1,258 research outputs found
Supplementary Material
No full textSupplementary Material for manuscript:
Trypsin-like inhibitor domain (TIL)-harboring protein is essential for Aedes aegypti reproduction
Tikhe, Chinmay Vijay1, Cardoso-Jaime, Victor 1, Dong, Shengzhang 1,2, Rutkowski, Natalie 1 and Dimopoulos, George1 *
1: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA, 21205. Johns Hopkins Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA, 21205
MICROBIOME DEPENDENT AND INDEPENDENT DETERMINANTS OF PLASMODIUM INFECTION IN THE MOSQUITO ANOPHELES GAMBIAE
No full textThe biology of Anopheles mosquitoes has been heavily investigated due to their ability to transmit Plasmodium parasites that cause malaria. In particular, interactions between the mosquito immune system, Plasmodium parasites, and the endogenous midgut microbiota are critical determinants of the outcome of pathogen infection and transmission. In this regard, we have investigated bacteria-independent, Plasmodium-specific mosquito immune responses as well as the role fungi play in mosquito-pathogen interactions; two areas of research that have not been well studied. Using whole-genome transcript microarray analysis, RNAi-mediated gene silencing, Plasmodium infection assays, and other tools we reported two novel findings. First, we identified the existence of bacteria- and IMD pathway-independent anti-Plasmodium defenses. This finding highlights non-canonical anti-Plasmodium defenses that could be exploited to interrupt pathogen transmission. Second, we showed that the non-pathogenic fungus P. chrysogenum is capable of enhancing Plasmodium susceptibility in Anopheles mosquitoes. To our knowledge, this is the first report of a fungus capable of increasing Plasmodium infection, which has implications for the success of Plasmodium transmission in nature. Overall, we elucidated a novel immune mechanism as well as a new microbial component influencing mosquito-pathogen interactions.
Keywords: Anopheles, immunity, Plasmodium, bacteria, fungi, microbiome
Thesis Advisory Committee: Dr. George Dimopoulos, Dr. Marcelo Jacobs-Lorena, Dr. Petros Karakousis, and Dr. William Moss
Alternates: Dr. Douglas Norris and Dr. Michael Matuni
Current and future treatment options for infections caused by multidrug-resistant Gram-negative pathogens
No full textThe spread of multidrug-resistant, extensively drug-resistant and pan-drug-resistant pathogens is causing an unprecedented public health crisis. The limited current therapeutic options led to the revival of two 'old' antibiotics - colistin and fosfomycin - for which a better understanding of their pharmacokinetics in the critically ill patient and in specific body compartments is required. Tigecycline's use in clinical practice for nonapproved indication based on its in vitro activity against problematic pathogens requires caution and probably higher doses. Furthermore, all three antibiotics should be used as part of combination regimens in order to prevent resistance and optimize outcomes. The development of new antibacterials in the near future, namely combinations of avibactam, ceftolozane/tazobactam and plazomicin, seems promising; however, they will only partially address current mechanisms of resistanc
O-Directed free radical hydrostannations of propargyl ethers, acetals and alcohols with Ph3SnH and Et3B
No full text[reaction: see text] The O-directed hydrostannation of various propargyloxy substrates is reported with Ph(3)SnH/Et(3)B.Paschalis Dimopoulos, Audrey Athlan, Soraya Manaviazar, Jonathan George, Marcus Walters, Linos Lazarides, Abil E. Aliev, and Karl J. Hal
Mechanistic Studies on the O-Directed Free Radical Hydrostannation of Disubstituted Acetylenes with Ph3SnH and Et3B, and on the Iodination of Allylically Oxygenated α-Triphenylstannylalkenes
No full text[reaction: see text] The free-radical hydrostannation of 1 with Ph(3)SnH and catalytic Et(3)B in PhMe has been mechanistically probed. At high Ph(3)SnH concentrations, the O-directed hydrostannation pathway dominates, and 2 is formed with good selectivity (ca. 11.1:1). Substantially lower stannane/substrate concentrations increase the amount of tandem 5-exo-trig cyclization product 3 that is observed.Paschalis Dimopoulos, Jonathan George, Derek A. Tocher, Soraya Manaviazar, and Karl J. Hal
