Boris Striepen, PhD
Boris Striepen, PhD
Department of Pathobiology
School of Veterinary Medicine
University of Pennsylvania
Hill Pavilion
380 S University Avenue
Philadelphia, PA 19104- Phone:215-573-9167
- Email:striepen@upenn.edu
- Web:www.striepenlab.org
Focus
I have studied the cell and molecular biology of apicomplexan parasites for thirty years. Using Toxoplasma gondii as a model my laboratory sought to understand how parasites cells are build, replicated, and powered by metabolism. We have been particularly interested in the biogenesis and function of the of the parasite chloroplast, and the mechanism of cell division through internal budding. Over the last decade our focus shifted to Cryptosporidium, a leading global cause of diarrheal disease and child mortality that had been largely intractable. Capping a longer effort, we established molecular genetics and natural mouse infection models for Cryptosporidium opening this pathogen to modern mechanistic studies.
Currently our research explores three areas:
1. What are the cellular and molecular mechanisms of parasite lifecycle progression and sex.
2. How does Cryptosporidium invade and manipulate intestinal epithelial cells to establish its unique intracellular but extracytoplasmatic niche in the brush border.
3. how does the host immune system recognize and restrict Cryptosporidium infection, and does the parasite antagonize these efforts?
MIST Research
The ability of recently activated T cells to express the cell surface molecule CD40L allows them to communicate with other immune and non-immune populations. This molecule is of particular importance in the gut to help control the parasitic infection caused by Cryptosporidium. Here we leverage a novel, natural mouse model of Cryptosporidium to dissect the impact of the CD40-CD40L interaction in T cell-mediated resistance to infection in the gut. In this model, WT mice (like humans) develop sterile immunity mediated by T cell production of IFN-, but mice that lack CD40L mice (like humans) do not resolve infection. In addition, treatment of chronically infected CD40L-deficient mice with soluble (s)CD40L results in rapid parasite clearance. We will test if protective effect of CD40L may be explained by either I. its ability to promote T cell responses essential for resistance and/or II. because CD40L directly activates EC to limit parasite growth. We are uniquely equipped to utilize parasite transgenesis, combined with sophisticated genetic approaches to define the key cellular interactions that allows CD40L to determine the outcome of an enteric infection.
Current Grant Support
NIH R01AI127798: Sexual development of Cryptosporidium. 2022-2027. PI: Boris Striepen. $1,250,000 total direct cost. Competitive renewal to unravel the cell and molecular biology of lifecycle progression and sex in Cryptosporidium. $1,397,540 total direct cost.
NIH U01AI163671: The role of CD40L in resistance to enteric infection. 2021-2026 MPI: Chris Hunter & Boris Striepen. New application to use the parasite Cryptosporidium to understand the role of the CD40/CD40 ligand pathway in intestinal immunity. $1,558,748 total direct cost.
NIH R01AI148249: Immunity to Cryptosporidium 2019-2024. MPI: Boris Striepen & Chris Hunter. New application to understand the basis of immunity in cryptosporidiosis combining molecular studies with immunology and a new natural mouse model of infection. $2,337,100 total direct cost.
NIH R01AI112427: Genetic Analysis of Cryptosporidium, 2019-2024 PI: Boris Striepen, Genetic Studies of parasite invasion and secreted pathogenesis factors. $1,250,000 total direct cost.
Publications
Boris Striepen, PhD
Pardy, R. D. et al. Analysis of intestinal epithelial cell responses to Cryptosporidium highlights the temporal effects of IFN-gamma on parasite restriction. PLoS Pathog 20, e1011820 (2024).
Wallbank, B., Pardy, R. D., Brodsky, I. E., Hunter, C. A. & Striepen, B. Cryptosporidium impacts epithelial turnover and is resistant to induced cell death. mBio in press (2024).
Walzer, K. A. et al. Transcriptional control of the Cryptosporidium life cycle. Nature (2024).
Cohn, I. S., Henrickson, S. E., Striepen, B. & Hunter, C. A. Immunity to Cryptosporidium: Lessons from Acquired and Primary Immunodeficiencies. J Immunol 209, 2261-2268 (2022).
Cohn, I. S. et al. Intestinal cDC1s provide cues required for CD4+ T cell-mediated resistance to Cryptosporidium. J Exp Med 221 (2024).
Haskins, B. E. et al. Dendritic cell-mediated responses to secreted Cryptosporidium effectors promote parasite-specific CD8(+) T cell responses. Mucosal Immunol 17, 387-401 (2024).
Pardy, R. D., Wallbank, B. A., Striepen, B. & Hunter, C. A. Immunity to Cryptosporidium: insights into principles of enteric responses to infection. Nat Rev Immunol 24, 142-155 (2024).
Gibson A.R., Sateriale A., Dumaine J.E., Engiles J.B., Pardy R.D., Gullicksrud J.A., O'Dea, K., Beiting, D. P., Hunter, C.A., and Striepen, B. (2022) A genetic screen identifies a protective type III interferon response to Cryptosporidium that requires TLR3 dependent recognition. PLoS Pathogens 18: e1010003.
