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Faculty
| Marcelo Jacobs-Lorena | |
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"My move to Johns Hopkins to join the Malaria Research Institute has been an exciting event for my team. We are greatly benefitting from the high quality of the intellectual environment, from the numerous opportunities to interact with other faculty members and from the superb support facilities."
For transmission to occur, Plasmodium, the causative agent of malaria, has to complete a complex set of developmental events in its mosquito host. A major objective of the Jacobs-Lorena team is to investigate these events at the molecular level.
We have previously demonstrated that mosquitoes genetically modified with a gene that interferes with parasite invasion of the midgut are impaired for parasite transmission [Ito et al. (2002) Nature 417:452-455]. The gene encodes a 12-amino acid peptide (SM1) that binds to putative receptors on the surface of midgut and salivary gland epithelia. Recent experiments demonstrated that mosquitoes that secrete SM1 into the hemocoel (instead of the midgut) are also impaired for parasite transmission, presumably through blockage of salivary gland invasion by sporozoites. Significantly, the genetically modified mosquitoes are as fit as their non-modified counterparts. Moreover, when transgenic mosquitoes ingested a Plasmodium-infected blood meal, they had a distinct fitness advantage over their non-transgenic counterparts. These discoveries are important for devising methods to spread the inserted gene through wild mosquito populations.
Little information is available about genes that are expressed during parasite development in the mosquito. To gain insight into these processes, libraries enriched in genes that are expressed by the parasite and the mosquito at different times during the differentiation process have been constructed [Abraham et al. (2004) J. Biol. Chem. 279:5573-5580; Srinivasan et al. (2004) J. Biol. Chem. 279:5581-5587]. Analysis of these libraries is starting to provide clues about critical events required for successful parasite development and about genes induced in the mosquito in response of the parasite. For example, a mosquito gene (SERPIN6) is dramatically up-regulated in the midgut of mosquitoes fed on an infective blood meal but not in controls fed a non-infective blood meal. If this induction is prevented by injection of interfering double-stranded RNA, parasite numbers increase substantially, indicating that this gene is involved in protection of the mosquito from the parasite. Current experiments aim at the elucidation of this protective pathway.
To complete development in the mosquito, Plasmodium has to invade two different mosquito epithelia: midgut and salivary gland. Strong circumstantial evidence suggests that invasion depends on recognition of mosquito surface molecules by Plasmodium proteins. Work is in progress to identify such interacting molecules. Our recent results suggest that to invade the salivary gland TRAP, which is an abundant protein on the surface of the Plasmodium sporozoite, interacts with SAGLIN, a putative receptor protein on the surface of the mosquito salivary gland. We also made progress in the identification of mosquito midgut epithelial surface molecules (putative receptors) that the Plasmodium ookinete needs to recognize in order to invade this cell layer. One of these molecules is aminopeptidase N (APN1). Antibodies against APN1 interfere with Plasmodium development in the mosquito and as such, APN1 is a candidate antigen for a transmission-blocking vaccine (Dinglasan et al. (2007) Proc. Natl. Acad. Sci. USA 104:13461-13466). Another class of molecules required for parasite invasion of the mosquito midgut are chondroitin surface proteoglycans (Dinglasan et al. (2007) Proc. Natl. Acad. Sci. USA. early edition www.pnas.org_cgi_doi_10.1073_pnas.0706340104). This type of knowledge may lead to novel approaches to interfere with the spread of disease.
CONTACT DR. JACOBS-LORENA
Johns Hopkins Bloomberg School of Public Health
615 North Wolfe Street
Room E4632
Baltimore, MD 21205
email: mlorena@jhsph.edu
phone: 443-287-0839
fax: 410-955-0105
LINKS
SELECTED PUBLICATIONS
Riehle MA, Moreira CK, Lampe D, Lauzon C and Jacobs-Lorena M (2007) Using bacteria to express and display anti-Plasmodium molecules in the mosquito midgut. Int. J. Parasit. 37:595-603.
Marrelli MT, Li C, Rasgon J and Jacobs-Lorena M (2007) Transgenic malaria-resistant mosquitoes have a fitness advantage when feeding on Plasmodium-infected blood. Proc. Natl. Acad. Sci. USA. 104:5580-5583.
Moreira CK, Rodrigues FG, Ghosh A, Varotti FP, Miranda A, Daffre S, Jacobs-Lorena M and Moreira LA (2007) Effect of the antimicrobial peptide gomesin against different life stages of Plasmodium spp. Exp. Parasit., 116:346-353.
Dinglasan RR, Kalume DE, Kanzok SM, Ghosh AK, Muratova O, Pandey A and Jacobs-Lorena M (2007) Characterization of a novel, conserved Plasmodium transmission-blocking mosquito midgut antigen. Proc. Natl. Acad. Sci. USA 104:13461-13466.
Sodja A, Fujioka H, Lemos FJA, Donnelly-Doman M and Jacobs-Lorena M (2007) Induction of actin gene expression in the mosquito midgut by blood ingestion correlates with striking changes of cell shape. J. Insect Physiol. 53:833-839.