The Anopheles FBN9 immune factor mediates Plasmodium species-specific defense through transgenic fat body expression
No full textMosquitoes have a multifaceted innate immune system that is actively engaged in warding off various pathogens, including the protozoan malaria parasite Plasmodium. Various immune signaling pathways and effectors have been shown to mediate a certain degree of defense specificity against different Plasmodium species. A key pattern recognition receptor of the Anopheles gambiae immune system is the fibrinogen domain-containing immunolectin FBN9, which has been shown to be transcriptonally induced by Plasmodium infection, and to mediate defense against both rodent and human malaria parasites and bacteria. Here we have further studied the defense specificity of FBN9 using a transgenic approach, in which FBN9 is overexpressed in the fat body tissue after a blood meal through a vitellogenin promoter. Interestingly, the Vg-FBN9 transgenic mosquitoes showed increased resistance only to the rodent parasite P. berghei, and not to the human parasite P. falciparum, pointing to differences in the mosquito's defense mechanisms against the two parasite species. The Vg-FBN9 transgenic mosquitoes were also more resistant to infection with both Gram-positive and Gram-negative bacteria and showed increased longevity when infected with P. berghei. Our study points to the importance of both experimentally depleting and enriching candidate anti-Plasmodium effectors in functional studies in order to ascertain their suitability for the development of transgenic mosquito-based malaria control strategies
Elderly versus non-elderly patients with intra-abdominal candidiasis in the ICU
No full textIntra-abdominal candidiasis (IAC) has a considerable cost in terms of mortality and morbidity. We sought to study the epidemiology, characteristics and outcome of elderly (>75 years old) versus non-elderly patients with IAC and risk factors for mortality in elderly patients
Ethnic Groups : Greeks
No full textImage of crowd in darkened Varsity Stadium participating in Greek Orthodox Good Friday Service. Caption reads " Approx. 6000 Greek Orthodoxs attended the candle service conducted by Archinidrite Iakovos Pililis and Father George Dimopoulos.
EXPLORE THE FUNCTION OF THE IMMUNE SIGNALING PROTEIN VAGO1 IN AEDES AEGYPTI
No full textAedes aegypti is the principal vector for multiple medically significant arboviruses, including dengue, Zika, chikungunya, and yellow fever viruses. With limited efficacious vaccines and antiviral therapeutics available, vector control remains crucial. However, conventional insecticide-based strategies face mounting challenges from resistance development, operational constraints, and environmental impacts. As an alternative, genetic control strategies using pathogens-resistant transgenic mosquitoes offer promising avenues for reducing arboviral transmission.
The invertebrate-specific cytokine-like protein Vago has been implicated in antiviral function in Drosophila and Culex mosquito species. In Ae. aegypti, Vago1 (AeVago1) has been shown to possess antiviral activity in cell culture-based studies, however, its function in the mosquito remains uncharacterized. To investigate immune function of AeVago1, we generated three transgenic mosquito lines with tissue-specific, blood meal-inducible AeVago1 overexpression in midguts (CpVago1), fat bodies (VgVago1), and both tissues (CpVgVago1). Evaluation of fitness-related traits revealed that tissue-specific AeVago1 overexpression had no significant impact on fecundity, egg hatching rates, or adult longevity, with only a modest acceleration in pupation timing observed across all transgenic lines.
Following the viral challenge, AeVago1 overexpression did not significantly affect Mayaro virus (MAYV) or dengue virus serotype 2 (DENV2) infections in midguts of all transgenic lines. However, viral titers were significantly reduced in carcasses (the mosquito whole body minus midgut) in all transgenic lines for both viruses. Infection prevalence in carcasses also decreased, with the VgVago1 line showing a significant reduction for MAYV infection and CpVgVago1 for DENV2 infection. These findings suggest AeVago1 may contribute to limiting systemic viral dissemination beyond the midgut.
