scholarly journals Infecting mosquitoes alters DENV-2 characteristics and enhances hemorrhage-induction potential in Stat1-/- mice

2021 ◽  
Vol 15 (8) ◽  
pp. e0009728
Author(s):  
Ka Wan Cheang ◽  
Wen-Yu Chen ◽  
Betty A. Wu-Hsieh ◽  
Shin-Hong Shiao
Keyword(s):  
Low Dose ◽  
Infected Mosquito ◽  
Effective Vaccine ◽  
Mammalian Host ◽  
Mosquito Vector ◽  
Salivary Gland Extract ◽  
Mammalian Cell Lines ◽  
Gland Extract ◽  
Mosquito Saliva ◽  
Severe Hemorrhage

Dengue is one of the most prevalent arthropod-borne viral diseases in humans. There is still no effective vaccine or treatment to date. Previous studies showed that mosquito-derived factors present in saliva or salivary gland extract (SGE) contribute to the pathogenesis of dengue. In this study, we aimed to investigate the interplay between mosquito vector and DENV and to address the question of whether the mosquito vector alters the virus that leads to consequential disease manifestations in the mammalian host. DENV2 cultured in C6/36 cell line (culture-DENV2) was injected to Aedes aegypti intrathoracically. Saliva was collected from infected mosquitoes 7 days later. Exploiting the sensitivity of Stat1-/- mice to low dose of DENV2 delivered intradermally, we showed that DENV2 collected in infected mosquito saliva (msq-DENV2) induced more severe hemorrhage in mice than their culture counterpart. Msq-DENV2 was characterized by smaller particle size, larger plaque size and more rapid growth in mosquito as well as mammalian cell lines compared to culture-DENV2. In addition, msq-DENV2 was more efficient than culture-DENV2 in inducing Tnf mRNA production by mouse macrophage. Together, our results point to the possibility that the mosquito vector provides an environment that alters DENV2 by changing its growth characteristics as well as its potential to cause disease.

scholarly journals Salivary gland extract from the deer tick, Ixodes scapularis, facilitates neuroinvasion by Powassan virus in BALB/c mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rodrigo I. Santos ◽  
Meghan E. Hermance ◽  
Erin S. Reynolds ◽  
Saravanan Thangamani
Keyword(s):  
Salivary Gland ◽  
Low Dose ◽  
Ixodes Scapularis ◽  
Ixodid Ticks ◽  
High Dose ◽  
Salivary Gland Extract ◽  
Gland Extract ◽  
Powassan Virus ◽  
The Impact ◽  
The Brain

AbstractPowassan virus (POWV) is a neuroinvasive flavivirus transmitted to mammals by the bite of ixodid ticks. In this study, we sought to investigate the impact of tick salivary gland extract (SGE) on POWV neuroinvasion. BALB/c mice were footpad inoculated with either a high dose or a low dose of POWV, with and without Ixodes scapularis salivary gland extract. Brain and spinal cord were extracted daily, and immunohistochemical techniques were used for temporal tracking of POWV antigen. The temporal pattern of POWV staining showed a caudal to rostral spread of POWV in the brains of mice from both high dose infection groups. For the high dose infection groups, the presence of tick SGE did not influence the spread of POWV in the brain. Mice infected with the low dose of virus alone did not present POWV staining in the brain; however, in the presence of SGE, low dose infected mice presented scattered foci of POWV-infected cells throughout the brain. This study shows that tick SGE facilitates POWV neuroinvasion when mice are infected with the lower dose of POWV. We also found two patterns of central nervous system invasion that were directly influenced by the dose of POWV administered.

scholarly journals Extensive Transcriptional and Translational Regulation Occur During the Maturation of Malaria Parasite Sporozoites

2019 ◽  
Author(s):  
Scott E. Lindner ◽  
Kristian E. Swearingen ◽  
Melanie J. Shears ◽  
Michael P. Walker ◽  
Erin N. Vrana ◽  
...  
Keyword(s):  
Translational Regulation ◽  
Plasmodium Yoelii ◽  
Translational Repression ◽  
Infected Mosquito ◽  
Mammalian Host ◽  
Mosquito Vector ◽  
Gene Products ◽  
Cycle Progression ◽  
Infectious State ◽  
Validation Experiments

