolates of HSV-1 and HSV-2. J Infect Dis. PMCID: PMC5853290</li>
<li>Retamal-Diaz, A., Weiss, K.A., Tognarelli, E.I., Freire, M., Bueno, S.M., Herold, B.C., Jacobs, W.R., Jr. and Gonzalez, P.A. (2017). US6 Gene Deletion in Herpes Simplex Virus Type 2 Enhances Dendritic Cell Function and T Cell Activation. Front Immunol. (8)1523. PMCID: PMC5686121</li>
</ol>
Steven A. Porcelli
<p>Dr. Porcelli's laboratory focuses on the control of acquired immune responses by T cells, which are the master regulatory and key effector cells of host defense and immune tolerance. In broad terms, the research being pursued in the laboratory covers two interrelated areas. The first is to understand the role of regulatory T cells, with particular emphasis on the activities of a specialized T cell subset known as CD1d-restricted NKT cells. These T cells have the highly unusual property of responding to specific glycolipid antigens, which they recognize in combination with a specialized lipid antigen presenting molecule known as CD1d. The laboratory is studying the details of the cellular mechanisms that lead to the uptake and presentation of lipid antigens by CD1d, and is using synthetic lipid antigens recognized by NKT cells to determine how antigen structure controls the immune responses that are generated by NKT cell activation. Methods for using lipid antigens that stimulate NKT cells to treat cancer or improve vaccination are also being studied. The laboratory's second major research area is the study of T cell responses against pathogenic microorganisms, especially <em>Mycobacterium tuberculosis.</em> Work in this area has led to significant progress in understanding how mycobacteria block effective host T cell responses, and this information is now being used to further the design of more effective vaccines for prevention of tuberculosis. A major near term goal of this research is to broaden the understanding of how organisms like <em>M. tuberculosis</em> successfully evade eradication by the immune system. The major long term goal is to create a genetically modified live attenuated <em>M. tuberculosis</em> strain that will be safe and effective as a vaccine against tuberculosis. Another related area of our work uses vaccine strains of mycobacteria to enhance antibody responses against pathogenic viruses including Ebola and SARS-CoV-2 viruses.</p>
<p class="MsoNormal" style="line-height: 15.6pt;"><span style="font-size: 9.0pt;">Dr. Porcelli studies the control of acquired immunity – the type that develops when our bodies generate specific responses involving antibodies or T cells following exposure to vaccines or infection by disease-causing microbes. In particular, he investigates how T cells – which supervise both defense against microbes and immune tolerance – control the acquired immune response.</span></p>
<p class="MsoNormal" style="line-height: 15.6pt;"><span style="font-size: 9.0pt;">Dr. Porcelli focuses on particular specialized T cells known as CD1d-restricted NKT cells. Using mouse models of autoimmune disorders, infections, and cancer, Dr. Porcelli is studying how the function of these specialized T cells can be altered to produce immune responses that are optimal for human health. </span></p>
<p class="MsoNormal" style="line-height: 15.6pt;"><span style="font-size: 9.0pt;">Another area of Dr. Porcelli’s research involves <em>Mycobacterium tuberculosis</em>, the bacterial species that causes tuberculosis (TB). With colleagues at Einstein, he has identified <em>M. tuberculosis</em> genes that help the microbe evade the body’s cell-mediated immunity. The Einstein researchers are using this information to create strains of TB bacteria that may be more effective than the existing vaccine at producing protective immunity against TB. Dr. Porcelli is a fellow of the American Society for Clinical Investigation.</span></p>
<ol>
<li><span class="underline">Porcelli, SA</span>. Tuberculosis: Shrewd survival strategy. Nature 454:702-3 (2008).</li>
