Parasitic flatworms of the genus Schistosoma cause schistosomiasis, a neglected tropical disease affecting hundreds of millions of people worldwide. There is no vaccine, and only a single drug (praziquantel; PZQ) available for treatment and control. Although PZQ was introduced decades ago, its mode of action is still not completely understood. However, one major effect of PZQ is to disrupt the tegument of the worm, likely resulting in exposure of parasite antigens that are normally hidden from the host. The effectiveness of PZQ drops significantly in immunocompromised mice, and it has been suggested that host antibodies act directly against parasite antigens that become exposed on the worm surface as a result of this PZQ-induced tegumental disruption. We have been using RNAseq to investigate transcriptomic changes that occur in schistosomes following administration of PZQ to S. mansoni-infected mice. We find that in response to low-dose PZQ (100 mg/kg), adult worms of each of 3 different S. mansoni strains dramatically increase expression (up to ~150-fold) of MEG-3 transcripts. MEG-3 is one of a group of micro-exon genes (MEG) found within the S. mansoni genome. MEGs have the potential to generate high levels of protein variation through alternative splicing of short, symmetric exons organized in tandem. Most of these proteins appear to be secreted by the worm, and others have postulated that expression of such a complex pool of variant MEG proteins could constitute a schistosome immune evasion mechanism. We hypothesize that in response to PZQ-dependent immune attack, schistosomes activate immune evasion/decoy mechanisms, one of which is increased expression of MEG-3 proteins (and associated transcripts). This exploratory project will test predictions of this hypothesis. We will compare expression of MEG-3 transcripts following low-dose PZQ in worms in contact with an intact immune system versus those in contact with a defective immune system (eg, infecting immunocompromised mice). We will also test whether other antischistosomal drugs that do not require an intact host immune system for activity do not induce upregulation of MEGs, and we will determine whether reconstitution of the immune system of an infected immunocompromised host with serum from schistosome-infected immune-intact mice can restore the PZQ-induced upregulation of MEG-3. These studies will lay the groundwork for a future R01 proposal that will examine the role of adaptive schistosome defenses in parasite drug susceptibility and long-term survival. This work could ultimately lead to novel therapeutic strategies for targeting parasite immune evasion mechanisms as a means to increase drug susceptibility or disrupt the schistosome life cycle.

Public Health Relevance

Schistosomiasis is a major tropical disease caused by parasitic flatworms called schistosomes, which evade the host immune system using mechanisms that are not entirely understood. We have found that low doses of the antischistosomal drug praziquantel induce upregulated expression of a member of a class of genes thought to be involved in parasite immune evasion. This project will perform tests to determine whether this response to praziquantel is consistent with an attempt by the parasite to evade praziquantel-dependent immune attack. The results could lead to a new understanding of both how this drug works and how schistosomes ward off host responses to infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI130665-02
Application #
9617206
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Pesce, John T
Project Start
2017-12-21
Project End
2019-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104