English, E.D., Guerin, A, Tandel, J. and Striepen, B. (2022) Live imaging of the Cryptosporidium parvum lifecycle reveals direct development of male and female gametes from type I meronts. PLoS Biology 20: e3001604.
Dumaine, J.E., Sateriale, A., Gibson, A.R., Redy, A., Gullicksrud, J.A., Hunter, E., and Striepen, B. (2021) The enteric pathogen Cryptosporidium parvum exports proteins into the cytosol of the infected host cell. eLife. e70451.
Gullicksrud, J.A., Sateriale, A., Engiles, J.B., Gibson, A., Shaw, S., Hutchins, Z.A., Martin, L., Christian, D., Taylor, G.A., Yamamoto, M., Beiting, D.P., Striepen, B., and Hunter, C.A. (2022) Crosstalk between enterocytes and innate lymphoid cell drives early IFN-γ-mediated control of Cryptosporidium. Mucosal Immunity 15: 362-372.
Guérin, A., Roy, N.H., Kugler, E.M., Berry, L., Burkhardt, J.K., Shin, J.-B., and Striepen, B. (2021) A screen for Cryptosporidium rhoptry proteins identifies ROP1 as an effector targeting the host cytoskeletal modulator LMO7. Cell Host & Microbe 29: 1-14.
Sateriale, A., Gullicksrud, J.A., Engiles, J.B., McLeod, B., Kugler, E.M., Henao-Mejia, J., Zhou, T., Ring, A.M., Brodsky, I.E., J.C. Hunter, C.A., and Striepen, B. (2021) The intestinal parasite Cryptosporidium is controlled by an enterocyte intrinsic inflammasome that depends on NLRP6. Proc. Natl. Acad. Sci. U.S.A. 118: e2007807118.
Guérin, A., and Striepen, B. (2020) The Biology of the intestinal intracellular parasite Cryptosporidium. Cell Host & Microbe 28: 509-515.
Vinayak, S., Jumani, R.S., Miller, P., Hasan, M.M., McLeod, B., Tandel, J., Stebbins, E.E., Teixeira, J.E., Borrel, J., Gonse, A., Zhang, M., Yu, X., Wernimont, A., Walpole, C., Eckley, S., Love, M.S., McNamara, C. W., Sharma, M., Sharma, A., Kato, N., Schreiber, S.L., Melillo, B., Striepen*, B., Huston*, C.D., and Comer*, E. (2020) Phenylalanyl-tRNA synthetase (PheRS), a novel drug target for Cryptosporidium: discovery of therapeutically relevant inhibitors with genetic, biochemical and chemical target validation. *co-corresponding authors. Science Transl. Med. 12, eaba8412
Pawlowic, M., Somepalli, M., Sateriale, A., Herbert, G.T. Gibson, A.R., Cuny, G., Hedstrom, L., and Striepen, B. (2019) Genetic ablation of purine salvage in Cryptosporidium parvum reveals nucleotide uptake from the host cell. Proc. Natl. Acad. Sci. U.S.A. 116: 21160-21165.
Tandel, J., English, E., Sateriale, A., Gullicksrud, J., Beiting, D.P., Sullivan, M.C., Pinkston, B., and Striepen, B. (2019) Lifecycle progression and sexual development of the apicomplexan parasite Cryptosporidium parvum. Nature Microbiology 4: 2226-2236
Sateriale, A., Slapeta, J., Baptista, R., Engiles, J.B., Gullicksrud, J.A., Herbert, G.T., Brooks, C.F., Kugler, E.M., Kissinger, J.C. Hunter, C.A., and Striepen, B. (2019) A genetically tractable, natural mouse model of cryptosporidiosis offers insights into host protective immunity. Cell Host & Microbe 26, 135–146
Manjunatha, U.H.†, Vinayak, S.†, Zambriski, J.A.*†, Chao, A.T., Sy, T., Noble, S.J., Bonamy, G., Kondreddi, R.R., Zou, B., Gedeck, P., Brooks, C.F., Herbert, G.T., Sateriale, A., Tandel, J., Noh, S., Lakshminarayana, S.B., Lim, S.H., Goodman, L.B., Yeung, B.K.S., Bodenreider, C., Feng, G., Zhang, L., Blasco, F., Wagner, J., Leong. F.J., Striepen, B.*, and Diagana T. * (2017) An inhibitor of the Cryptosporidium PI(4)K is a candidate drug for cryptosporidiosis. Nature 546: 376-380 (*equal contribution)
Vinayak, S.*, Pawlowic, M.C.*, Sateriale, A*, Brooks, C.F., Studstill, J.C., Bar-Peled, Y., Cirpriano, M.J. and Striepen, B. (2015) Genetic modification of the diarrheal pathogen Cryptosporidium parvum. Nature 523: 477–480 (*equal contribution)