Profile

Lakshmi Rajagopal, PhD

Lakshmi Rajagopal, PhD

Infectious Disease

Academic Title: Associate Professor

Research Center: Center for Global Infectious Disease Research

Lakshmi Rajagopal, PhD: Associate Professor of Pediatric Infectious Diseases and Microbiology. Our research interest is to understand signaling events that occur during bacterial disease pathogenesis. The human pathogens that we study are Group B Streptococcus (GBS) and Staphylococcus aureus.

Although both GBS and S. aureus are commensal organisms, these bacteria can also become disease-causing pathogens. GBS are commonly found in the recto-vaginal tract of healthy women but can cause severe invasive disease in human newborns and adults that include elderly, immunocompromised and diabetic individuals. Our studies on GBS are focused on understanding how these bacteria adapt to the environmental niches encountered during their life cycle. Studies from our research have shown that GBS encodes signaling factors such as a serine/threonine kinase; these proteins were previously thought only to exist in higher forms such as eukaryotic organisms. Our research showed that the kinase regulates the expression of the GBS toxin known as hemolysin/cytolysin and also enables the bacteria to adapt to nutrient starvation.

In recent studies, we demonstrated that the kinase affects toxin expression based upon its interaction with a DNA-binding response regulator known as CovR. The interaction between the kinase and CovR represents novel findings in bacterial environmental adaptation. Current research is focused toward identifying the environmental cues/signals that are sensed by these bacteria for regulation of toxin expression and virulence. Like GBS, S. aureus are also Gram-positive bacteria that can cause severe invasive disease in humans. We have recently identified a number of novel genes/signaling factors that regulate toxin expression in S. aureus. Current studies are focused on elucidating how these signaling factors regulate toxin expression and S. aureus virulence. The ultimate goal is to use the information gathered from our research to identify novel compounds that can be used to treat these bacterial infections.

For more information, please visit http://www.seattlechildrens.org/research/global-infectious-disease-research/rajagopal-lab/.

Overview

Medical/Professional School

Jawaharlal Nehru University, New Delhi
Bangalore University, Karnataka
Madurai Kamaraj University, Madurai

Fellowship

University of Washington, Seattle

Research Description

Our research interest is to understand signaling events that occur during bacterial disease pathogenesis. The human pathogens that we study are Group B Streptococcus (GBS) and Staphylococcus aureus.

GBS is a Gram-positive bacteria that causes invasive infections in human newborns and certain adult populations. Our studies on GBS focus on elucidating the role of a serine/threonine kinase in regulation of adaptive responses and virulence of the organism. We have shown that a serine/threonine kinase called Stk1 regulates de novo purine biosynthesis and toxin expression and is important for virulence of GBS.

In recent studies, we have shown that phosphorylation of the two-component regulator CovR by Stk1 eliminates CovR regulation of the GBS toxins. Current studies are focused toward identifying extracellular signals that dictate toxin expression of GBS (Lin, et al., Mol Microbiol 2009;71:1477-1495.

Like GBS, S. aureus is also Gram-positive cocci that can cause severe invasive disease in humans. We have recently begun to explore the role of a serine/threonine kinase homolog in virulence of S. aureus.

Lab URL

http://www.seattlechildrens.org/research/global-infectious-disease-research/rajagopal-lab/

