vaccine requires lFNy but not IL-4 for protection;3) the vaccine retains e invasive candidal infections. We have also found that: 1) antibody titers d Als3p (rAls3p-N). We have found that vaccination of mice with r a vaccine to prevent life threatening Candida i Furthermore, infections caused by strains and species resistant to a Candida spp. are among the most common causes of nosocomial i mice;and 4) adoptive transfer of CD4+ T but neither B cells nor i We are developing an anti-candidal vaccine based on the recombinant N (l1 nfections is particularly attractive. ''. =/1 c_'0 w(? .-. (DC found that adoptive transfer of CD4+ T cells from vaccinated, wild type d transferred protection, but not visa versa. Thus CD4+ derived IFN-'y is necessary f particularly if they are activated by exposure to lymphocyte-derived, enhance recruitment to and activation of phagocytes at sites of infection. which the rAls3p-N vaccine protects against disseminated candidiasis is b that mice deficient in IL-17A are not protected by the vaccine. in mice congenitally deficient in CCR6, a surface marker for T splenocyte expression of the neutrophil chemoattractants, IL-I 7 into wild type recipient mice is protective, but not visa versa. We have found that adoptive transfer of CD4+ lymphocytes from v upstream adaptive and downstream innate immune cells in m vaccine-induced polarization of these lymphocyte phenotypes. and flow cytometry, and ELlSpot assays. Furthermore, we will define populations present in vaccinated versus control mice during infection by at sites of infection in vaccinated as compared to unvaccinated c hypothesize that vaccination induces differing lymphocyte populations ( 2) Define the specific cell types and regulatory cytokines responsible f Determine the impact of vaccination on neutrophil recruitment and c intermediary and phagocytes serve as the end-effectors of protection. groundwork for immunological assays to define surrogate markers of p cytokines expressed by specific regulatory cells necessary for protection. enabling focusing of future adjuvant and dosing strategies to maximize e fungi. Furthermore, the studies will define strategies to further enhance t into potential vaccine strategies which could be used to target e help define patient populations to be targeted in those studies. However, T lymphocytes cannot kill Candida in culture. In contrast, The proposed studies will elucidate a novel concept in vaccinology--that l 'C-' fl.>I C)<0rna-D0o 0-a nfections in countries with advanced medical nacceptable mortality of 40%-50%. ntifungats are increasing. For these reasons, (-0D C)) L-. U)' an, 0-0 -a=m '(D >,.C 0C)ojo- cam- 5.O .-r 0._,c.=:0omCv Imo. 0-0 r-' '6j ediating rAls3p-N-induced protection, we will: I) We have found that the vaccine induces h17 cells. Furthermore, we have recently found We therefore hypothesize that the mechanism by and KC, and that the vaccine is not efficacious pro-inflammatory cytokines, including IFN-y. accinated, superoxide-deficient donor mice ytokine production at sites of infection, and To define the mechanistic links between y activating T lymphocytes, which then phagocytes do kill Candida in culture, ... -terminus of the candidal adhesin, Als3p-N results in significant protection against o not correlate with protection;2) the fficacy in B cell but not T cell deficient mmune serum transfers protection. Recently we onor to IFN-'y-deficient recipient mice or vaccine-mediated protection. moo ?-' ?-? ALL a:: cps on:o:wr ,., o'< n'. (U6 con M5?,- ontrol mice. We will identify lymphocyte cell or vaccine-mediated protection. We which regulatory cytokines mediate i.e. Thi, ThI 7, or other) to be present using intracellular cytokine staining +-' 5mC0D o!.C-DI,C<(? ??-o.Crn ,CD 5,v, 6.0m '-A ?-a co- v)?) a4) c>; 0 t/) 'tom :,+ v""""""""- a-5 -,, ymphocytes may serve as Hence, the studies will provide insights xtracellular pathogens ranging from bacteria to he rAls3p-N vaccine's efficacy, by xpression of critical pro-inflammatory Finally, the studies will lay the rotection in future clinical trials, and will coo-r mom' 0-0 come -n? fl. PNS 398/2590 (Rev. 11/07) Page - Continuation Format Page
We have discovered a highly promising vaccine candidate to prevent life-threatening infections of the blood caused by the fungus Candida. In the current studies we will define how the vaccine trains hunter-killer white blood cells to kill the fungus, thereby protecting against Candida infections. These results will lay the groundwork for maximizing the efficacy of the vaccine, and will also elucidate fundamental ways by which the immune system defends the body from infections similar to those caused by Candida.
| Luo, Guanpingshen; Lin, Lin; Ibrahim, Ashraf S et al. (2012) Active and passive immunization protects against lethal, extreme drug resistant-Acinetobacter baumannii infection. PLoS One 7:e29446 |
| Spellberg, Brad; Daum, Robert (2012) Development of a vaccine against Staphylococcus aureus. Semin Immunopathol 34:335-48 |
| Spellberg, Brad (2011) Vaccines for invasive fungal infections. F1000 Med Rep 3:13 |
| Lin, Lin; Ibrahim, Ashraf S; Xu, Xin et al. (2009) Th1-Th17 cells mediate protective adaptive immunity against Staphylococcus aureus and Candida albicans infection in mice. PLoS Pathog 5:e1000703 |
