Our current research focuses on the characterization of the cellular and molecular mechanisms underlying the induction of protective T-cell mediated immunity against malaria parasites. We generated strains of transgenic mice bearing T cell receptors specific for parasite antigens recognized by CD8+ or CD4+ T cells. Using these mice, we are currently conducting studies to characterize the molecular and genetic events involved in the development and maintenance of effector anti-parasite T cells, and the mechanisms by which CD4+ /CD8+ T cells interact during the development of immunity against infection. Our research combines in vivo immuno-physiology studies together with molecular and genetic approaches. Particular emphasis is given to research aimed at characterizing the mechanisms involved in tissue-trafficking of activated CD8+ T cells and identifying the nature of the molecular processes leading to the development of memory subsets.

These studies using a rodent parasite system provides the rationale and experimental basis for research aimed at developing an anti-malaria vaccine for humans. Furthermore, these rodent models are excellent systems for studying the general principles of protective immunity against intracellular pathogens, as they develop in vivo. These studies enhance our understanding of the immune system at the most fundamental level.

Molecular Microbiology and Immunology, malaria, transgenic mice, T-cells, memory, vaccines

SELECTED PUBLICATIONS OF THE LAST SEVEN YEARS

Srivastava S K, Cockburn IA, Swaim A, Thompson LE, Tripathi A, Fletcher C A , Shirk EM., Sun H, Kowalska A, Fox-Talbot K, Sullivan D, Lowenstein C J , Zavala F and Morrell CN. 2008 Platelet Factor 4 Mediates Inflammation in Cerebral Malaria. Cell Host Microbe. 4:179-87.

Overstreet M, Cockburn IA., Chen YC ., Zavala F. 2008 Protective CD8+ T cell responses against malaria liver stages: Immunobiology of an “unnatural” immune response Immunol Revs. 225:271-83

Chakravarty S, Baldeviano GC, Overstreet MG, Zavala F. Effector CD8+ T lymphocytes against malaria liver stages do not require IFN-{gamma} for anti-parasite activity.2008. Infect Immun. 76: 3628-31

Sinnis P, Zavala F. The skin stage of malaria infection: biology and relevance to the malaria vaccine effort. 2008. Future Microbiol. Jun;3:275-8.

Dalai SK., Mirshadidi S, Morrot A, Zavala F and Sadegh-Nasseri S. 2008 Anergy in memory CD4+ T cells in induced by B cells J. Immunol 181:3221-31

Cockburn I A., Chakravarty S., Overstreet M., García-Sastre A and Zavala F. 2008 Memory CD8+ T cell responses expand when antigen presentation overcomes T-cell self-regulation. J. Immunol. 180:64-71

Chakravarty S., Cockburn I A.., Kuk S., Overstreet M., Sacci J., and Zavala F 2007. CD8+ T lymphocytes protective against malaria liver stages are primed in skin-draining lymph nodes. Nature Med. 13:1035-1041

Hafalla JCR, Rai, U., Bernal- D., Rodriguez A and Zavala F. 2007 Efficient development of Plasmodium liver stage-specific memory CD8+ T cells during the course of blood stage malaria infection. J. Infect. Diseases 196:1827-1835

Melendi GA, Zavala F, Bucholz UJ, Boivin G, Collins PL, Kleeberger S, Polack FP. 2007 Mapping and characterization of the primary and anamnestic H-2d restricted cytotoxic T lymphocyte response in mice against human metapneumovirus. J Virol. 81:11461-67

Cockburn I A and Zavala F. 2007 T cell memory in malaria Curr. Opin. Immunol. 19:1-6

Pinheiro A , Morrot, A., Chakravarty S., Overstreet, M., Bream,JH., Irusta, PM.,and Zavala F. 2007 IL-4 induces a wide-spectrum intracellular signaling cascade in CD8+ T cells J. Leuk. Biol 81-1102-10

Li S, Locke E, Bruder J, Clarke D, Doolan DL, Havenga MJ, Hill AV, Liljestrom P, Monath TP, Naim HY, Ockenhouse C, Tang DC, Van Kampen KR, Viret JF, Zavala F, Dubovsky F. 2007 Viral vectors for malaria vaccine development. Vaccine. 25:2567-74

Kumar K A, Sano GI, Boscardin S, Nussenzweig RS, Nussenzweig MC, Zavala F and Nussenzweig V.2006 The circumsporozoite protein is an immunodominant protective antigen in irradiated sporozoites. Nature 444 (7121):937-40

Hafalla JC, Urvashi Rai, Alexandre Morrot, Dabeiba Bernal-Rubio, Fidel Zavala and Ana Rodriguez. 2006 Priming of CD8+ T cell responses following immunization with heat-killed Plasmodium sporozoites. Eur. J Immunol 36:1179-86.

