By Cedric Kouam, Postbac in the Malaria Genetics Section, Laboratory of Malaria and Vector Research (LMVR) and Madison Hebner, Postbac in the Virus Ecology Unit, Laboratory of Virology (LV), Rocky Mountain Laboratories (RML)
The NIAID Summer Seminar Series was held virtually in 2020 to provide NIAID postbacs with the opportunity to learn about the outstanding research conducted in their institute. The principal investigators selected for these talks come from various research areas with the aim of highlighting the unique and diverse community at NIAID. This summer’s speakers included Steven Holland, M.D., Carolina Barillas-Mury, M.D., Ph.D., Eli Boritz, M.D., Ph.D., and Sonja Best, Ph.D.
Innovative Approaches to Treat Rare Diseases
By Cedric Kouam, LMVR
Brief Summary of Dr. Holland's research seminar
Being a physician-scientist at the NIH Clinical Center often means treating some of the most unusual cases. Leucocyte adhesion deficiency type 1 (LAD-1) is a primary immunodeficiency that was considered one of the recurring chronic infections with treatment limited to antibiotics or bone marrow transplant. An important hallmark of this disease is the failure of neutrophil diapedesis leaving patients with abnormal wound healing and almost universal tooth loss by adolescence. However, a breakthrough came when Dr. Holland and his team treated a 20-year-old LAD-1 patient. Instead of following standard therapeutics, he joined forces with investigators in the National Institute of Dental and Craniofacial Research (NIDCR) led by Dr. Niki Moutsopoulos, and they focused on understanding the basic mechanism of the disease. This led to the discovery of a targetable IL17-dependent pathway that indicated the drug ustekinumab as an effective treatment.
A significant point that resonated with me during the talk is the idea of grasping the foundational elements of the human host, its immunity, and its pathogens to seek solutions for health problems. In Dr. Holland’s words, “applying basic science to human health is what we do”, which was in large the message he imparted on us. In addition, he also encouraged postbacs to engage in “the pursuit of knowledge, health, and justice”. This aligns with the intramural program’s mission to develop trainees into the best scientists we can be.
Mosquitoes: Primed for Defense
By Cedric Kouam, LMVR
Brief Summary of Dr. Barillas-Mury's research seminar
For a long time, it was believed that the innate immune system of invertebrates was unable to “learn” from previous exposure to a pathogen. Dr. Barillas-Mury discussed the role of signaling lipids, such as prostaglandins (PGs) and lipoxins (Lxs), in the mosquito’s antiplasmodial defense and their contribution in priming its immune system. Leading her team in this work, she revealed the role of PGE2 in hemocyte stimulation and recruitment to fight against plasmodial invasion in the mosquito midgut. In addition, PGE2 triggers the release of a hemocyte differentiation factor, a complex of LxA4 bound to a protein carrier, that stimulates granulocyte recruitment and enhances their response to subsequent plasmodial infections. Most importantly, this immune response is more effective and rapid in primed mosquitoes pre-exposed to Plasmodium infection.
Working during the pandemic has come with advantages and challenges. In the case of Dr. Barillas-Mury, this experience has been beneficial from a family and a work perspective. In terms of family, she has been spending more time with her loved ones and especially her daughter. Regarding work, Dr. Barillas-Mury and her team have been committing more time toward literature reviews and the arduous process of writing papers for publication. However, she has not been able to touch base with her team as much and misses the daily interactions that comes with being present in the lab, sharing meals, laughing and discussing new exciting results. During these unprecedented times, Dr. Barillas-Mury encouraged postbacs to “stay strong and be patient”. “We will get through this and come back stronger”. These are uplifting words which were important for us to hear as many postbacs face different obstacles in their research as well as their personal lives.
The "ART" of HIV Antiretroviral Therapy Research
By Madison Hebner, LV
Brief summary of Dr. Boritz’ research seminar
The goal of the Virus Persistence and Dynamics Section (VPDS) is to help develop a means of targeting virus reservoirs and reducing disease progression in people living with HIV. The lab focuses specifically on the CD4 T cell reservoir and examines the idea that, “CD4 T cells with distinct gene expression patterns behave differently as hosts for HIV in vivo.” Dr. Boritz highlighted HIV persistence and how his lab investigates this topic by utilizing molecular methods to study the reservoir cell populations in the blood and lymph nodes of HIV positive patients undergoing antiretroviral therapy (ART). In order to be competitive in the crowded field of HIV research, resourceful thinking and ingenuity are critical. The lab has developed what they call a “forward approach” to analyzing HIV-infected cells, instead of the classic method of choosing a surface marker to define the cells of interest, sorting cells by flow cytometry, and eventually analyzing the virus in cells. They worked with bioengineering collaborators to develop a microfluidic droplet-based cell sorting procedure termed HIV PCR-activated cell sorting (HIV-PACS). This method uses fluorescent signaling to sort the cells that have the virus, followed by comprehensive characterization of those cells based on that information. This work from Dr. Boritz and his collaborators may lead to important discoveries that advance the field of translational HIV research.
Dr. Boritz began his career at NIH as a fellow in NIAID working on infectious disease. Once he had completed the clinical portion of his fellowship, he joined the Vaccine Research Center (VRC). Not long after, Dr. Boritz joined NIH as a faculty member, establishing VPDS. When asked what it’s like to work at the NIH, Dr. Boritz emphasized the unique and valuable opportunity of conducting research here. He shared an inspiring sentiment that resonated with him during his orientation to the NIH as a clinical fellow: “the NIH is where you come to work if you want your primary focus to be improving the health of Americans and all humankind [and] that is why I am here.”
Flavivirus: Surviving the Human Host
By Madison Hebner, LV
Brief summary of Dr. Best’s research seminar
The primary goal of the Innate Immunity and Pathogenesis Section is to observe flaviviruses as a model of infection to discover novel cellular proteins essential for antiviral innate immune responses with the goal of detecting virus-encoded mechanisms that antagonize innate immune responses. Dr. Best highlighted the significance of studying flaviviruses, not only because of the strong diversity of diseases this family of viruses can cause, but also because they are emerging into the human population via a multitude of enzootic hosts. This leads to the big picture question: “does the evolution of these viruses in their different enzootic host effect how human immune responses react?” To tackle this question, Dr. Best and her team are studying the restriction factor TRIM5α, originally thought to have limited antiviral activity to retroviruses. They demonstrated that TRIM5α also restricts replication of specific tick-borne flaviviruses. Further research will aim to determine how significant TRIM5α is in limiting flavivirus emergence into human populations.
Key Publication: Chiramel, et al. (2019). TRIM5α restricts flavivirus replication by targeting the viral protease for proteasomal degradation. Cell Reports, 27: 27(11):3269-3283.e6.
Dr. Best completed her Ph.D. in biochemistry and molecular biology at Australian National University, later joining RML as a postdoctoral researcher in 1999. After completing her postdoc, she stayed on as a research fellow, then a staff scientist. While at RML, Dr. Best realized she could be competitive in the position of a principal investigator and in 2009, she became an NIAID tenure-track investigator. A key element Dr. Best loves about RML is its location; nestled in a remote town in the Rocky Mountains, it boasts a picturesque view. But even more than the scenery, Dr. Best said one of the greatest things about RML is its “supportive and collaborative research environment.”