AbstractPlasmodium sporozoites are transmitted from an infected mosquito to mammals in which they infect the liver. The infectivity profile of sporozoites changes as they egress from oocysts on the mosquito midgut into the hemocoel, and then invade the salivary glands, where they maintain a poised and infectious state until transmission occurs. Upon transmission, the sporozoite must then navigate the host skin, vasculature, and liver. All of these feats require distinct repertoires of proteins and capabilities that are coordinated in an appropriate temporal manner. Here, we report the comprehensive and dynamic transcriptomes and proteomes of both oocyst sporozoite and salivary gland sporozoite stages in both rodent-infectious Plasmodium yoelii parasites and human-infectious Plasmodium falciparum parasites. These data robustly define mRNAs and proteins that are Upregulated in Oocyst Sporozoites (UOS) or Upregulated in Infectious Sporozoites (UIS), which include critical gene products for sporozoite functions, as well as many of unknown importance that are similarly regulated. Moreover, we found that Plasmodium uses two overlapping, extensive, and independent programs of translational repression across sporozoite maturation to temporally regulate specific genes necessary to successfully navigate the mosquito vector and mammalian host environments. Finally, gene-specific validation experiments of selected, translationally repressed transcripts in P. yoelii confirmed the interpretations of the global transcriptomic and proteomic datasets. Together, these data indicate that two waves of translational repression are implemented and relieved at different times in sporozoite maturation to promote its successful life cycle progression.

scholarly journals Aedes aegyptiNeSt1 Protein Enhances Zika Virus Pathogenesis by Activating Neutrophils

2019 ◽  
Vol 93 (13) ◽  
Author(s):  
Andrew K. Hastings ◽  
Ryuta Uraki ◽  
Hallie Gaitsch ◽  
Khushwant Dhaliwal ◽  
Sydney Stanley ◽  
...  
Keyword(s):  
Virus Infection ◽  
Immune Cells ◽  
Zika Virus ◽  
Passive Immunization ◽  
Infected Mosquito ◽  
Human Populations ◽  
Mosquito Vector ◽  
Primary Mouse ◽  
Mosquito Saliva ◽  
Stimulating Factor

ABSTRACTSaliva from the mosquito vector of flaviviruses is capable of changing the local immune environment, leading to an increase in flavivirus-susceptible cells at the infected bite site. In addition, an antibody response to specific salivary gland (SG) components changes the pathogenesis of flaviviruses in human populations. To investigate whether antigenic SG proteins are capable of enhancing infection with Zika virus (ZIKV), a reemerging flavivirus primarily transmitted by theAedes aegyptimosquito, we screened for antigenic SG proteins using a yeast display library and demonstrate that a previously undescribed SG protein we term neutrophil stimulating factor 1 (NeSt1) activates primary mouse neutrophilsex vivo. Passive immunization against NeSt1 decreases pro-interleukin-1β and CXCL2 expression, prevents macrophages from infiltrating the bite site, protects susceptible IFNAR−/−IFNGR–/–(AG129) mice from early ZIKV replication, and ameliorates virus-induced pathogenesis. These findings indicate that NeSt1 stimulates neutrophils at the mosquito bite site to change the immune microenvironment, allowing a higher level of early viral replication and enhancing ZIKV pathogenesis.IMPORTANCEWhen a Zika virus-infected mosquito bites a person, mosquito saliva is injected into the skin along with the virus. Molecules in this saliva can make virus infection more severe by changing the immune system to make the skin a better place for the virus to replicate. We identified a molecule that activates immune cells, called neutrophils, to recruit other immune cells, called macrophages, that the virus can infect. We named this molecule neutrophil-stimulating factor 1 (NeSt1). When we used antibodies to block NeSt1 in mice and then allowed Zika virus-infected mosquitoes to feed on these mice, they survived much better than mice that do not have antibodies against NeSt1. These findings give us more information about how mosquito saliva enhances virus infection, and it is possible that a vaccine against NeSt1 might protect people against severe Zika virus infection.

scholarly journals The fibrinolytic system enables the onset of Plasmodium infection in the mosquito vector and the mammalian host

