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Nathan T. Mortimer
Nathan T. Mortimer
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​Cellular Immunology Lab Research

Research in my lab is focused on understanding cellular immune responses, and uncovering the tricks that pathogens and parasites use to overcome them. We use the fruit fly Drosophila melanogaster and parasitoid wasps that infect flies as a model host-parasite system. 

Our work is described in more detail below:

Molecular genetics of Drosophila melanogaster cellular immunity

Parasitoid wasps infect Drosophlia melanogaster larvae, leading to the production of a robust cellular immune response. This response is known as melanotic encapsulation, and is characterized by a multi-step process in which fly immune cells surround the parasitoid egg, forming a capsule that becomes melanized resulting in the death of the developing wasp. In the melanotic encapsulation response, fly immune cells go through several common cell biological processes including cell differentiation, activation, migration and adhesion (Mortimer, 2013). We are interested in understanding the molecular genetic basis of the various stages of the encapsulation response, and multiple projects in the lab are geared towards this goal.

Wasp egg surrounded by fly immune cells 
Wasp egg surrounded by fly immune cells (shown in red)
Fly larva with encapsulated wasp eggs 
Fly larva with encapsulated wasp eggs. The eggs have been 
melanized and appear black
In one example project (Mortimer et al., 2012), we uncovered the role of protein N-glycosylation in cell adhesion during the encapsulation response. We found that proteins on the surface of fly immune cells are highly glycosylated, and that disrupting the protein N-glycosylation pathway prevented the formation of intercellular adhesions. Wasp larvae were then able to escape from these incompletely formed capsules.

Fly immune cell showing surface protein N-glycosylation 
Fly immune cell imaged in brightfield to show detail (left) and under fluorescence
to show surface protein N-glycosylation (right, green indicates sites of N-glycosylation)
Without N-glycosylation cells fail to adhere and fall off of capsule 
When protein N-glycosylation is disrupted, intercellular adhesions fail to form

Fly larva with a broken capsule
In the absence of intercellular adhesions, the capsule falls apart allowing
the wasp larva to escape (note small pieces of melanized capsule in black)

Parasitoid wasp virulence mechanisms

In order to successfully parasitize the fly host, the parasitoid wasp must overcome the fly’s cellular immune response. Parasitoids accomplish this using virulence factors found in their venoms. During infection, the wasp injects this venom, along with its egg, directly into the fly larva, and the virulence factors found in the venom block host immunity allowing the parasitoid to develop normally.
A major goal of the lab is to identify and functionally characterize wasp virulence factors. We have used a combined transcriptomics and proteomics approach to identify the venom proteomes of three parasitoid wasp species (Mortimer et al., 2013; Goecks et al., 2013). Interestingly, we found that one venom protein from the wasp Ganaspis species 1 acts as a virulence factor by disrupting fly immune cell activation. This protein (vSERCA) is homologous to the SERCA family of calcium pumps, and amazingly, acts to decrease the calcium concentration of fly immune cells, thereby blocking cell activation. Future projects in the lab will continue to investigate the functions of these potential virulence factors.

Parasitoid infecting a fly larva 
 A parasitoid wasp infecting a fly larva (Photo credit: Todd Schlenke)

Parasitoid wasp larva 
Developing parasitoid wasp dissected out of a fly larva

Genetics of host autoimmunity

We are particularly interested in understanding the first stage of the encapsulation response: parasitoid egg recognition. Flies, and other invertebrates, don’t have an antibody-based immune response, and the ability of flies to discriminate their own tissues from the tissue of another insect in the absence of antibodies is quite a feat. To gain insight into this process, we are investigating the genetic architecture of several Drosophila melanogaster autoimmune mutants. These mutant flies mount a melanotic encapsulation response against their own tissues in the absence of wasp infection. By understanding the basis for lack of the ability to discriminate self tissues in these mutants, we will begin to uncover the underlying genetic basis of parasitoid egg recognition.

Comparative genomics of insect immune responses

A straightforward way to characterize an immune response is to look at global changes in gene expression in the host organism following infection. There have been a multitude of such studies focused on differential gene expression in a wide variety of infected insects. These studies often result in hundreds or even thousands of differentially expressed genes, many of which have unknown functions. We are hoping to apply the principles of comparative genomics to leverage these differential gene expression data to identify those genes that have conserved expression changes across insect species, and in this way identify novel candidate genes that may play important and conserved roles in insect immunity.