Identification of an Anopheles Lineage-Specific Unique Heme Peroxidase HPX15: A Plausible Candidate for Arresting Malaria Parasite Development

Kajla, Mithilesh; Gupta, Kuldeep; Kakani, Parik; Dhawan, Rini; Choudhury, Tania Pal; Gupta, Lalita; Gakhar, S. K.; Kumar, Sanjeev

doi:10.4172/2329-9002.1000160

Cited by 8 publications

(14 citation statements)

References 37 publications

(48 reference statements)

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“…Because HPX15 is highly conserved gene exclusively among anophelines (Kajla et al, 2015b, 2016a), then the proposed idea might be applicable for other worldwide distributed malaria vectors as a common strategy.…”

Section: Discussionmentioning

confidence: 99%

Silencing of Anopheles stephensi Heme Peroxidase HPX15 Activates Diverse Immune Pathways to Regulate the Growth of Midgut Bacteria

et al. 2016

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Anopheles mosquito midgut harbors a diverse group of endogenous bacteria that grow extensively after the blood feeding and help in food digestion and nutrition in many ways. Although, the growth of endogenous bacteria is regulated by various factors, however, the robust antibacterial immune reactions are generally suppressed in this body compartment by a heme peroxidase HPX15 crosslinked mucins barrier. This barrier is formed on the luminal side of the midgut and blocks the direct interactions and recognition of bacteria or their elicitors by the immune reactive midgut epithelium. We hypothesized that in the absence of HPX15, an increased load of exogenous bacteria will enormously induce the mosquito midgut immunity and this situation in turn, can easily regulate mosquito-pathogen interactions. In this study, we found that the blood feeding induced AsHPX15 gene in Anopheles stephensi midgut and promoted the growth of endogenous as well as exogenous fed bacteria. In addition, the mosquito midgut also efficiently regulated the number of these bacteria through the induction of classical Toll and Imd immune pathways. In case of AsHPX15 silenced midguts, the growth of midgut bacteria was largely reduced through the induction of nitric oxide synthase (NOS) gene, a downstream effector molecule of the JAK/STAT pathway. Interestingly, no significant induction of the classical immune pathways was observed in these midguts. Importantly, the NOS is a well known negative regulator of Plasmodium development, thus, we proposed that the induction of diverged immune pathways in the absence of HPX15 mediated midgut barrier might be one of the strategies to manipulate the vectorial capacity of Anopheles mosquito.

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Section: Discussionmentioning

confidence: 99%

Silencing of Anopheles stephensi Heme Peroxidase HPX15 Activates Diverse Immune Pathways to Regulate the Growth of Midgut Bacteria

et al. 2016

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“…In parallel, a 428-bp cDNA fragment of AsHPX15 gene that reported in our previous publication (10) was also cloned in the same vector. These recombinant plasmids were used individually as a template for in vitro transcription.…”

Section: Methodsmentioning

confidence: 99%

“…Our previous studies identified AgHPX15 ortholog in major Indian malaria vector Anopheles stephensi , and we termed it as AsHPX15 ( 9 , 10 ). In addition, putative orthologs of AsHPX15 gene were also found in the genome of 17 other anophelines with no orthology in other insects, mosquitoes ( Aedes and Culex ), or human.…”

Section: Introductionmentioning

confidence: 99%

“…These findings revealed that HPX15 is an anopheline lineage-specific unique gene. Interestingly, these 19 HPX15 orthologs are also highly conserved and reveal 65–99% amino acid identity among them ( 10 , 11 ). Based on these facts, we hypothesized that HPX15 might be functionally conserved in anophelines and can be considered as a general target to block the insect cycle of Plasmodium development.…”

