Carolina V. Barillas-Mury, M.D., Ph.D.

Investigator
Chief, Mosquito Immunity and Vector Competence Unit

Education
1981: B.S. in biology, Universidad del Valle de Guatemala
1985: M.D., Universidad Francisco Marroquín de Guatemala
1992: Ph.D. in biochemistry, University of Arizona

Postdoctoral Training
1992-1993: University of Arizona, Biochemistry Dept., Dr. M. Wells' lab
1993-1994: Harvard Univ., Dept. of Cell. and Dev. Biol., Dr. F. Kafatos' Lab
1994-1998: European Molecular Biology Lab, Dr. Fotis Kafatos' Lab

Assistant Professor
1998-2003: Colorado State University, Dept. of Microbiology, Immunology and Pathology

Unit Head
2003-present: Mosquito Immunity and Vector Competence Unit, LMVR, NIH

Description of Research Program

We are exploring the interactions between the mosquito immune system and the malaria parasite to understand how they determine vector competence. There are three major areas of interest in our group:

1. Cell biology of ookinete invasion
   Detailed studies of the cellular responses of mosquito midgut epithelial cells to parasite invasion in the A. stephensi-P.berghei system revealed that parasites inflict extensive damage as they migrate through midgut epithelial cells, which ultimately leads to apoptosis. These studies led us to propose the Time-Bomb Model of Invasion, which states that ookinetes have a limited time window to escape unharmed from the invaded cell, as the cascade of responses mediating epithelial cell death are also potentially lethal to the parasite.
   

   Time bomb model of parasite invasion of mosquito midgut epithelial cells (Download larger version, 293k)

2. The role of reactive oxygen species (ROS) in A. gambiae refractoriness to malaria infection
   A genetically selected refractory strain of A. gambiae blocks Plasmodium development, melanizing and encapsulating the parasite. Morphological, microarray mRNA, and physiological studies indicate that the refractory strain is in a chronic state of oxidative stress, which is exacerbated by blood feeding, resulting in increased steady-state levels of ROS, which favor melanization of parasites as well as Sephadex beads. Dietary supplementation with antioxidants reduced parasite and bead encapsulation.
3. The role of the STAT pathway in epithelial responses to malaria infection
   Band shift experiments from midgut nuclear extracts indicate that parasite invasion activates the STAT (Signal Transducers and Activators of Transcription) pathway. We have characterized two members of this family of transcription factors in A. gambaie as well as two repressors, SOCS and PIAS, which are induced by malaria infection at the transcriptional and translational level, respectively. We are currently performing a series of dsRNA silencing experiments in vivo and in tissue culture to establish the relevance of the STAT pathway in the outcome of parasite midgut infection.

Research Group Members

Randall DeJong rdejong@niaid.nih.gov	Lalita Gupta lgupta@niaid.nih.gov	Giovanna Jaramillo-Gutierrez gutierrgi@niaid.nih.gov
Sanjeev Kumar skumar@niaid.nih.gov	Alvaro Molina-Cruz amolina-cruz@niaid.nih.gov

Selected Publications

(View list in PubMed.)

Barillas-Mury C, Kumar S. Plasmodium-mosquito interactions: a tale of dangerous liaisons. Cell Microbiol. 2005. 7(11):1539-45. (review)

Gupta L., Kumar S, Han YS, Pimenta PF, Barillas-Mury C. Midgut epithelial responses in different mosquito-Plasmodium combinations: the Actin Cone Zipper Model of epithelial repair in Aedes Aegypti. Proc. Natl. Acad. Sci. USA 2005.102(11):4010-5

Molina-Cruz A, Gupta L, Richardson J, Bennett K, Black IV W, Barillas-Mury C. Effect of mosquito midgut trypsin activity on dengue-2 virus infection and dissemination in Aedes aegypti. Am. J. Trop. Med. Hyg. 2005. 72(5):631-7.

Kumar S, Christophides GK, Cantera R, Charles B, Han YH, Meister S, Dimopoulos G, Kafatos FC, Barillas-Mury C. The role of reactive oxygen species on Plasmodium melanotic encapsulation in Anopheles gambiae. Proc. Natl. Acad. Sci. USA 2003. 100 (24):14139-14144.

Christophides GK, Zdobnov E, Barillas-Mury C, Birney E, Blandin S, Blass C, Brey PT, Collins FH, Danielli A, Dimopoulos G, Hetru C, Hoa NT, Hoffmann JA, Kanzok SM, Letunic I, Levashina EA, Loukeris TG, Lycett G, Meister S, Michel K, Moita LF, Muller HM, Osta MA, Paskewitz SM, Reichhart JM, Rzhetsky A, Troxler L, Vernick KD, Vlachou D, Volz J, von Mering C, Xu J, Zheng L, Bork P, Kafatos FC. Immunity-related genes and gene families in Anopheles gambiae. Science 2002. 298:159-65.

Han YS, Thompson J, Kafatos, FC, Barillas-Mury C. Molecular interactions between Anopheles stephensi midgut cells and Plasmodium berghei: the time bomb theory of ookinete invasion of mosquitoes. EMBO J. 2000.19:6030-6040.

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