The Role of Key Schistosoma mansoni Invadolysins in Infection Establishment and Persistence in Biomphalaria glabrata and Mammalian Hosts: Functional Characterization of SmLeish and SmCI-1
Creators: Hambrook, Jacob
Publisher: name: University of Alberta Library
Year: 2023

<p>Despite significant advancements in treatment coverage, schistosomiasis remains the second most impactful parasitic disease to human health after malaria. This deadly and debilitating parasite infects more than 230 million people worldwide and causes an estimated 200,000 deaths every year. The parasite’s complex life cycle sees it cycle between a vertebrate definitive host in which sexual replication takes place, and an intermediate gastropod mollusc host in which the worm asexually replicates. Despite the significant differences between the immune system of a mammal and a snail, all life cycle stages of schistosomes have developed complex immunomodulatory mechanisms to fight the cellular and humoral immune responses put forward by both their human and snail hosts. During the initial infectious stages of the Schistosoma mansoni life cycle, a particular class of metalloproteases known as invadolysins have been shown to be released into the host. To date, these invadolysins have yet to be functionally characterized, despite their prominent featuring in larval excretory/secretory (E/S) products.<br>
    My doctoral research focused on the immune manipulation employed by S. mansoni via its release of invadolysins during penetration and development in a host. One invadolysin, which we termed S. mansoni Leishmanolysin (SmLeish), was found to be released by developing sporocysts inside of the snail host Biomphalaria glabrata during the first 48 hours of infection. I discovered that SmLeish features canonical MMP activity, is present in host E/S products, and has the capacity to alter susceptible snail (M-line) haemocyte chemokinesis, but not resistant snail (BS-90) haemocyte chemokinesis. In addition to this, I showed that specific knock down of SmLeish is sufficient to alter infection kinetics and success of S. mansoni infecting M-line B. glabrata. While SmLeish was then found to be present during the cercarial stages of the S. mansoni life cycle, it did not successfully target relevant mammalian substrates.<br>
     I then moved to characterize an invadolysin comprising roughly 12.8% of cercarial acetabular glands, which I termed S. mansoni cercarial invadolysin (SmCI-1). This protein was found to be localized to the acetabular glands and released upon transformation into schistosomula. It featured canonical MMP activity and was able to cleave key structural and immunological human proteins such as collagen type IV, fibrinogen, and complement component C3. It was also demonstrated to be capable of altering the production of key inflammatory cytokines in human leukocytes exposed to various stimulants such as whole cercarial lysate and lipopolysaccharides. This effect was confirmed to require MMP activity, as an inactive SmCI-1 mutant did not downregulate inflammatory cytokines. Despite this observation, both active and inactive SmCI-1 were able to elicit the production of IL-10. While SmLeish also featured an ability to alter cytokine production in a similar manner, its low abundance during mammalian infection suggests less of a role during mammalian infection than SmCI-1.<br>
    All together, this research helped further our understanding of host immune system modulation by schistosomes, while also serving as the first known characterization of invadolysins in the context of a parasitic helminth.</p>