Dinglasan RR, Alaganan A, Ghosh AK, Saito A, van Kuppervelt TH and Jacobs-Lorena M (2007) Plasmodium falciparum ookinetes require mosquito midgut chondroitin sulfate proteoglycans for cell invasion. Proc. Natl. Acad. Sci. USA. Early edition www.pnas.org_cgi_doi_10.1073_pnas.0706340104
Abraham EG, Donnelly-Doman M, Fujioka H, Ghosh A, Moreira L, Jacobs-Lorena M. Driving midgut-specific expression and secretion of a foreign protein in transgenic mosquitoes with AgAper1 regulatory elements. Insect Mol Biol 14:271-279, 2005. Article
Abraham EG, Pinto SB, Ghosh A, Vanlandingham DL, Budd A, Higgs S, Kafators FC, Jacobs-Lorena M, Michel K. An immune-responsive serpin, SRPN6, mediates mosquito defense against malaria parasites. Proc Natl Acad Sci USA 102:16327-16332, 2005. Article
Brotto MA, Marrelli MT, Brotto LS, Jacobs-Lorena M, Nosek TM. Functional and biochemical modifications in skeletal muscles from malarial mice. Exp Physiol Feb 22, 2005. Abstract
Devenport M, Fujioka H, Donnelly-Doman M, Shen Z, Jacobs-Lorena M. Storage and secretion of Ag-Aper14, a novel peritrophic matrix protein, and Ag-Muc1 from the mosquito Anopheles gambiae. Cell Tissue Res 320:175-185, 2005. Article
Dinglasan RR, Jacobs-Lorena M. Insight into a conserved lifestyle: Protein-carbohydrate adhesion strategies of vector-borne pathogens. Infect Immun. 73:7797-807, 2005. Article
Riehle MA, Jacobs-Lorena M. Using bacteria to express and display anti-parasite molecules in disease vectors:current and future strategies. Insect Biochem Molec Biol 35:699-707, 2005. Article
Shao L, Devenport M, Fujioka H, Ghosh A, Jacobs-Lorena M. Identification and characterization of a novel peritrophic matrix protein, Ae-APER50, and the microvillar membrane protein, AEG12, from the mosquito, Aedesaegypti. Insect Biochem Mol Biol 35:947-959, 2005. Article
Xu X, Dong Y, Abraham EG, Kocan A, Srinivasan P, Ghosh AK, Sinden RE, Ribeiro JM, Jacobs-Lorena M, Kafatos FC, Dimopoulos G. Transcriptome analysis of Anopheles stephensi-Plasmodium berghei interactions. Mol Biochem Parasito 142:76-87, 2005. Article
Abraham EG, Jacobs-Lorena M. Mosquito midgut barriers to malaria parasite development. Insect Biochem Mol Biol 34:667-671, 2004. Abstract
Abraham EG, Islam S, Srinivasan P, Ghosh AK, Valenzuela J, Ribeiro JMC, Kafatos FC, Dimopoulos G, Jacobs-Lorena M. Analysis of the Plasmodium and Anopheles transcriptional repertoires during ookinete development and midgut invasion. J Biol Chem 279:5573-5580, 2004. Abstract
Abraham EG, Jacobs-Lorena M. Mosquito midgut barriers to malaria parasite development. Insect Biochem Mol Biol 34:667-671, 2004. Article
Devenport M, Fujioka H, Jacobs-Lorena M. Storage and secretion of the peritrophic matrix protein Ag-Aper1 and trypsin in the midgut of Anopheles gambiae. Insect Mol Biol 13:349-358, 2004. Abstract
Moreira LA, Wang J, Collins FH, Jacobs-Lorena M. Fitness of anopheline mosquitoes expressing transgenes that inhibit Plasmodium development. Genetics 166:1337-1341, 2004. Article
Moreira CK, Marrelli MT, Jacobs-Lorena M. Gene expression in Plasmodium:from gametocytes to sporozoites. Int J Parasitol 34:1431-1440, 2004. Abstract
Srinivasan P, Abraham EG, Ghosh AK, Valenzuela J, Ribeiro JMC, Dimopoulos G, Kafatos FC, Adams JH, Fujioka H, Jacobs-Lorena M. Analysis of the Plasmodium and Anopheles transcriptomes during oocyst differentiation. J Biol Chem 279:5581-5587, 2004. Abstract
Ghosh A, Srinivasan P, Abraham EG, Fujioka H, Jacobs-Lorena M. Molecular strategies to study Plasmodium-mosquito interactions. Trends Parasitol 19:94-101, 2003. Abstract
Jacobs-Lorena M. Interrupting malaria transmission by genetic manipulation of anopheline mosquitoes. J Vect Borne Dis 40:73-77, 2003. Abstract
Riehle MA, Srinivasan P, Moreira CK, Jacobs-Lorena M. Towards genetic manipulation of wild mosquito populations to combat malaria:advances and challenges. J Exp Biol 206:3809-3816, 2003. Article
Villalón JM, Ghosh A, Jacobs-Lorena M. The peritrophic matrix limits the rate of digestion in adult Anopheles stephensi and Aedesaegypti mosquitoes. J Insect Physiol 49:891-895, 2003. Abstract
Alphey L, Beard CB, Billingsley P, Coetzee M, Crisanti A, Curtis C, Eggleston P, Godfray C, Hemingway J, Jacobs-Lorena M, James AA, Kafatos FC, Mukwaya LG, Paton M, Powell JR, Schneider W, Scott TW, Sina B, Sinden R, Sinkins S, Spielman A, Touré Y, Collins FH. Malaria control with genetically manipulated insect Vectors. Science 298:119-121, 2002. Article
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