2021 ◽  
Vol 7 (6) ◽  
pp. eabe3362 ◽  
Author(s):  
Thiago Luiz Alves e Silva ◽  
Andrea Radtke ◽  
Amanda Balaban ◽  
Tales Vicari Pascini ◽  
Zarna Rajeshkumar Pala ◽  
...  
Keyword(s):  
Plasminogen Activators ◽  
Fibrinolytic System ◽  
Matrix Proteins ◽  
Parasite Development ◽  
Mammalian Host ◽  
Mosquito Vector ◽  
Plasminogen Activation ◽  
Plasmodium Infection ◽  
Human Plasminogen ◽  
Vertebrate Hosts

Plasmodium parasites must migrate across proteinaceous matrices to infect the mosquito and vertebrate hosts. Plasmin, a mammalian serine protease, degrades extracellular matrix proteins allowing cell migration through tissues. We report that Plasmodium gametes recruit human plasminogen to their surface where it is processed into plasmin by corecruited plasminogen activators. Inhibition of plasminogen activation arrests parasite development early during sexual reproduction, before ookinete formation. We show that increased fibrinogen and fibrin in the blood bolus, which are natural substrates of plasmin, inversely correlate with parasite infectivity of the mosquito. Furthermore, we show that sporozoites, the parasite form transmitted by the mosquito to humans, also bind plasminogen and plasminogen activators on their surface, where plasminogen is activated into plasmin. Surface-bound plasmin promotes sporozoite transmission by facilitating parasite migration across the extracellular matrices of the dermis and of the liver. The fibrinolytic system is a potential target to hamper Plasmodium transmission.

Rhipicephalus sanguineus salivary gland extract as a source of immunomodulatory molecules

2021 ◽  
Author(s):  
Melissa Carolina Pereira ◽  
Elen Fernanda Nodari ◽  
Marina Rodrigues de Abreu ◽  
Lisiery Negrini Paiatto ◽  
Patrícia Ucelli Simioni ◽  
...  
Keyword(s):  
Salivary Gland ◽  
Rhipicephalus Sanguineus ◽  
Salivary Gland Extract ◽  
Gland Extract

scholarly journals Cyclic GMP Balance Is Critical for Malaria Parasite Transmission from the Mosquito to the Mammalian Host

mBio ◽  
2015 ◽  
Vol 6 (2) ◽  
Author(s):  
Viswanathan Lakshmanan ◽  
Matthew E. Fishbaugher ◽  
Bob Morrison ◽  
Michael Baldwin ◽  
Michael Macarulay ◽  
...  
Keyword(s):  
Salivary Glands ◽  
Cyclic Gmp ◽  
Cyclic Nucleotide ◽  
Malaria Parasite ◽  
Plasmodium Yoelii ◽  
Pcr Analysis ◽  
Mammalian Host ◽  
Mosquito Vector ◽  
Parasite Transmission ◽  
Mosquito Bite

ABSTRACT Transmission of malaria occurs during Anopheles mosquito vector blood meals, when Plasmodium sporozoites that have invaded the mosquito salivary glands are delivered to the mammalian host. Sporozoites display a unique form of motility that is essential for their movement across cellular host barriers and invasion of hepatocytes. While the molecular machinery powering motility and invasion is increasingly well defined, the signaling events that control these essential parasite activities have not been clearly delineated. Here, we identify a phosphodiesterase (PDEγ) in Plasmodium, a regulator of signaling through cyclic nucleotide second messengers. Reverse transcriptase PCR (RT-PCR) analysis and epitope tagging of endogenous PDEγ detected its expression in blood stages and sporozoites of Plasmodium yoelii. Deletion of PDEγ (pdeγ−) rendered sporozoites nonmotile, and they failed to invade the mosquito salivary glands. Consequently, PDEγ deletion completely blocked parasite transmission by mosquito bite. Strikingly, pdeγ− sporozoites showed dramatically elevated levels of cyclic GMP (cGMP), indicating that a perturbation in cyclic nucleotide balance is involved in the observed phenotypic defects. Transcriptome sequencing (RNA-Seq) analysis of pdeγ− sporozoites revealed reduced transcript abundance of genes that encode key components of the motility and invasion apparatus. Our data reveal a crucial role for PDEγ in maintaining the cyclic nucleotide balance in the malaria parasite sporozoite stage, which in turn is essential for parasite transmission from mosquito to mammal. IMPORTANCE Malaria is a formidable threat to human health worldwide, and there is an urgent need to identify novel drug targets for this parasitic disease. The parasite is transmitted by mosquito bite, inoculating the host with infectious sporozoite stages. We show that cellular signaling by cyclic nucleotides is critical for transmission of the parasite from the mosquito vector to the mammalian host. Parasite phosphodiesterase γ is essential for maintaining cyclic nucleotide balance, and its deletion blocks transmission of sporozoites. A deeper understanding of the signaling mechanisms involved in transmission might inform the discovery of novel drugs that interrupt this essential step in the parasite life cycle.