<li>Im JS, Arora P, Bricard G, Molano A, Venkataswamy MM, Baine I, Jerud ES, Goldberg MF, Yu KOA, Ndonye RM, Howell AR, Yuan W, Cresswell P, Chang YT, Illarionov PA, Besra GS and <span class="underline">Porcelli SA</span>. Kinetics and cellular site of glycolipid loading control the outcome of Natural Killer T cell activation. Immunity 30:888-98 (2009).</li>
<li>Venkataswamy MM, Baena A, Goldberg M, Bricard G, Im JS, Besra GS, Chan J, Jacobs Jr. WR and <span class="underline">Porcelli SA</span>. Enhancement of immunogenicity of <em>M. bovis</em> BCG by incorporation of NKT cell activating glycolipids. J Immunol. 183:1644-56 (2009).</li>
<li>Arora P, Baena A, Yu KO, Saini NK, Kharkwal SS, Goldberg MF, Kunnath-Velayudhan S, Carreño LJ, Venkataswamy MM, Kim J, Lazar-Molnar E, Lauvau G, Chang YT, Liu Z, Bittman R, Al-Shamkhani A, Cox LR, Jervis PJ, Veerapen N, Besra GS, Porcelli SA. A single subset of dendritic cells controls the cytokine bias of natural killer T cell responses to diverse glycolipid antigens. Immunity. 40:105-16 (2014).</li>
<li>Singh M, Quispe-Tintaya W, Chandra D, Jahangir A, Venkataswamy MM, Ng TW, Sharma S, Carreño LJ, <span class="underline">Porcelli SA</span>*, Gravekamp C*. Direct incorporation of the NKT cell activator a-galactosylceramide improves efficacy and safety of a recombinant Listeria monocytogenes breast cancer vaccine. (*Joint senior/corresponding author). Br J Cancer. 2014 Nov 11;111(10):1945-54.</li>
<li><span style="font-size: 11.0pt; font-family: 'Arial',sans-serif; mso-fareast-font-family: 'Times New Roman'; mso-ansi-language: EN-US; mso-fareast-language: EN-US; mso-bidi-language: AR-SA;">Saini NK, Baena A, Ng TW, Venkataswamy MM, Kennedy SC, Kunnath-Velayudhan S, Carreno L, Xu J, Chan J, Larsen MH, Jacobs Jr. WR, <strong style="mso-bidi-font-weight: normal;">Porcelli SA</strong>.<span style="mso-spacerun: yes;"> </span>Suppression of autophagy and antigen presentation by Mycobacterium tuberculosis PE_PGRS47.<span style="mso-spacerun: yes;"> </span>Nat Microbiol (9):16133 (2016).</span> <span style="font-size: 11.0pt; font-family: 'Arial',sans-serif; mso-fareast-font-family: 'Times New Roman'; mso-ansi-language: EN-US; mso-fareast-language: EN-US; mso-bidi-language: AR-SA;">PMID: 27562263</span></li>
<li><span style="font-size: 11.0pt; font-family: 'Arial',sans-serif;">Saavedra-Avila NA, Keshipeddy S, Guberman-Pfeffer MJ, Pérez-Gallegos A, Saini NK, Schäfer C, Carreño LJ, Gascón JA, Porcelli SA, Howell AR. Amide-Linked C4″-Saccharide Modification of KRN7000 Provides Potent Stimulation of Human Invariant NKT Cells and Anti-Tumor Immunity in a Humanized Mouse Model.<span style="mso-spacerun: yes;"> </span>ACS Chem Biol. 2020 Dec 18;15(12):3176-3186. doi: 10.1021/acschembio.0c00707. Epub 2020 Dec 9. PMID: 33296161</span> <!-- [if gte mso 9]><xml>
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<li><span style="font-size: 11.0pt; font-family: 'Arial',sans-serif;">Ng TW, Wirchnianski AS, Wec AZ, Fels JM, Johndrow CT, Saunders KO, Liao HX, Chan J, Jacobs WR Jr, Chandran K, Porcelli SA. Exploiting Pre-Existing CD4+ T Cell Help from Bacille Calmette-Guérin Vaccination to Improve Antiviral Antibody Responses. J Immunol. 2020 Jul 15;205(2):425-437. doi: 10.4049/jimmunol.2000191. Epub 2020 Jun 8. PMID: 32513849</span></li>
<li><span style="font-size: 11.0pt; font-family: 'Arial',sans-serif; mso-fareast-font-family: 'Times New Roman'; mso-ansi-language: EN-US; mso-fareast-language: EN-US; mso-bidi-language: AR-SA;">Kharkwal SS, Johndrow CT, Veerapen N, Kharkwal H, Saavedra-Avila NA, Carreño LJ, Rothberg S, Zhang J, Garforth SJ, Jervis PJ, Zhang L, Donda A, Besra AK, Cox LR, Almo SC, Howell A, Evans EE, Zauderer M, Besra GS, Porcelli SA. Serial Stimulation of Invariant Natural Killer T Cells with Covalently Stabilized Bispecific T Cell Engagers Generates Anti-Tumor Immunity While Avoiding Anergy.<span style="mso-spacerun: yes;"> </span>Cancer Res. 2021 Jan 22:canres.2219.2020. doi: 10.1158/0008-5472.CAN-20-2219. Online ahead of print. PMID: 33483371</span><!-- [if gte mso 9]><xml>
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