Bacteria challenge assays showed that survival rates following bacterial injection remained comparable between CpVago1, VgVago1, and the wild-type control mosquitoes. Moreover, neither recombinant AeVago1 nor AeVago2 exhibited antimicrobial activity in bacterial radial diffusion assays. Midgut microbiota composition remained largely unaltered, with only a modest reduction observed in sugar-fed CpVago1 mosquitoes. These results suggest that AeVago1 overexpression did not substantially alter resistance to bacterial infection.
Interestingly, both CpVago1 and VgVago1 lines exhibited enhanced survival following infection with the entomopathogenic fungus Beauveria bassiana, indicating a broader immunomodulatory role for AeVago1 beyond its antiviral activity.
In summary, our results indicate that AeVago1 contributes to systemic antiviral and antifungal immunity in Ae. aegypti without incurring major fitness costs. The lack of antibacterial effects suggests a pathogen-specific role for AeVago1. This study expands the current understanding of mosquito immune signaling and provides implications for the development of novel vector-based disease control strategies
EXPLORE THE FUNCTION OF THE IMMUNE SIGNALING PROTEIN VAGO1 IN AEDES AEGYPTI
No full textAedes aegypti is the principal vector for multiple medically significant arboviruses, including dengue, Zika, chikungunya, and yellow fever viruses. With limited efficacious vaccines and antiviral therapeutics available, vector control remains crucial. However, conventional insecticide-based strategies face mounting challenges from resistance development, operational constraints, and environmental impacts. As an alternative, genetic control strategies using pathogens-resistant transgenic mosquitoes offer promising avenues for reducing arboviral transmission.
The invertebrate-specific cytokine-like protein Vago has been implicated in antiviral function in Drosophila and Culex mosquito species. In Ae. aegypti, Vago1 (AeVago1) has been shown to possess antiviral activity in cell culture-based studies, however, its function in the mosquito remains uncharacterized. To investigate immune function of AeVago1, we generated three transgenic mosquito lines with tissue-specific, blood meal-inducible AeVago1 overexpression in midguts (CpVago1), fat bodies (VgVago1), and both tissues (CpVgVago1). Evaluation of fitness-related traits revealed that tissue-specific AeVago1 overexpression had no significant impact on fecundity, egg hatching rates, or adult longevity, with only a modest acceleration in pupation timing observed across all transgenic lines.
Following the viral challenge, AeVago1 overexpression did not significantly affect Mayaro virus (MAYV) or dengue virus serotype 2 (DENV2) infections in midguts of all transgenic lines. However, viral titers were significantly reduced in carcasses (the mosquito whole body minus midgut) in all transgenic lines for both viruses. Infection prevalence in carcasses also decreased, with the VgVago1 line showing a significant reduction for MAYV infection and CpVgVago1 for DENV2 infection. These findings suggest AeVago1 may contribute to limiting systemic viral dissemination beyond the midgut.
Bacteria challenge assays showed that survival rates following bacterial injection remained comparable between CpVago1, VgVago1, and the wild-type control mosquitoes. Moreover, neither recombinant AeVago1 nor AeVago2 exhibited antimicrobial activity in bacterial radial diffusion assays. Midgut microbiota composition remained largely unaltered, with only a modest reduction observed in sugar-fed CpVago1 mosquitoes. These results suggest that AeVago1 overexpression did not substantially alter resistance to bacterial infection.
Interestingly, both CpVago1 and VgVago1 lines exhibited enhanced survival following infection with the entomopathogenic fungus Beauveria bassiana, indicating a broader immunomodulatory role for AeVago1 beyond its antiviral activity.
In summary, our results indicate that AeVago1 contributes to systemic antiviral and antifungal immunity in Ae. aegypti without incurring major fitness costs. The lack of antibacterial effects suggests a pathogen-specific role for AeVago1. This study expands the current understanding of mosquito immune signaling and provides implications for the development of novel vector-based disease control strategies
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