Research Focus Area

Infectious Disease

Publications

  • Vanderhoeven JP, Bierle CJ, Kapur RP, McAdams RM, Beyer RP, Bammler TK, Farin FM, Bansal A, Spencer M, Deng M, Gravett MG, Rubens CE, Rajagopal L, Adams Waldorf KM
    Group B streptococcal infection of the choriodecidua induces dysfunction of the cytokeratin network in amniotic epithelium: a pathway to membrane weakening.
    PLoS pathogens , 2014 Mar. : 10(3)e1003920
  • Patras KA, Wang NY, Fletcher EM, Cavaco CK, Jimenez A, Garg M, Fierer J, Sheen TR, Rajagopal L, Doran KS
    Group B Streptococcus CovR regulation modulates host immune signalling pathways to promote vaginal colonization.
    Cellular microbiology , 2013 July : 15(7)1154-67
  • Whidbey C, Harrell MI, Burnside K, Ngo L, Becraft AK, Iyer LM, Aravind L, Hitti J, Waldorf KM, Rajagopal L
    A hemolytic pigment of Group B Streptococcus allows bacterial penetration of human placenta.
    The Journal of experimental medicine , 2013 June : 210(6)1265-81
  • Burnside K, Lembo A, Harrell MI, Klein JA, Lopez-Guisa J, Siegesmund AM, Torgerson TR, Oukka M, Molina DM, Rajagopal L
    Vaccination with a UV-irradiated genetically attenuated mutant of Staphylococcus aureus provides protection against subsequent systemic infection.
    The Journal of infectious diseases , 2012 Dec. : 206(11)1734-44
  • Burnside K, Rajagopal L
    Regulation of prokaryotic gene expression by eukaryotic-like enzymes.
    Current opinion in microbiology , 2012 Apr, : 15(2)125-31
  • Burnside K, Lembo A, Harrell MI, Gurney M, Xue L, BinhTran NT, Connelly JE, Jewell KA, Schmidt BZ, de los Reyes M, Tao WA, Doran KS, Rajagopal L
    Serine/threonine phosphatase Stp1 mediates post-transcriptional regulation of hemolysin, autolysis, and virulence of group B Streptococcus.
    The Journal of biological chemistry , 2011 Dec. : 286(51)44197-210
  • Vega C, Chou S, Engel K, Harrell ME, Rajagopal L, Grundner C
    Structure and substrate recognition of the Staphylococcus aureus protein tyrosine phosphatase PtpA.
    Journal of molecular biology , 2011 Oct. : 413(1)24-31
  • Qin X, Poon B, Kwong J, Niles D, Schmidt BZ, Rajagopal L, Gantt S
    Two paediatric cases of skin and soft-tissue infections due to clindamycin-resistant Staphylococcus aureus carrying a plasmid-encoded vga(A) allelic variant for a putative efflux pump.
    International journal of antimicrobial agents , 2011 July : 38(1)81-3
  • Burnside K, Rajagopal L
    Aspects of eukaryotic-like signaling in Gram-positive cocci: a focus on virulence.
    Future microbiology , 2011 July : 6(7)747-61
  • Lembo A, Gurney MA, Burnside K, Banerjee A, de los Reyes M, Connelly JE, Lin WJ, Jewell KA, Vo A, Renken CW, Doran KS, Rajagopal L
    Regulation of CovR expression in Group B Streptococcus impacts blood-brain barrier penetration.
    Molecular microbiology , 2010 July : 77(2)431-43
  • Burnside K, Lembo A, de Los Reyes M, Iliuk A, Binhtran NT, Connelly JE, Lin WJ, Schmidt BZ, Richardson AR, Fang FC, Tao WA, Rajagopal L
    Regulation of hemolysin expression and virulence of Staphylococcus aureus by a serine/threonine kinase and phosphatase.
    PloS one , 2010 June : 5(6)e11071
  • Silvestroni A, Jewell KA, Lin WJ, Connelly JE, Ivancic MM, Tao WA, Rajagopal L
    Identification of serine/threonine kinase substrates in the human pathogen group B streptococcus.
    Journal of proteome research , 2009 May : 8(5)2563-74
  • Lin WJ, Walthers D, Connelly JE, Burnside K, Jewell KA, Kenney LJ, Rajagopal L
    Threonine phosphorylation prevents promoter DNA binding of the Group B Streptococcus response regulator CovR.
    Molecular microbiology , 2009 Mar. : 71(6)1477-95
  • Rajagopal L
    Understanding the regulation of Group B Streptococcal virulence factors.
    Future microbiology , 2009 Mar. : 4(2)201-21
  • Rantanen MK, Lehtiö L, Rajagopal L, Rubens CE, Goldman A
    Structure of Streptococcus agalactiae serine/threonine phosphatase. The subdomain conformation is coupled to the binding of a third metal ion.
    The FEBS journal , 2007 June : 274(12)3128-37
  • Rantanen MK, Lehtiö L, Rajagopal L, Rubens CE, Goldman A
    Structure of the Streptococcus agalactiae family II inorganic pyrophosphatase at 2.80 A resolution.
    Acta crystallographica. Section D, Biological crystallography , 2007 June : 63(Pt 6)738-43
  • Rajagopal L, Vo A, Silvestroni A, Rubens CE
    Regulation of cytotoxin expression by converging eukaryotic-type and two-component signalling mechanisms in Streptococcus agalactiae.
    Molecular microbiology , 2006 Nov. : 62(4)941-57
  • Rantanen MK, Lehtiö L, Rajagopal L, Rubens CE, Goldman A
    Crystallization and preliminary crystallographic analysis of two Streptococcus agalactiae proteins: the family II inorganic pyrophosphatase and the serine/threonine phosphatase.
    Acta crystallographica. Section F, Structural biology and crystallization communications , 2006 Sept. : 62(Pt 9)891-4
  • Rajagopal L, Vo A, Silvestroni A, Rubens CE
    Regulation of purine biosynthesis by a eukaryotic-type kinase in Streptococcus agalactiae.
    Molecular microbiology , 2005 June : 56(5)1329-46
  • Shelver D, Rajagopal L, Harris TO, Rubens CE
    MtaR, a regulator of methionine transport, is critical for survival of group B streptococcus in vivo.
    Journal of bacteriology , 2003 Nov. : 185(22)6592-9
  • Rajagopal L, Clancy A, Rubens CE
    A eukaryotic type serine/threonine kinase and phosphatase in Streptococcus agalactiae reversibly phosphorylate an inorganic pyrophosphatase and affect growth, cell segregation, and virulence.
    The Journal of biological chemistry , 2003 Apr, : 278(16)14429-41
  • Goel AK, Rajagopal L, Nagesh N, Sonti RV
    Genetic locus encoding functions involved in biosynthesis and outer membrane localization of xanthomonadin in Xanthomonas oryzae pv. oryzae.
    Journal of bacteriology , 2002 July : 184(13)3539-48
  • Lakshmi Rajagopal, PhD
    US PATENT: Kinase inhibitors capable of increasing the sensitivity of bacterial pathogens to -lactam antibiotics
    PCT/US2012/050635. 8/13/2012
  • Lakshmi Rajagopal, PhD
    US PATENT: Bacterial mutant BX065 and a method thereof (Shikimate dehydrogenase as a target for developing novel bactericides against plant pathogens)
    Patent Number: 68,69,601. 3/22/2005.

