Kaushansky Lab

Malaria host-parasite interactions

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 blood stream. 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 human liver environment in order to counteract host defenses and ensure for 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 malaria parasite requires for survival.

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 disease because of their massive world-wide 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 which 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.

Cross-pathogen studies and co-infections

Infectious diseases are often studied in isolation, using different experimental platforms. Yet, in the field, people are often infected with many infectious diseases simultaneously. Conventional experimental design cannot compare and contrast how divergent pathogens impact their hosts. Traditional approaches also generally fail to describe how divergent pathogens interact on a molecular level. We are developing technologies that allow us to monitor the changes that occur in response to a variety of infectious diseases . Our goal is two-fold: to better understand how pathogens interact during co-infection and identify ways to eliminate multiple pathogens with a single drug regimen.

Insectaries

Our work and the work of colleagues critically depend on malaria parasite infection in mosquitoes and 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.