Vector survival and parasite infection: the effect of Wuchereria bancrofti on its vector Culex quinquefasciatus

Parasitology ◽  
2004 ◽  
Vol 129 (1) ◽  
pp. 43-50 ◽  
Author(s):  
K. KRISHNAMOORTHY ◽  
S. SUBRAMANIAN ◽  
G. J. VAN OORTMARSSEN ◽  
J. D. F. HABBEMA ◽  
P. K. DAS
Keyword(s):  
Incubation Period ◽  
Culex Quinquefasciatus ◽  
Geometric Mean ◽  
Wuchereria Bancrofti ◽  
Parasite Load ◽  
Infected Mosquito ◽  
Parasite Development ◽  
Mosquito Vector ◽  
Extrinsic Incubation Period ◽  
Parasite Loss

This paper investigates a cohort of 2187 laboratory reared Culex quinquefasciatus fed on 69 human volunteers, including 59 persons with different levels of Wuchereria bancrofti microfilariae and 10 without microfilaria. Mosquitoes were followed until death. Mosquito survival was analysed in relation to the level of microfilaria in the human and larval count in the dead mosquito. Vector mortality during the extrinsic incubation period (12 days post-engorgement) was significantly higher in mosquitoes fed on microfilaraemic volunteers (50%) than in those fed on amicrofilaraemics (29%). Both the percentage infected and the geometric mean parasite density was significantly higher among mosquitoes which died before 13 days (45% infected and 10 larvae per infected mosquito) than those surviving beyond 13 days (39% and 2·2), suggesting a parasite loss of more than 80% during the extrinsic incubation period. A large proportion (62%) of the mosquitoes that died during the early of phase of parasite development were infected (36% in low, 26% in medium and 90% in high human Mf-density). Survival analysis showed that the parasite load in mosquitoes and the human Mf-density for a given parasite load are independent risk factors of vector survival. Overall, the hazard of dying was found to be 11–15 times higher among mosquitoes fed on microfilaraemic volunteers than those fed on amicrofilaraemics. The hazard doubles for every increase of about 60–70 parasites in the vector. As a consequence of the parasite-induced reduction in vector survival, the transmission success of the parasite is reduced. The implication of the results on control/elimination of lymphatic filariasis using mass-drug administration is discussed.

scholarly journals Evaluation of Hexane Extract of Tuber of Root ofCyperus rotundusLinn (Cyperaceae) for Repellency against Mosquito Vectors

2009 ◽  
Vol 2009 ◽  
pp. 1-5 ◽  
Author(s):  
S. P. Singh ◽  
K. Raghavendra ◽  
A. P. Dash
Keyword(s):  
Culex Quinquefasciatus ◽  
Low Dose ◽  
Anopheles Stephensi ◽  
Hexane Extract ◽  
Cyperus Rotundus ◽  
Protective Measure ◽  
Mosquito Vector ◽  
Anopheles Culicifacies ◽  
Clear Dose Response ◽  
Tuber Extract