Presentations

Presentations Title Event Location Date
Adams Waldorf KM, Sooranna SR, Gravett MG, Paolella L, Gough M, Ngo L, Bammler T, MacDonald JW, Farin FM, Rajagopal L and Johnson MR. Acute Uterine Stretch Induces an Inflammatory "Pulse" in Amniotic Fluid and Maternal Plasma Followed by Preterm Labor in Nonhuman Primates. Society for Gynecologic Investigation, Florence, Italy, March 28, 2014.
Bierle CJ, Adams-Waldorf KM and Rajagopal L. Nonhuman primate and ex vivo models of intra-amniotic bacterial infection. Northwest Branch Meeting of the American Society for Microbiology. Seattle, Washington, November 15-16, 2013.
Whidbey C, Ngo L, Adams Waldorf K and Rajagopal L. A mouse model of Group B Streptococcal associated preterm birth. 17th International Conference on Gram-Positive Microorganisms and 17th International Conference on Bacilli, Montecatini Terme, Italy, June 23-27, 2013.
Whidbey C, Harrell M, Adams-Waldorf K and Rajagopal L. Penetration of human placenta by Group B Streptococci, presented at the Northwest Branch Meeting of the American Society for Microbiology. Seattle, WA. November 9-10, 2012.
Whidbey C, Harrell M, Adams-Waldorf K and Rajagopal L. Penetration of human placenta by Group B Streptococci, presented at the International Conference for Gram-Positive Pathogens. Omaha, NE. October 7-10, 2012.
Lembo A, Gurney MA, Burnside K, Connelly JE, Doran KS and Rajagopal L. The two component system RgfC/A regulates CspA expression and Group B Streptococcal virulence, presented at the International Conference on Gram-Positive Microorganisms. Omaha, NE. October 10-13, 2010.
Burnside K, Jewell K, Connelly JE and Rajagopal L. Role of a serine/threonine kinase in virulence of Staphylococcus aureus, presented at the 5th International Conference on Gram-Positive Microorganisms. San Diego, CA. June 14-18, 2009.
Rajagopal L, Clancy A and Rubens CE. A novel serine/threonine kinase essential for cell growth and division in Group B Streptococci, presented at the 6th Streptococcal Genetics Meeting. Asheville, NC. April 13-17, 2002.

Research Funding

Grant Title Grantor Amount Award Date
Role of an ornithine rhamnolipid pigment in GBS virulence - R01 AI112619 NIH/NIAID $250,000 annual direct costs July 1, 2014 - June 30, 2019
Environmental signals that regulate GBS virulence - R21 AI109222 NIH/NIAID $150,000 annual direct costs Sept. 1, 2013 - Aug. 31, 2015
Eukaryotic-type signaling mediates two-component regulation of GBS virulence - R56 AI070749-06A1 NIH/NIAID $247,362 annual direct costs June 11, 2013 - Dec. 31, 2014
GBS mediated in utero fetal injury - R01 AI100989 (Co-PI with Kristina Adams Waldorf) NIH/NIAID $499,906 annual direct costs July 1, 2012 - June 30, 2017