Making Discoveries that Make a Difference

Ramin Hakami, PhD, Associate Professor

Contact info: rhakami@gmu.edu

Ramin Hakami

Biosketch

Dr. Hakami obtained his Ph.D. in Biochemistry in the laboratory of the Nobel Laureate Professor Har Gobind Khorana at the Massachusetts Institute of Technology (MIT), and was subsequently awarded a NRSA fellowship from NIH to complete postdoctoral training at Harvard Medical School (HMS). He is currently an Associate Professor of Microbiology and Infectious Diseases at GMU. The main focus of research in Dr. Hakami’s laboratory is to understand the fundamental mechanisms by which vesicular trafficking within the host regulates innate immune responses during infection with pathogenic agents. In particular, a major focus is the molecular mechanisms by which exosomes, a subtype of extracellular vesicles (EVs), regulate innate immunity. The broad goal of these studies is identifying new strategies for development of highly effective host-based countermeasures.

 

Research program

Regulation of innate immunity through intracellular and extracellular vesicle (exosome) trafficking, Molecular basis of coordinated host signaling response to pathogens, Development of novel therapeutic and vaccine strategies

Ramin HakamiIntercellular Vesicle Transport (Exosome Exchange) and Regulation of the Innate Immune Response: Recent work in the exosome field has demonstrated the critical importance of their communicative functions for a variety of human diseases, including several infectious diseases. A main focus of our lab is to understand the role of host exosomes during infection with Yersinia pestis (Yp), the agent of plague, and the Rift Valley fever virus (RVFV) [e.g., 1-4]. Both agents are classified as highest priority (Category A) pathogens, and there are no approved human vaccines or highly effective therapeutics currently available. Our lab has developed and optimized methods for purification of host exosomes released from either Yp-infected or RVFV-infected cells (EXi), and characterized the preparations using exosome-specific markers along with confocal and electron microscopy studies. We have demonstrated that EXi released from RVFV-infected cells carry viral genome and proteins and can destroy immune cell types that are known to act as reservoirs for RVFV replication [2]. We have also demonstrated that non-immune cell types that are pre-treated with purified EXi have a drastically reduced capacity for virus production, suggesting that the EXi released during RVFV infection serve a dual protective role for the host. We are currently investigating the molecular mechanisms underpinning these effects. Our lab has also developed a mechanistic model of how the EXi released during Yp infection regulate the innate immune response. We have shown that these EXi carry cargo that is distinct from exosomes purified from uninfected cells (EXu) [1], including four specific Yp proteins. In addition, we have demonstrated that treating naïve human monocytes with EXi (but not EXu) induces effects that are identical to when the cells are infected with Yp. These include induction of monocyte differentiation to macrophages, the induction of naïve monocytes to release a specific set of inflammatory cytokines, and imparting dramatic improvement in the ability of the treated cells to clear out internalized Yp bacteria in an IL-6-dependent manner. These results have led to a model of EXi function during Yp infection in which released EXi induce distant naïve monocytes to release cytokines that in turn induce differentiation to macrophages, thus leading to improved ability for Yp clearance when the bacteria reach these cells. We are currently investigating further the molecular mechanisms of these effects and transitioning to in vivo studies of the EXi effects.

Intracellular Vesicle Transport and Regulation of the Innate Immune Response: Our lab has used a novel reverse phase protein microarray (RPMA) platform to quantitatively survey intracellular protein pathway modulation across the cell in response to infection with Yp, followed by ongoing functional studies of select pathways that emerged from the analysis. These studies demonstrated the importance of a number of host cell pathways during Yp infection that had not been previously known to contribute (12 new protein hits), and also led to the first demonstration that host response to Yp involves a coordinated down-regulation of autophagy [5]. This inhibition involves modulating the activities of multiple proteins, including AKT, AMPK, and p53. Complementing the RPMA approach, we have also performed quantitative mass spectrometry analysis of highly purified CD14+ primary human monocytes to measure host phosphorylation changes during infection. This work confirmed the importance of several pathways identified through RPMA, including the AKT pathway, and also highlighted a potential role for a number of specific AKT interacting proteins. We are currently assessing the respective contributions of the different pathways that we have identified to the inhibition of autophagy during Yp infection, and are transitioning to in vivo analysis of the role of autophagy as part of the host response to infection.

