Our Faculty : Primary Faculty

Natasa Strbo, M.D., D.Sc.

Current Research Interests
The main goal of my current research is to devise a novel strategy for achieving as complete a protection as possible, the ultimate goal being the future development of an efficacious vaccine against HIV and malaria. In addition, we want to understanding the dynamic interaction of innate immune responses and pathogens at mucosal barriers such as: skin, reproductive tract and gut. These studies may provide major insights into the ultimate development of highly effective mucosal vaccines.

Specific areas of research interest in my lab include:

1. Cellular and molecular mechanism of secreted heat shock fusion protein, gp96-Ig and development of secreted gp96-Ig vaccine against infectious diseases
Heat shock protein, gp96 when released is a molecular warning signal for necrotic cell death. The unique localization of gp96 in the ER, and its function as chaperone for all peptides destined for presentation by MHC I enable gp96 to serve as warning signal for DC and macrophages and as carrier for foreign antigens in case of infection. To take advantage of this unique adjuvant effect and ability to transport relevant peptides, we have made a secreted form of gp96, gp96-Ig. We engineered a tumor cells secreted fusion protein, gp96-Ig, and tested it as CTL-inducing vaccine. We were the first one to confirm the effect of gp96-Ig vaccination on mucosal immune system and dramatic induction of antigen specific immune responses at mucosal surfaces. (Strbo N et al. Immunity 2003 and Strbo et al Mucosal Immunol. 2010). Subsequent work led us to development of gp96-Ig based vaccine against HIV and malaria. With the novel combination of cell secreted gp96SIVIg and gp120 protein as immunogen we have achieved significant reduction (72%) in the risk for SIV acquisition in non-human primates (Strbo et al J Immunol. 2013). Recently, in collaboration with Naval Medical Research Center we completed in vivo immunogenicity studies with secreted gp96-Ig malaria vaccine. Our findings are strongly supportive of the novel gp96-Ig malaria vaccine as unique systemic and liver-homing, sporozoite specific CD8 CTL vaccine strategy.

2. The role of Perforin-2 at mucosal barriers: skin, reproductive tract and gut
Over the last five years I have being actively involved in discoveries of novel pore-forming protein Perforin-2 (P2) (McCormick et all, eLife 2015). P2 is part of the innate immune system, essential to eliminate pathogenic bacteria that have invaded cells. P2 is expressed constitutively in professional immune cells and can be induced in all other cells by IFNs or by intracellular pathogen invasion. Interestingly, epidermis expresses P2 at the levels that are not inducible, rather constitutive reflecting the importance of both, P2 as an antimicrobial and epidermis as barrier forming tissue that guards against infection. My recent translational research interests aim to understand cellular and molecular basis of Perforin 2 expressing innate immune cells in different mucosal tissues, including skin. I have establish collaboration with Dr. Tomic Canic team to investigate how elements of the immune system and P2 contribute to the re-epithelialization of damaged skin.

3. Development of humanized-mouse model
I was actively involved in the establishment of the technology of generating humanized mice from NOD,SCID,c-/- mice as well as in the study of mucosal immune responses in these mice. In the KL12 awarded application I am currently testing an innovative vaccine approaches and their effect on mucosal compartments: gut and reproductive tract. The accumulated data strongly supports the hypothesis that humanized mice are an excellent predictor for human HIV-vaccine responses (Gonzelez, L et al Immunol Res 2013).

4. Mucosal Immune system in female reproductive tract
The mucosal immune system in the female reproductive tract is unique as it has evolved to protect against potential pathogens without compromising survival of the fetus. In the human uterus, the allogenic embryo is protected from the maternal immune response. The uterine mucosa (decidua), like other mucosal surfaces, must be able to respond to diverse foreign antigens, including pathogens, seminal plasma and fetal trophoblasts. Our findings about abundance of perforin at the maternal–fetal interface demonstrated existence of highly significant cytotoxic armamentarium for the fetal placental unit (FPU). Our work had a significant impact in the field of reproductive immunology proving that decidual NK cells are maximally primed for function (killing) during pregnancy but are simultaneously very efficiently controlled to prevent accidental activation that could result in the loss of the FPU. Infection is likely to be trigger mechanisms for activation of novel P2 cytolytic pathway.

Pubmed Link