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Alternative Splicing of the Anopheles Gambiae Dscam Gene in Diverse Plasmodium Falciparum Infections

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Alternative Splicing of the Anopheles Gambiae Dscam Gene in Diverse Plasmodium Falciparum Infections UC Irvine UC Irvine Previously Published Works Title Alternative splicing of the Anopheles gambiae Dscam gene in diverse Plasmodium falciparum infections Permalink https://escholarship.org/uc/item/4b74q7p0 Journal Malaria Journal, 10(1) ISSN 1475-2875 Authors Smith, Paul H Mwangi, Jonathan M Afrane, Yaw A et al. Publication Date 2011 DOI 10.1186/1475-2875-10-156 License https://creativecommons.org/licenses/by/4.0/ 4.0 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Smith et al. Malaria Journal 2011, 10:156 http://www.malariajournal.com/content/10/1/156 RESEARCH Open Access Alternative splicing of the Anopheles gambiae Dscam gene in diverse Plasmodium falciparum infections Paul H Smith1*, Jonathan M Mwangi2, Yaw A Afrane3, Guiyun Yan4, Darren J Obbard1, Lisa C Ranford-Cartwright2 and Tom J Little1 Abstract Background: In insects, including Anopheles mosquitoes, Dscam (Down syndrome cell adhesion molecule) appears to be involved in phagocytosis of pathogens, and shows pathogen-specific splice-form expression between divergent pathogen (or parasite) types (e.g. between bacteria and Plasmodium or between Plasmodium berghei and Plasmodium falciparum). Here, data are presented from the first study of Dscam expression in response to genetic diversity within a parasite species. Methods: In independent field and laboratory studies, a measure of Dscam splice-form diversity was compared between mosquitoes fed on blood that was free of P. falciparum to mosquitoes exposed to either single or mixed genotype infections of P. falciparum. Results: Significant increases in Anopheles gambiae Dscam (AgDscam) receptor diversity were observed in parasite- exposed mosquitoes, but only weak evidence that AgDscam diversity rises further upon exposure to mixed genotype parasite infections was found. Finally, a cluster of AgDscam exon 4 variants that become especially common during Plasmodium invasion was identified. Conclusions: While the data clearly indicate that AgDscam diversity increases with P. falciparum exposure, they do not suggest that AgDscam diversity rises further in response to increased parasite diversity. Background Invertebrates, lacking antibodies and having only an The innate immune system is common to both inverte- innate immune system, rely on germline encoded pat- brates and vertebrates, and although less well studied tern recognition receptors (PRRs) to detect pattern asso- than the adaptive immune response, is probably respon- ciated molecular patterns and initiate a response [2,7-9]. sible for eliminating the majority of infectious organ- The absence of an equivalent of the vertebrate adap- isms. This is achieved through engulfing cells (e.g. tive immune system has long fostered doubts that the phagocytes), antimicrobial compounds (e.g. defensins) invertebrate immune system could incorporate specifi- and non-specific reactive intermediates such as nitric city and/or memory [10-12]. However, the absence of oxide [1-5]. The vertebrate adaptive immune system the cellular and genetic components of a vertebrate-like appears to have more complex features: functional anti- anticipatory immune system does not preclude a func- bodies assembled by V-(D)-J joining of gene segments tional equivalent in invertebrates [13], and there exists and diversified by somatic hypermutation accommodate evidence of enhanced secondary responses to homolo- an unrivalled resolution in terms of pathogen recogni- gous infectious challenges [14-22]. Moreover, in inverte- tion for the vertebrate adaptive immune response [6]. brates, the genetic background of both hosts and parasites plays a critical role in determining the prob- * Correspondence: [email protected] ability of infection, a phenomenon called genetic specifi- 1 Institute of Evolutionary Biology and Centre for Immunity, Infection and city [13,23,24]. Thus invertebrate defences do not lack Evolution, School of Biological Sciences, University of Edinburgh, EH9 3JT Edinburgh, UK sophistication, but the genetic and cellular mechanisms Full list of author information is available at the end of the article © 2011 Smith et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Smith et al. Malaria Journal 2011, 10:156 Page 2 of 7 http://www.malariajournal.com/content/10/1/156 that underlie either invertebrate genetic specificity or was studied in two ways. First, a diversity index was cal- enhanced secondary responses remain obscure (but see culated based on exon 4 and exon 6 frequencies to [25]). assess whether