Hexane extract of tuber of plantCyperus rotundus(Cyperaceae) was screened under laboratory conditions for repellent activity against mosquito vectorAnopheles culicifaciesGiles species A (Diptera: Culicidae),Anopheles stephensiListon (Diptera: Culicidae), andCulex quinquefasciatusSay (Diptera: Culicidae). TheCyperus rotundustuber extract was used to determine their effect on mosquito vector, and comparison with the DEET (NN Diethyl 1-3 methyl Benzamide, formerly known as diethyl 1-m-toluamide). The tuber extracts showed more effective at all the dose. Result obtained from the laboratory experiment showed that the tuber extracts are more effective for repellency of allthe mosquito vector even at low dose. Clear dose response relationships were established with the highest dose of 10% tuber extract evoking 100% repellency. Percent protection obtained againstAn. culicifaciesGiles species A 100% repellency in 4 hours, 6 hours,An. stephensi100% repellency in 6 hours andCx. quinquefasciatuswas 100% repellency in 6 hours at the 10% concentration. Against DEET- 2.5%An. culicifaciesA 100% repellency in 1 hour, 2 hours, 6 hours, An.stephensihave shown 100% repellency in 6 hours, andCulex quinquefasciatushave shown 100% repellency in 1 hour, 2 hours, 6 hours. The consolidated data of the repellency observed in different species is given and it is evident that the over all repellency rates varied between 80 and 100% for different repellents concentrations (2.5%, 5%, and 10%). The extract can be applied as an effective personal protective measure against mosquito bites.

scholarly journals Salivary Gland Extract from Aedes aegypti Improves Survival in Murine Polymicrobial Sepsis through Oxidative Mechanisms

Cells ◽  
2018 ◽  
Vol 7 (11) ◽  
pp. 182 ◽  
Author(s):  
Rafaelli de Souza Gomes ◽  
Kely Navegantes-Lima ◽  
Valter Monteiro ◽  
Ana de Brito Oliveira ◽  
Dávila Rodrigues ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Salivary Gland ◽  
Aedes Aegypti ◽  
Bacterial Load ◽  
Polymicrobial Sepsis ◽  
Antioxidant Defenses ◽  
Oxidative Stress Marker ◽  
Trolox Equivalent Antioxidant Capacity ◽  
Salivary Gland Extract ◽  
Gland Extract

Sepsis is a systemic disease with life-threatening potential and is characterized by a dysregulated immune response from the host to an infection. The organic dysfunction in sepsis is associated with the production of inflammatory cascades and oxidative stress. Previous studies showed that Aedes aegypti saliva has anti-inflammatory, immunomodulatory, and antioxidant properties. Considering inflammation and the role of oxidative stress in sepsis, we investigated the effect of pretreatment with salivary gland extract (SGE) from Ae. aegypti in the induction of inflammatory and oxidative processes in a murine cecum ligation and puncture (CLP) model. Here, we evaluated animal survival for 16 days, as well as bacterial load, leukocyte migration, and oxidative parameters. We found that the SGE pretreatment improved the survival of septic mice, reduced bacterial load and neutrophil influx, and increased nitric oxide (NO) production in the peritoneal cavity. With regard to oxidative status, SGE increased antioxidant defenses as measured by Trolox equivalent antioxidant capacity (TEAC) and glutathione (GSH), while reducing levels of the oxidative stress marker malondialdehyde (MDA). Altogether, these data suggest that SGE plays a protective role in septic animals, contributing to oxidative and inflammatory balance during sepsis. Therefore, Ae. aegypti SGE is a potential source for new therapeutic molecule(s) in polymicrobial sepsis, and this effect seems to be mediated by the control of inflammation and oxidative damage.

Low Dose Heparin Versus Oral Anticoagulants in the Prevention of Postoperative Venous Thrombosis in Gynecology

1975 ◽  
Author(s):  
A. E. Schaer ◽  
L. Huber ◽  
P. Bader ◽  
U. Baertschi ◽  
P. Morf
Keyword(s):  
Low Dose ◽  
Oral Anticoagulants ◽  
Randomised Trial ◽  
Postoperative Hemorrhage ◽  
Heparin Group ◽  
Vein Thrombosis ◽  
Dose Heparin ◽  
Severe Hemorrhage ◽  
Fibrinogen Test ◽  
Low Dose Heparin

In a randomised trial involving 458 patients low dose heparin, peri- and postoperatively given subcutaneousely (Liquemin subcutan Roche) 2 × 5000 U twice daily for one week, was compared with oral anticoagulants. Deep vein thrombosis, diagnosed clinically and by the 125-J-fibrinogen test, was less frequent in the heparin group (2,3%/4,6%). However, the incidence of pulmonary embolism was rather high (6 cases in the heparin group, only one with oral anticoagulants). Mild postoperative hemorrhage occured more often with heparin, but the incidence of severe hemorrhage remained the same (4,5%).These results suggest to examine a combination of the two methods: low dose heparin perioperatively, oral anticoagulants in the postoperative course.

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