Kaushansky Lab
Welcome to the Kaushansky Lab
Infectious diseases remain a substantial cause of mortality around the world. This is particularly true in resource-poor areas, where access to treatment is sparse and people fight a multitude of infections simultaneously. In the case of malaria, hundreds of millions are infected every year, and the disease takes the lives of half a million people annually. Yet the malaria parasite and other pathogens that burden the world cannot survive independently. To cause sickness and travel through the population, they must appropriate resources from the people they infect. Our work aims to identify what pathogens need from their host and to use this knowledge to prevent and eliminate infectious diseases.
Malaria Host–Parasite Interactions in the Liver
When malaria parasites are transmitted from mosquito to human, they are first deposited into the skin, then quickly travel to the liver. In the liver, each parasite replicates tens of thousands of times within the confines of a single hepatocyte. During this stage of infection, the parasite causes no clinical symptoms, yet elimination of the parasite in the liver prevents disease and transmission and can even elicit sterile immunity from subsequent infection. Failure to stop the parasite during the liver stage leads to the release of parasites into the bloodstream. When in the bloodstream, parasites infect red blood cells and cause the clinical symptoms of malaria, including severe fever, anemia, organ failure, coma and even death.
Our work focuses on the basic question of how the malaria parasite is able to modify its liver environment in order to counteract host defenses and ensure its own survival. The malaria parasite is able to alter its environment quite significantly, yet only some of these parasite-induced changes are critical for the parasite to survive. We use a variety of approaches and technologies to identify the changes that are initiated by the malaria parasite, and hone in on the environment the parasite requires for survival.
Malaria Host–Parasite Interactions in Cerebral Malaria
In rare but deadly cases of malaria infection, the parasite causes breakdown of the blood-brain barrier, leading to brain swelling. This is known as cerebral malaria and is most commonly diagnosed in children under the age of 5. It is also extremely deadly: even with current front-line therapies, 15–20% of kids who get cerebral malaria die of the disease. Even for those who recover, long-term impacts are common. We aim to better understand what happens during this disease, and how it is shaped by the complex reality in the field, where some kids are exposed to malaria by the bite of an infected mosquito every day.
Host-Based Drug Discovery
Our research is driven by a deep curiosity about the fundamental properties by which pathogens control their hosts. We are inspired to focus our efforts on malaria and other infectious diseases because of their massive worldwide impact. By identifying specific needs that the malaria parasite has in the liver, we can target these host factors with drugs and eliminate the malaria parasite.
Many of the host factors the malaria parasite uses in the liver are already the subject of well-established drug development efforts. Targeting host factors that impact the parasite is far less likely to lead to the development of drug-resistant parasites. This approach is in sharp contrast to existing antimalarial drugs, which target the malaria parasite directly and thus require de novo development. The host-targeted approach is particularly well-suited to malaria, which afflicts people who, on average, live on two dollars a day, and to which drug resistance is widespread.
Pathogen-Based Drug Discovery
One-third of the global population faces the constant threat of infection by malaria-causing Plasmodium vivax parasites. P. vivax infection is unique in that it results in dormant forms that remain in the liver for weeks to months before reactivation and recurrence of blood-stage infection. The existing treatment landscape for P. vivax dormant liver stages is severely limited, as current drugs are unsuitable for a significant portion of the population in endemic areas, including pregnant women and individuals with glucose-6-phosphate dehydrogenase deficiency. The escalating challenge of drug resistance to traditional antimalarials further compounds this limited treatment landscape. Consequently, there is a critical need for new therapeutic options to effectively mitigate the global health and economic impacts of malaria.
Our work focuses on developing novel compounds to drive the inhibition of N-myristoyltransferase (NMT), a crucial enzyme in eukaryotic organisms. Although Plasmodium NMT is essential for lifecycle progression, and inhibition has been shown to eliminate parasites, previous attempts at developing P. vivax-specific NMT (PvNMT) inhibitors have been unsuccessful due to low selectivity and crossover inhibition of human NMTs. Our work aims to overcome the limited treatment landscape for dormant forms of P. vivax by developing effective PvNMT inhibitors that have high parasite selectivity and are effective at eliminating parasites at multiple stages of their life cycle.
Insectaries
Our work and the work of colleagues critically depend on malaria parasite infection in mosquitoes and the production of sporozoites for lab experiments. We maintain state-of-the-art insectaries that breed and house Anopheles mosquitoes. Mosquitoes are infected with rodent malaria parasites and with Plasmodium falciparum, which are maintained under safe containment conditions. Malaria parasite mosquito stages are then isolated and used for experimentation. Infected mosquitoes are also used for malaria challenge studies of human volunteers in our Malaria Clinical Trials Center. Learn more about the CGIDR insectaries.
Beyond Malaria
While many of the projects in our laboratory have started with an interest in malaria, because we often develop tools and technologies to enable new experimental lines of research, we often have the opportunity to work collaboratively to apply these lines of new technologies to other areas. As one example, we have developed a series of innovative computational tools to elucidate the host factors, particularly protein kinases, that control pathogen infection and development in their hosts. These tools are broadly applicable and have been applied to traumatic brain injury, sepsis, dengue infection and many other areas.
Our Best Hope in Fighting Global Disease Is Open Collaboration
Dr. Alexis Kaushansky is a research biologist, but her experience in engineering school and social justice issues before grad school has made her a scientist who looks at social and economic constraints as a path to creativity. She has implemented innovative techniques and made some startling discoveries in the quest for a malaria cure — discoveries that might help us fight other infectious diseases as well.
Partnership Opportunities: Host-Based Drug Discovery for Infectious Diseases
Learn about partnering opportunities with Dr. Kaushansky.
In the News
Dr. Kaushansky awarded endowment
Congratulations to Dr. Kaushansky, who has been awarded the Tom Hansen Pediatric Investigator in Pediatric Innovation Endowment. Established to empower bold ideas and innovative approaches to research, this three-year endowment award recognizes Dr. Kaushansky's exceptional scientific achievements in infectious disease research, creativity, and visionary leadership across the broader Seattle Children’s Research Institute community.
Selasi Dankwa selected as Next Generation Faculty Symposium speaker
One of 14 invited to speak at the prestigious event, Dankwa shared insights into why the blood-brain barrier fails in cerebral malaria. Read more in Selasi Dankwa Selected as Next Generation Faculty Symposium Speaker.
A path toward eliminating relapsing malaria
Dr. Kaushansky and an international team successfully identified malaria protein inhibitors, an approach for relapsing malaria prevention. Read more in A Path Toward Eliminating Relapsing Malaria.
What makes a particular hepatocyte attractive to the malaria parasite?
A new study in Cell Reports led by Drs. Alexis Kaushansky and Elizabeth Glennon found that higher levels of RPS6 are associated with susceptibility to infection. Read more from Science in Seattle.
Opportunities for host-targeted therapies for malaria
Cell Press announces one of the best reviews published in 2018 is from Alexis Kaushansky and her colleagues which describes host factors and dependencies that contribute to malaria pathogenesis during various parasite life cycle stages and their potentials for host-targeted therapies. Read more in Trends in Parasitology.