Regulation of Anti-Plasmodium Immunity by a LITAF-like Transcription Factor in the Malaria Vector Anopheles gambiae

Smith, Ryan C.; Eappen, Abraham G.; Radtke, Andrea J.; Jacobs-­Lorena, Marcelo

doi:10.1371/journal.ppat.1002965

Cited by 34 publications

(53 citation statements)

References 30 publications

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“…The colony of A. gambiae (Keele strain) was obtained from the Johns Hopkins insectary core facility. Mosquitoes were maintained on 10% sucrose at 27°C and 80% relative humidity with a 14-h/10-h light/dark cycle as reported previously (30). P. falciparum infections were performed by diluting stage V control and API-minus gametocytes to ϳ0.3% gametocytemia and fed to A. gambiae mosquitoes using an artificial membrane feeder for 1 h in the absence of IPP.…”

Section: Previously Described Methods Involving Ip-rp-uplc-ms/ms (28) mentioning

confidence: 99%

“…Fed mosquitoes were sorted immediately. Oocyst counts were performed by midgut dissection in 1ϫ PBS at 6, 12, and 17 days postfeeding, staining with 0.2% mercurochrome, and visualization with a compound microscope as described previously (30). Pictures of oocysts were processed using Adobe Photoshop CS2.…”

Section: Previously Described Methods Involving Ip-rp-uplc-ms/ms (28) mentioning

confidence: 99%

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Isoprenoid Precursor Biosynthesis Is the Essential Metabolic Role of the Apicoplast during Gametocytogenesis in Plasmodium falciparum

et al. 2015

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The malaria parasite harbors a relict plastid called the apicoplast and its discovery opened a new avenue for drug discovery and development due to its unusual, nonmammalian metabolism. The apicoplast is essential during the asexual intraerythrocytic and hepatic stages of the parasite, and there is strong evidence supporting its essential metabolic role during the mosquito stages of the parasite. Supply of the isoprenoid building blocks isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) is the essential metabolic function of the apicoplast during the asexual intraerythrocytic stages. However, the metabolic role of the apicoplast during gametocyte development, the malaria stages transmitted to the mosquito, remains unknown. In this study, we showed that production of IPP for isoprenoid biosynthesis is the essential metabolic function of the apicoplast during gametocytogenesis, by obtaining normal gametocytes lacking the apicoplast when supplemented with IPP. When IPP supplementation was removed early in gametocytogenesis, developmental defects were observed, supporting the essential role of isoprenoids for normal gametocytogenesis. Furthermore, mosquitoes infected with gametocytes lacking the apicoplast developed fewer and smaller oocysts that failed to produce sporozoites. This finding further supports the essential role of the apicoplast in establishing a successful infection in the mosquito vector. Our study supports isoprenoid biosynthesis as a valid drug target for development of malaria transmission-blocking inhibitors.

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Section: Previously Described Methods Involving Ip-rp-uplc-ms/ms (28) mentioning

confidence: 99%

Section: Previously Described Methods Involving Ip-rp-uplc-ms/ms (28) mentioning

confidence: 99%

Isoprenoid Precursor Biosynthesis Is the Essential Metabolic Role of the Apicoplast during Gametocytogenesis in Plasmodium falciparum

et al. 2015

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“…Previous experiments have established that LL3 is an important component of the mosquito anti-Plasmodium response in An. gambiae (12). However, little information exists regarding the timing, expression, and mechanism of LL3 action.…”

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confidence: 99%

“…Previously, we have characterized a LITAF-like transcription factor, LPS-induced TNFα transcription factor (LITAF)-like 3 (LL3), in Anopheles gambiae that mediates a potent antiPlasmodium immune response against both Plasmodium berghei and Plasmodium falciparum parasites (12). LL3 expression is strongly up-regulated in response to ookinete invasion and positively regulates the expression of SRPN6, a serine protease inhibitor implicated in anti-Plasmodium immunity (13)(14)(15), by directly binding to regions of its promoter (12).…”

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Hemocyte differentiation mediates the mosquito late-phase immune response against Plasmodium in Anopheles gambiae

Smith

Barillas‐Mury

Jacobs-Lorena

2015

Proc. Natl. Acad. Sci. U.S.A.

