Julie-Anne Gabelich

November 2018

Given the thorough reaches of the human immune system within the body, it is surprising that not only can successful infections establish, but these infectious organisms can take up intracellular residence. Plasmodium, the organism causing malaria, is one such parasite, and it lives and reproduces within its host’s liver and red blood cells. However, successful infection does not mean it is shielded from interaction from the host – in fact quite the opposite. These relationships are often marked by, in many cases unidentified, types of interactions between the host and parasite. These interactions can be purely physical in nature, but they can cause a direct impact or interference on either organism’s growth and physiological responses.

My own research addresses host-parasite interactions, and I am particularly interested in the potential role the proteins, IBIS2 and IBIS3, that are found at the interface of the parasite and host cytoplasm in both infectious stages: the parasitophorous vacuole membrane encapsulating the parasite in the liver stage, and the IBIS in blood stages. It is fully understood that proteins are necessary to facilitate functions of any given organism, so by identifying and characterizing proteins that encounter both the host and parasite may reveal a function specific to mediating interactions between the two. Furthermore, proteins found at membrane interfaces are of particular interest because, in the case of Plasmodium, these interfaces represent a series of parasite-induced modifications of the host cell architecture.

My research objective of investigating host cell remodeling is shared with Olivia Carmo from the group of Leann Tilley at the University of Melbourne. Her research focuses on Maurer’s cleft protein interactions responsible for the trafficking of the cytoadherence mediator, PfEMP1, to the surface of P. falciparum infected red blood cells (iRBC). Knock out of two different Maurer’s clefts proteins, GEXP07 or 85c, both result in impaired trafficking of PfEMP1 and related reduction in cytoadherance and knob formation. Her research illustrates how proteins found in parasite-induced host cell modifications such as Maurer’s clefts facilitate protein trafficking, and thus the pathogenicity of the parasite. P. berghei contains similar modifications in the iRBC, termed IBIS, and also displays membrane associated proteins such as IBIS2 and IBIS3. However, aside from work published in Pasini, 2012, there are no identified proteins on the surface of the P. berghei iRBC. This raises the question of whether these membrane alterations between the two species serve similar functions, or if it is simply a residual membrane system left over after a genetic diverging point. To support a connection between conservation of membrane- alteration function, a P. knowlesi ortholog of IBIS2 has a predicted role in cytoadherence. Should this be true, this would indicate that it somehow facilitates a cytoadherence mediator to the surface of the iRBC.

The previous example illustrates an interaction between host and parasite that is largely defined by direct contact, however the parasite can exert more dynamic effects on the host. One such example is the observation that Plasmodium infected liver cells are less likely to undergo apoptosis. In such a situation, the parasite needs to produce a direct mediator that interacts with a tightly regulated host cell signalling pathway. June Hu from the group of Sarah Charnaud at the Walter and Eliza Hall Institute investigated the ability of P. vivax to inhibit host cell apoptosis, specifically in the context of hypnozoite formation. She took a computer-predictive approach to identifying parasite protein structure similarities to host apoptotic proteins in order to identify a mechanism. Through this, she identified candidates that could potentially inhibit cytochrome C. This work is supported by research done in the group of Justin Boddey also from the Walter and Eliza Hall Institute. Here, his group observed that antagonizing host apoptosis inhibitors results in decreased parasite burden in the livers of infected mice.

The three talks highlighted above give insight into the types of host parasite interactions that can occur in both infection stages of Plasmodium, and illustrate the importance of furthering the understanding of these host-parasite interaction components.