Additional Host Response Studies: Our lab also has focused host response projects that complement our main areas of research. As an example, we have profiled host factors that play significant roles during infection with RVFV, including the demonstration that several specific heat shock proteins such as HSP90 are critical for viral production [6]. Specifically, we have shown that host HSP90 stabilizes the RNA-dependent RNA polymerase of RVFV to allow viral transcription and replication. As several HSP90 inhibitors are already in Phase II or III clinical trials for cancer treatment, these findings suggest the exciting possibility of repurposing them to treat RVF.

Hakami Lab in the News

https://www2.gmu.edu/news/488311

https://academic.oup.com/bioscience/article-lookup/doi/10.1093/biosci/biw074

https://www2.gmu.edu/news/1924

Awards and Recognitions

2016   Nominated for the Office of Scholarship, Creative Activities, and Research Excellence Award, George Mason University, VA
2016   Guest editor by invitation from Frontiers in Microbiogy journal for a special topic on the role of exosomes during infectious diseases
2015   Nominated for the Office of Scholarship, Creative Activities, and Research Excellence Award, George Mason University, VA
2014   Elected to the editorial board of the PLoS ONE journal
2003   Fellows Award for Research Excellence, National Institutes of Health, MD
1989   Outstanding Leadership and Service Award, Stony Brook University, NY
1989   American Institute of Chemists Outstanding Senior Award
1989   Undergraduate Excellence Award, Stony Brook University, NY
1988   Undergraduate Excellence Award, Stony Brook University, NY
1988   George Emerson Outstanding Junior Award, Stony Brook University, NY

Representative Peer-Reviewed Publications

Star symbol denotes corresponding authorship(s)

  1. The Carrying Pigeons of the Cell: Exosomes and their Role in Diseases Caused by Human Pathogens. A. Fleming, G. Sampey, M.-C. Chung, C. Bailey, M. van Hoek, F. Kashanchi, and R.M. Hakami* (2014) Pathogens and Disease, 2,109-20.
  2. Presence of viral RNA and proteins in exosomes from the cellular clones resistant. Ahsan, G.C. Sampey, B. Lepene, Y. Akpamagbo, R.A. Barclay, S. Iordanskiy, R.M. Hakami*, and F. Kashanchi* (2016) Front Microbiol., 7:139.
  3. Extracellular vesicles from infected cells: potential for direct pathogenesis. A. Schwab, S.S. Meyering, B. Lepene, S. Iordanskiy, M.L. van Hoek, R.M. Hakami*, and F. Kashanchi* (2015) Front Microbiol., 6:1132.
  4. Exosomes and their role in CNS viral infections. G. Sampey, S. Meyering, M. Zadeh, Saifuddin, R.M. Hakami*, and F. Kashanchi* (2014) J. Neurovirol., 20(3), 199-208.
  5. Host response during Yersinia pestis infection of human bronchial epithelial cells involves negative regulation of autophagy and suggests a modulation of survival-related and cellular growth pathways. F. Alem, K. Yao, D. Lane, V. Calvert, E.F. Petricoin, L. Kramer, M.L. Hale, S. Bavari, R.G. Panchal, and R.M. Hakami* (2015) Front Microbiol., 6:50.
  6. Multi-Faceted Proteomic Characterization of Rift Valley Fever Virus Virions and Identification of Specific Heat Shock Proteins, Including HSP90, as Important Viral Host Factors. J.E. Nuss, K. Kehn-Hall, A. Benedict, J. Costantino, M. Ward, B.D. Peyser, L.E. Tressler, L.M. Wanner, H.F. McGovern, A. Zaidi, S. Anthony, K.P. Kota, S. Bavari, and R.M. Hakami* (2014) PloS ONE, 9(5):e93483.
  7. M-C. Chung, F. Alem, S.G. Hamer, A. Narayanan, K. Shatalin, C. Bailey, E. Nudler, and R.M. Hakami* (2016). S-nitrosylation of Peroxiredoxin 1 Contributes to Viability of Lung Epithelial Cells during Bacillus anthracis Infection. Biochimica et Biophysica Acta, General Subjects, 1861, 3019–3029.
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