Morrot A, Ian A. Cockburn, Michael Overstreet, Dolores Rodríguez and Fidel Zavala. 2006. Protective CD8+ T cells induced by malaria sporozoites do not undergo modulation of IL-7 receptor expression. Infect. Immun. 74: 2495-2497

Boscardin AB, Hafalla JCR, Masilamani RF, Kamphorst, AO, Zebroski, HA Rai U, Morrot A, Zavala F, Steinman RM, Nussenzweig, RS and Nussenzweig MC. 2006. Antigen targeting to dendritic cells elicits long-lived T cell help for antibody responses. J. Exp. Med. 203: 599-606

Hafalla JC, Cockburn IA, and Zavala F. 2006. Protective and Pathogenic roles of CD8+ T cells during malaria infection. Parasite Immunol. 28:15-24

Morrot, A., Hafalla J.C., Cockburn I.A., Carvalho L.H., and Zavala F. 2005. IL-4 R expression is required for the development of protective memory responses against liver stages of malaria parasites. J Exp Med. 202(4):551-60.

Morrot, A. and Zavala, F. 2004 Effector and memory CD8+ T cell as seen in immunity to malaria liver stages . Immunol. Revs. 201:291-303

Tongren, JE., Zavala F., Roos DS., and Riley E.M. 2004. Malaria vaccines: if at first you don’t succeed. Trends in Parasitol. 20:604-610

Hafalla, JC., Morrot A, Sano G, Milon G, Lafaille J and Zavala F. 2003. Early self-regulatory mechanisms control the magnitude of CD8+ T cell responses against liver stages of murine malaria. J Immunol. 171(2):964-70.

Tsuji M. and Zavala F. 2003 T cells as mediators of protective immunity against the liver stages of Plasmodium. Trends Parasitol. 19: 88-93

Hafalla, JC., Sano. G, Carvalho L., Morrrot A., and Zavala F. 2002. Short-term antigen presentation and single clonal burst limit the magnitude of the CD8+ T cell responses against malaria liver stages. Proc. Natl. Acad. Sci.. (USA) 99:11819-11824

Jung, S. , Unutmaz D., Wong D. .P, Sano G. I., De los Santos K., Sparwasser T., Wu S., Zavala, F., Pamer E.G., Littman D.R. and Lang R. 2002. Abrogation of Cytotoxic T cell Cross Priming by Induced In vivo Ablation of CD11c+ Dendritic Cells. Immunity 17:211-220

Carvalho, L.H., Sano,G.,Hafalla J.C, Morrot A., Curotto M. and Zavala F. 2002. IL-4 secreting CD4+ T cells are crucial to the development ofCD8+ T cell responses against malaria liver stages. Nature. Med. 8(2):166-170

Tsuji M. and Zavala F. 2001. Peptide-based vaccines to induce protective antibody and T-cell mediated immunity against liver stages of malaria. Mol. Immnunol. 38:433-442

Sano G., Hafalla J.C., Abe R., Lafaille J., and Zavala F. 2001. Swift development of protective effector functions in naïve CD8+ T cells against malaria liver stages J. Exp. Med. 194:173-179

Bruna-Romero O.B., Hafalla J.C., Gonzales Gloria., Sano, G., Tsuji M. and Zavala F. 2001 Detection of malaria liver stages in mice infected through the bite of a single Anopheles mosquitoes using a highly sensitive real-time PCR. Int. J. Parasitology 31:1499-1502

Zavala F., Rodrigues M., Rodriguez D. Rodriguez J.R., Nussenzweig R.S., and Esteban M. 2001. A striking property of recombinant poxviruses: efficient inducers of in vivo expansion of primed CD8+ T cells. Virology 280: 55-159