Section: Introductionmentioning

confidence: 99%

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Anopheles stephensi Heme Peroxidase HPX15 Suppresses Midgut Immunity to Support Plasmodium Development

et al. 2017

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The heme peroxidase HPX15 is an evolutionary conserved anopheline lineage-specific gene. Previously, we found that this gene is present in the genome of 19 worldwide distributed different species of Anopheles mosquito and its orthologs are absent in other mosquitoes, insects, or human. In addition, 65–99% amino acid identity among these 19 orthologs permitted us to hypothesize that the functional aspects of this gene might be also conserved in different anophelines. In this study, we found that Anopheles stephensi AsHPX15 gene is mainly expressed in the midgut and highly induced after uninfected or Plasmodium berghei-infected blood feeding. RNA interference-mediated silencing of midgut AsHPX15 gene drastically reduced the number of developing P. berghei oocysts. An antiplasmodial gene nitric oxide synthase was induced 13-fold in silenced midguts when compared to the unsilenced controls. Interestingly, the induction of antiplasmodial immunity in AsHPX15-silenced midguts is in absolute agreement with Anopheles gambiae. In A. gambiae, AgHPX15 catalyzes the formation of a dityrosine network at luminal side of the midgut that suppresses the activation of mosquito immunity against the bolus bacteria. Thus, a low-immunity zone created by this mechanism indirectly supports Plasmodium development inside the midgut lumen. These indistinguishable functional behaviors and conserved homology indicates that HPX15 might be a potent target to manipulate the antiplasmodial immunity of the anopheline midgut, and it will open new frontiers in the field of malaria control.

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“…Thus, we can conclude that the regulation of Plasmodium development inside the mosquito midgut is a multifaceted phenomenon and has been exploited by a number of transmission blocking strategies. For example, the mosquito midgut specific molecules such as alanyl amino peptidase 1 (APN1), carboxypeptidase B (CPB) and a heme peroxidase HPX15 are proposed to design transmission blocking vaccines because inhibition of these molecules suppressed Plasmodium development ( Lavazec et al, 2007 ; Atkinson et al, 2015 ; Kajla et al, 2015b ).…”

Section: Apoptosis In Plasmodium During Sexual Stamentioning

confidence: 99%

Ambivalent Outcomes of Cell Apoptosis: A Barrier or Blessing in Malaria Progression

et al. 2016

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The life cycle of Plasmodium in two evolutionary distant hosts, mosquito, and human, is a complex process. It is regulated at various stages of developments by a number of diverged mechanisms that ultimately determine the outcome of the disease. During the development processes, Plasmodium invades a variety of cells in two hosts. The invaded cells tend to undergo apoptosis and are subsequently removed from the system. This process also eliminates numerous parasites along with these apoptotic cells as a part of innate defense against the invaders. Plasmodium should escape the invaded cell before it undergoes apoptosis or it should manipulate host cell apoptosis for its survival. Interestingly, both these phenomena are evident in Plasmodium at different stages of development. In addition, the parasite also exhibits altruistic behavior and triggers its own killing for the selection of the best ‘fit’ progeny, removal of the ‘unfit’ parasites to conserve the nutrients and to support the host survival. Thus, the outcomes of cell apoptosis are ambivalent, favorable as well as unfavorable during malaria progression. Here we discuss that the manipulation of host cell apoptosis might be helpful in the regulation of Plasmodium development and will open new frontiers in the field of malaria research.

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Identification of an Anopheles Lineage-Specific Unique Heme Peroxidase HPX15: A Plausible Candidate for Arresting Malaria Parasite Development

Cited by 8 publications

References 37 publications

Silencing of Anopheles stephensi Heme Peroxidase HPX15 Activates Diverse Immune Pathways to Regulate the Growth of Midgut Bacteria

Silencing of Anopheles stephensi Heme Peroxidase HPX15 Activates Diverse Immune Pathways to Regulate the Growth of Midgut Bacteria

Anopheles stephensi Heme Peroxidase HPX15 Suppresses Midgut Immunity to Support Plasmodium Development

Ambivalent Outcomes of Cell Apoptosis: A Barrier or Blessing in Malaria Progression

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