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143

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Plasmodium parasites must complete development in the mosquito vector for transmission to occur. The mosquito innate immune response is remarkably efficient in limiting parasite numbers. Previous work has identified a LPS-induced TNFα transcription factor (LITAF)-like transcription factor, LITAF-like 3 (LL3), which significantly influences parasite numbers. Here, we demonstrate that LL3 does not influence invasion of the mosquito midgut epithelium or ookinete-to-oocyst differentiation but mediates a late-phase immune response that decreases oocyst survival. LL3 expression in the midgut and hemocytes is activated by ookinete midgut invasion and is independent of the mosquito microbiota, suggesting that LL3 may be a component of a wound-healing response. LL3 silencing abrogates the ability of mosquito hemocytes to differentiate and respond to parasite infection, implicating hemocytes as critical modulators of the late-phase immune response.osquitoes of the genus Anopheles are the obligate vectors for the transmission of the malaria parasite. Despite much effort invested to understand the interactions between the mosquito immune system and the parasite, our knowledge of these processes remains incomplete. The mosquito innate immune response effectively reduces parasite numbers, resulting in a severe bottleneck at the oocyst stage (1). There is evidence to suggest that multiple pathways contribute to parasite killing during two separate stages, or phases, of parasite development (1). An "early phase" occurs ∼18-24 h after blood feeding, as Plasmodium ookinetes invade the midgut epithelium and emerge on the basal side facing the hemocoel. During invasion, ookinetes are marked by epithelial nitration in a response regulated by the Jun N-terminal kinase (JNK) pathway, to promote thioester-containing protein 1 (TEP1) binding to the ookinete surface (2, 3). Once bound, TEP1 is believed to initiate a complement-like cascade that ultimately leads to parasite lysis or melanization (4-7).Parasites that evade this early-phase complement-like recognition and elimination are thought to be subjected to a second, "latephase" immune response that further decreases parasite numbers. This model is supported by the observation that the number of mature oocysts is significantly less than the number of early oocysts (8). Silencing the transcription factors STAT-A and STAT-B significantly increases oocyst survival, thus implicating the STAT pathway in this response (8). Conversely, constitutive activation of the STAT pathway via silencing the repressor SOCS (suppressor of cytokine signaling) resulted in increased levels of nitric oxide synthase (NOS) production and enhanced oocyst killing (8). These observations are in agreement with other studies that implicate NOS and subsequent NO production as important determinants of malaria parasite survival (9-11).Previously, we have characterized a LITAF-like transcription factor, LPS-induced TNFα transcription factor (LITAF)-like 3 (LL3), in Anopheles gambiae that mediates a potent antiPlasmod...

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GILP family: a stress-responsive group of plant proteins containing a LITAF motif

Cabreira-Cagliari

Fagundes

Dias

et al. 2017

Funct Integr Genomics

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Lipopolysaccharide-induced tumor necrosis factor-α (LITAF) is a membrane protein that is highly dependent on correct location to exert transcription factor activity and protein quality control. In humans, LITAF, PIG7 (p53-inducible gene 7), and SIMPLE (small integral membrane protein of the lysosome/late endosome) refer to the same gene, which acts as a tumor suppressor. Several studies have shown that the transcription factor activity and nuclear translocation of LITAF protein are critical for the induction of several immune cells via classical pathways. In plants, LITAF protein corresponds to the plasma membrane protein AtGILP (Arabidopsis thaliana GSH-induced LITAF domain protein). The conservation of LITAF proteins across species and their putative role is still unclear. In this study, we investigate the LITAF-containing proteins, which we call GILP proteins, in Viridiplantae. We identified a total of 59 genes in 46 species, whose gene copies range from one to three. Phylogenetic analysis showed that multiple copies were originated via block duplication posteriorly to monocot and eudicot separation. Analysis of the LITAF domain of GILP proteins allowed the identification of a putative domain signature in Viridiplantae, containing a CXXCX41HXCPXC motif. The subcellular location for the majority of GILP proteins was predicted to be in the plasma membrane, based on a transmembrane domain positioned within the LITAF domain. In silico analysis showed that the GILP genes are neither tissue-specific nor ubiquitously expressed, being responsive to stress conditions. Finally, investigation of the GILP protein network resulted in the identification of genes whose families are known to be involved with biotic and/or abiotic stress responses. Together, the expression modulation of GILP genes associated with their plasma membrane location suggests that they could act in the signaling of biotic/abiotic stress response in plants.

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Regulation of Anti-Plasmodium Immunity by a LITAF-like Transcription Factor in the Malaria Vector Anopheles gambiae

Cited by 34 publications

References 30 publications

Isoprenoid Precursor Biosynthesis Is the Essential Metabolic Role of the Apicoplast during Gametocytogenesis in Plasmodium falciparum

Isoprenoid Precursor Biosynthesis Is the Essential Metabolic Role of the Apicoplast during Gametocytogenesis in Plasmodium falciparum

Hemocyte differentiation mediates the mosquito late-phase immune response against Plasmodium in Anopheles gambiae

GILP family: a stress-responsive group of plant proteins containing a LITAF motif

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