Metabolism and drug development against protozoan parasites. Calcium signaling and storage in Toxoplasma gondii.
Our laboratory works with Toxoplasma gondii, an apicomplexan parasite that infects almost one third of the world population. Toxoplasma also infects animals like cats, dogs and cattle worldwide. The infection with Toxoplasma is lifelong and it can cause encephalitis and cardiogenic shock in immuno-compromised patients. The infection of pregnant women could result in devastating effects for the unborn fetus. The pathologies associated with toxoplasmosis stem from its lytic cycle, characterized by active invasion, replication inside a parasitophorous vacuole and egress from host cells. Host cell entry is an obligatory and parasite-specific process choreographed by a unique set of proteins that are sequentially released from apical organelles termed micronemes, rhoptries and dense granules. Our laboratory is interested in discovering unique metabolic differences in Toxoplasma that could be exploited as targets for chemotherapy. The treatments available for Toxoplasmosis are restricted to only one phase of the disease and they have harmful side effects after continuous use. A constant source of new drugs and potential drug targets is needed to stay ahead of the threat posed by this successful pathogen.
In Toxoplasma Ca2+ signaling is involved in the stimulation of critical and essential steps of the lytic cycle (invasion, replication and egress) of the parasite. We study Ca2+ signaling and homeostasis in T. gondii and its role in virulence traits like attachment, and invasion of the host cell. Our laboratory created a number of genetic tools to study calcium signaling in Toxoplasma and we are investigating new mechanisms and characterizing new molecules with critical roles in signaling.
We also study the isoprenoid pathway as a potential target for chemotherapy and we have discovered that the parasite is able to take isoprenoid intermediates from the host. We proposed a double-hit strategy combining drugs that block both parasite and the host isoprenoid pathway.
Hortua Triana, M.A., Marquez-Nogueras. K., Chang, L., Stasic, A.J., Li, Z., Moreno, S.N.J. (2018). High-Performance probes for the detection of weakly expressed Toxoplasma gondii calcium-related genes. J. Euk. Microbiol. In press
Li, Z.H., Li, C., Szajnman, S.H., Rodriguez, J.B. and Moreno, S.N.J. (2017). Synergistic activity of statins and bisphosphonates against acute experimental toxoplasmosis. Antimicrob. Agents and Chemother. 61, e02628
Chasen, N., Asady, B., Lembruguer, L. Vommaro, R. C. Kissinger, J.C., Coppens, I. Moreno, S.N.J. (2017) A GPI-anchored carbonic anhydrase related protein of Toxoplasma gondii is important for rhoptry biogenesis and virulence. mSphere, 2(3), e00027
Sidik, S.M., Hortua Triana, M.A., Paul, A.S., Bakkouri, M.E., Hackett, C, Hui, R., Tran, F. Westwood, N.J., Duraisingh, M.J., Moreno, S.N.J., Lourido, S. (2016). Using a genetically encoded sensor to identify inhibitors of Toxoplasma gondii Ca2+ signaling. J. Biol. Chem, 291(18):9566-80
Lourido, S. and Moreno S.N.J. (2015) The Calcium Signaling Toolkit of the Apicomplexan Parasites Toxoplasma gondii and Plasmodium spp. Cell Calcium, Invited review. 57:186-193
Borges, L.#, Budu, A. #, McKnight, C#, Moore, C. #, Vella, S., Hortua Triana, M.A., Liu, J., Garcia, C., Pace, D. A., Moreno, S.N.J. (2015) Calcium signaling throughout the Toxoplasma gondii lytic cycle. A study using genetically encoded calcium indicators. J. Biol. Chem 290:26914-26. # Authors contributed equally
Pace, D.A., Mcknight, C., Liu, J., Jimenez, V., Moreno, S.N.J. Calcium entry in Toxoplasma gondii and its enhancing effect of invasion-linked traits. (2014) J. Biol. Chem., 289:19637-47
Tang, Q., Andenmatten, N., Deng, B., Hortua-Triana, M.A., Moreno, S.N.J., Meissner, M. Ballif, B.A., Ward, G. E. Calcium-dependent phosphorylation alters Class XIVa myosin function in the protozoan parasite Toxoplasma gondii. (2014) Mol. Biol. Cell., 25: 2579-91
Liu, J., Pace, D.A., Dou, Z., King, T.P., Carruthers, V., Moreno, S.N.J. (2014) A Vacuolar-H+-Pyrophosphatase (TgVP1) is required for microneme secretion, host cell invasion, and extracellular survival of Toxoplasma gondii. Mol. Microbiol. 93:698-712
Li, Z., Ramakrishnan, S., Striepen, B. and Moreno, S.N.J. (2013) Toxoplasma gondii Relies on both host and parasite isoprenoids and can be rendered sensitive to Atorvastatin. PLoS Pathog. 9:e1003665.
Moreno, S.N.J. and Docampo, R. (2013) Polyphosphate and its diverse functions in host cells and pathogens. PLoS Pathog. 9:e1003230.
Huang, G. Barlett, P. Thomas, A., Moreno, S.N.J. and Docampo, R. (2013) Acidocalcisomes of Trypanosoma brucei have an inositol 1,4,5-trisphosphate receptor that is required for growth and infectivity. Proc. Nat. Acad. Sci. USA, 110:1887-92.
Li, Z., Cintrón, R., Koon, N.A., and Moreno, S.N.J. (2012). The N-terminus and the chain-length determination (CLD) domain play a role in the determination of the isoprenoid product length in the bifunctional Toxoplasma gondii farnesyl-diphosphate/geranylgeranyl-diphosphate synthase. Biochemistry, 51:7533-7540.
Pace, D.A., Fang, J., Cintron, R., Docampo, M.D., Moreno, S.N.J. (2011) Overexpression of a cytosolic pyrophosphatase (TgPPase) reveals a regulatory role of pyrophosphate on glycolysis in Toxoplasma gondii. Biochem. J. 440:229-240.
Nair, S., Brooks, C.F., Goodman, C.D., Strurm, A., McFadden, G.I., Sundriyal, S., Anglin, J.L., Song,Y., Moreno, S.N.J. and Striepen B. (2011) Apicoplast isoprenoid precursor synthesis and the molecular basis of fosmidomycin resistance. J. Exp.Med. 208:1547-1559
Rohloff, P., Miranda, K., Rodrigues, J.C.F., Fang, J., Plattner, H., Hentschel, J., Galizzi, M. and Moreno, S.N.J. (2011) Calcium uptake and proton transport by acidocalcisomes of Toxoplasma gondii. PLoS One. 2011 6(4):e18390.
Miranda, K.#, Pace, D.A.#, Cintron, R., Rodrigues, J.C.F., Fang, J., Smith, A., Rohloff, P., Coelho, E., de Haas, F., de Souza, W., Coppens, I., Sibley, L.D., and Moreno, S.N.J. Characterization of a novel organelle in Toxoplasma gondii with similar composition and function to the plant vacuole. (2010) Mol. Microbiol. 76(6) 1358-1375.
# Both authors contributed equally
This article was featured on the cover and commented:
Novel vacuoles in Toxoplasma. van Dooren GG, Ralph SA. Mol Microbiol. (2010) 76(6):1335-9.
Ling Y, Li ZH, Miranda K, Oldfield E, Moreno, S.N.J. The farnesyl diphosphate/geranylgeranyl diphosphate synthase of Toxoplasma gondii is a bifunctional enzyme and the molecular target of bisphosphonates (2007) J. Biol. Chem. 282:30804-16.