overall AgDscam expression diversity Alternative splicing could permit a single gene to increased under exposure to P. falciparum parasites, and mediate alternative immune responses via the produc- if it increased further with greater parasite infection tion of multiple proteins, and the flexibility of such a diversity. Second, it was assessed whether particular mechanism could have important implications for the Dscam exon transcripts were associated with infection spread of resistance alleles [26]. The Down syndrome diversities (in the field study) or particular parasite gen- cell adhesion molecule (Dscam), which can take some otypes (in the laboratory study). tens of thousands of different forms through alternative splicing, is commonly associated with its function in the Methods vertebrate and invertebrate nervous systems, but seems Mosquito infection in Kenya to also play a role in invertebrate immunity [27-30]. In Blood was obtained from primary school students in the fruit fly Drosophila, Dscam is expressed in cell types Iguhu (34°45’E, 0°10’N) in Kakamega district, western that play major roles in the fly’s immune system, and Kenya. The predominant malaria vector species in the RNA interference-mediated depletion of Dscam was area is An. gambiae s.s. [33,34]. During and shortly after shown to impair the insect’s capacity to engulf bacteria the rainy season, children (5-14 years of age) were by phagocytosis [29]. Similarly, the silencing of Ano- screened for gametocytes by thick blood-films stained in pheles gambiae Dscam (AgDscam) compromises the Giemsa’s stain. mosquito’s ability to resist Plasmodium [30]. Moreover, Gametocyte carriers who had >40 gametocytes/μLof AgDscam produces pathogen-specific splice form reper- blood and who consented to participate in the study toires upon immune challenge [30]. In particular, the were asked to donate 10 mL of blood, which was Dscam repertoire in response to parasite exposure dif- obtained intravenously by a clinician, and drawn into fers between bacteria and Plasmodium and between heparinized tubes. A total of six gametocyte donors Plasmodium berghei and Plasmodium falciparum [30]. were used in this study (two donors per gametocyte- However, such specificity has so far only been observed positive infection group). Most of this blood was used in studies comparing these divergent Plasmodium para- for mosquito infections through membrane feeders, with sites, which probably last shared a common ancestor around 50 μL also spotted onto Whatman paper for around 55 million years ago [31]. later DNA extraction using a Chelex-100 isolation tech- TheresponseofAgDscam transcription to P. falci- nique [35]. Methods for infecting mosquitoes are parum diversity (i.e. within-species rather than between- described in [36]. Drawn blood was immediately centri- species parasite exposure) may shed light on the resolu- fuged at 700 × g, and the serum discarded and replaced tion of the innate immune system’s specificity and with human AB serum (Cambrex Bio Science, Walkers- dynamics, as well as its limitations. In theory, 31,920 ville, MD, USA). Blood was then placed in warmed unique splice forms of Dscam can be generated through membrane feeders. Five to seven-day old Anopheles the alternative splicing of 84 variable exons contained gambiae Kisumu strain mosquitoes were placed in paper within three variable exon cassettes (these are exon 4, cups at a density of 60/cup and allowed to feed on the exon 6, and exon 10) [30], and which could potentially infected blood for 30 minutes. Mosquitoes used in this contribute to a capability to distinguish between differ- experiment were originally obtained near the Kenya ent genotypes of Plasmodium. This capability would Medical Research Institute in Kisumu [37], but had imply a more specific innate immune response than pre- been bred in an insectary and adapted to feed from a viously supposed. Here, research is described that relates membrane feeder for many years (thus the mosquitoes P. falciparum genetic diversity to the expression charac- were unlikely to be highly polymorphic). teristics of the alternatively spliced Dscam receptor in A total of twenty four mosquitoes were used in the the An. gambiae mosquito. field study (three mosquitoes per treatment × four infec- Two independent experiments were performed. The tion groups × two independent replicates). Mosquitoes first was a field study that utilized freshly harvested were transferred to cages post-blood meal, and then blood from human subjects for which the genetic diver- placed into RNAlater (Ambion) at 24-hours post-blood sity of naturally acquired P. falciparum infections was meal. Mosquitoes were harvested 24-hours post-feeding characterized. The second experiment
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