Welcome

Our lab is interested in the molecular events that enable apicomplexan parasites to remain widespread and deadly infectious agents. These single-celled eukaryotes comprise a phylum of organisms that parasitize diverse animal hosts. Many important human pathogens belong to this group, including the causative agents of malaria (Plasmodium spp.), cryptosporidiosis (Cryptosporidium spp.), and toxoplasmosis (Toxoplasma gondii). We use T. gondii to model features conserved throughout the phylum, such as their reliance on calcium signaling to regulate motility. We combine several approaches that span phospho-proteomics, chemical-genetics, and genome editing to investigate the unique biology of these organisms. Our work seeks to expand our understanding of eukaryotic diversity and identify specific features that can be targeted to treat parasite infections. For more information on our work, visit iBiology.org for Sebastian’s lectures on Toxoplasma and other stories of cutting-edge research in the life sciences, available for free to a global audience.

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Lab News

Research

Calcium Signaling

Changes in cytosolic calcium regulate eukaryotic cellular responses as diverse as membrane repair and muscle contraction. In apicomplexan parasites, calcium regulates motility in part through the regulation of adhesin exocytosis and myosin-motor function. We seek to understand the molecular details of these processes, examining both the events that lead to cytosolic calcium changes and the signaling events that follow them.


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  • CDPK3 Immunofluorescence 


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Protein Kinases

We are interested in how calcium signals are decoded by protein kinases, and in particular the role of calcium-dependent protein kinases (CDPKs) as the primary calcium-responsive kinases in parasites. Our work, and that of many others, has defined diverse roles for these kinases in regulating important events during the life cycle of apicomplexans. We have recently used alpaca-derived single-domain antibodies to probe the structure of CDPKs, defining a new mode of allosteric inhibition. We continue to develop biochemical methods to study these kinases, in addition to chemical-genetic approaches to study their function in vivo.

Chemical Genetics

We have engineered a panel of strains to study individual CDPKs. This approach relies on mutating the “gatekeeper” residue that restricts the depth of the ATP-binding pocket. This allows us to specifically inhibit or identify the targets of individual kinases. Using this approach, we have previously elucidated the distinct roles of TgCDPK1 and TgCDPK3 during the T. gondii lytic cycle. We continue to investigate the functions of these and other CDPKs, relying in part on phospho-proteomic methods to identify specific kinase targets.


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Genome Engineering

Much of our work is made possible through a variety of genome-engineering methods. We are interested in developing new methods to enable efficient functional analysis of parasite genes and polymorphisms. Our lab was among the first to adapt CRISPR/Cas9 to engineer the T. gondii genome, and our plasmids are available to anyone through Addgene. We continue to improve these systems to enable genome-scale screening in parasites, which will allow­­ exploration of the multitude of apicomplexan genes with unknown functions.

Lab Members

Staff

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Support Team

Publications

  • The multifaceted roles of Myb domain-containing proteins in apicomplexan parasites.

    Schwarz D, Lourido S.

    Curr Opin Microbiol. 2023 Dec;76:102395.

    PMID: 37866202


    A conserved complex of microneme proteins mediates rhoptry discharge in Toxoplasma.

    Valleau D, Sidik SM, Godoy LC, Acevedo-Sánchez Y, Pasaje CFA, Huynh MH, Carruthers VB, Niles JC, Lourido S.

    EMBO J. 2023 Dec 1;42(23):e113155.

    PMID: 37886905


    Translation initiation factor eIF1.2 promotes Toxoplasma stage conversion by regulating levels of key differentiation factors.

    Wang F, Holmes MJ, Hong HJ, Thaprawat P, Kannan G, Huynh MH, Schultz TL, Licon MH, Lourido S, Sullivan WJ, O’Leary SE, Carruthers VB.

    bioRxiv [Preprint]. 2023 Nov 3:2023.11.03.565545.

    PMID: 37961607


    Discovery of antibiotics that selectively kill metabolically dormant bacteria.

    Zheng EJ, Valeri JA, Andrews IW, Krishnan A, Bandyopadhyay P, Anahtar MN, Herneisen A, Schulte F, Linnehan B, Wong F, Stokes JM, Renner LD, Lourido S, Collins JJ.

    2023 Nov 15:S2451-9456(23)00387-2.

    PMID: 38029756


    SPARK regulates AGC kinases central to the Toxoplasma gondii asexual cycle.

    Herneisen AL, Peters ML , Smith TA, Lourido S.

    bioRxiv [Preprint]. 2023 Oct 30:2023.10.30.564746.

    PMID: 37961644


    CDPK2A and CDPK1 form a signaling module upstream of Toxoplasma motility.

    Shortt E, Hackett CG, Stadler RV, Kent RS, Herneisen AL, Ward GE, Lourido S.

    mBio. 2023 Aug 23:e0135823.

    PMID: 37610220


    A positive feedback loop controls Toxoplasma chronic differentiation.

    Licon MH, Giuliano CJ, Chan AW, Chakladar S, Eberhard JN, Shallberg LA, Chandrasekaran S, Waldman BS, Koshy AA, Hunter CA, Lourido S.

    Nat Microbiol. 2023 May;8(5):889-904.

    PMID: 37081202


    Functional profiling of the Toxoplasma genome during acute mouse infection.

    Giuliano CJ, Wei KJ, Harling FM, Waldman BS, Farringer MA, Boydston EA, Lan TCT, Thomas RW, Herneisen AL, Sanderlin AG, Coppens I, Dvorin JD, Lourido S.

    bioRxiv. 2023 Mar 6:2023.03.05.531216.

    PMID: 36945434


    Analysis of CDPK1 targets identifies a trafficking adaptor complex that regulates microneme exocytosis in Toxoplasma.

    Chan AW, Broncel M, Yifrach E, Haseley NR, Chakladar S, Andree E, Herneisen AL, Shortt E, Treeck M, Lourido S.

    eLife 12:RP85654

    PMID: 36712004

Contact

Lourido Lab

Whitehead Institute for Biomedical Research
Room 561D (Office), Room 555 (Lab)
455 Main Street
Cambridge, MA 02142-1479
Tel.: 617-324-4920 (Office), 617-324-5869 (Lab)

Administrative Lab Manager

Gabrielle McCauley
Tel.: 617-258-5251

Join Us

The Whitehead Institute is a world-renowned research institution doing cutting-edge biomedical research. We offer highly competitive salaries and benefits to postdoctoral fellows and associates. We welcome highly motivated individuals with training in molecular genetics, biochemistry, and cell biology. For additional information about ongoing research projects, please send inquiry to Sebastian Lourido, along with your CV and names of references.