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Nabil M Abraham, Lei Liu, Brandon L Jutras, Kristen Murfin, Ali Acar, Timur O Yarovinsky, Erica Sutton, Martin Heisig, Christine Jacobs-Wagner, Erol Fikrig
New strategies are needed to combat antibiotic resistance, especially against pathogens such as methicillin-resistant Staphylococcus aureus A tick antifreeze glycoprotein, IAFGP, possess potent anti-biofilm properties against a variety of clinical pathogens including S. aureus Synergy between IAFGP, or a peptide (P1) representative of a repeat region of the protein, with different antibiotics was assessed in vitro Antibiotics that synergized with either IAFPG or P1 were further evaluated in vivo using vertebrate and invertebrate infection models...
April 24, 2017: Antimicrobial Agents and Chemotherapy
Andrew K Hastings, Laura J Yockey, Brett W Jagger, Jesse Hwang, Ryuta Uraki, Hallie F Gaitsch, Lindsay A Parnell, Bin Cao, Indira U Mysorekar, Carla V Rothlin, Erol Fikrig, Michael S Diamond, Akiko Iwasaki
Tyro3, Axl, and Mertk (TAM) receptors are candidate entry receptors for infection with the Zika virus (ZIKV), an emerging flavivirus of global public health concern. To investigate the requirement of TAM receptors for ZIKV infection, we used several routes of viral inoculation and compared viral replication in wild-type versus Axl(-/-), Mertk(-/-), Axl(-/-)Mertk(-/-), and Axl(-/-)Tyro3(-/-) mice in various organs. Pregnant and non-pregnant mice treated with interferon-α-receptor (IFNAR)-blocking (MAR1-5A3) antibody and infected subcutaneously with ZIKV showed no reliance on TAMs for infection...
April 18, 2017: Cell Reports
Juliana M Ansari, Nabil M Abraham, Jenna Massaro, Kelsey Murphy, Jillian Smith-Carpenter, Erol Fikrig
Streptococcus mutans is the primary agent of dental cavities, in large part due to its ability to adhere to teeth and create a molecular scaffold of glucan polysaccharides on the tooth surface. Disrupting the architecture of S. mutans biofilms could help undermine the establishment of biofilm communities that cause cavities and tooth decay. Here we present a synthetic peptide P1, derived from a tick antifreeze protein, which significantly reduces S. mutans biofilm formation. Incubating cells with this peptide decreased biofilm biomass by approximately 75% in both a crystal violet microplate assay and an in vitro tooth model using saliva-coated hydroxyapatite discs...
2017: Frontiers in Microbiology
Ryuta Uraki, Jesse Hwang, Kellie Ann Jurado, Sarah Householder, Laura J Yockey, Andrew K Hastings, Robert J Homer, Akiko Iwasaki, Erol Fikrig
Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that has recently been found to cause fetal infection and neonatal abnormalities, including microcephaly and neurological dysfunction. ZIKV persists in the semen months after the acute viremic phase in humans. To further understand the consequences of ZIKV persistence in males, we infected Ifnar1(-/-) mice via subcutaneous injection of a pathogenic but nonlethal ZIKV strain. ZIKV replication persists within the testes even after clearance from the blood, with interstitial, testosterone-producing Leydig cells supporting virus replication...
February 2017: Science Advances
Dana K Shaw, Xiaowei Wang, Lindsey J Brown, Adela S Oliva Chávez, Kathryn E Reif, Alexis A Smith, Alison J Scott, Erin E McClure, Vishant M Boradia, Holly L Hammond, Eric J Sundberg, Greg A Snyder, Lei Liu, Kathleen DePonte, Margarita Villar, Massaro W Ueti, José de la Fuente, Robert K Ernst, Utpal Pal, Erol Fikrig, Joao H F Pedra
The insect immune deficiency (IMD) pathway resembles the tumour necrosis factor receptor network in mammals and senses diaminopimelic-type peptidoglycans present in Gram-negative bacteria. Whether unidentified chemical moieties activate the IMD signalling cascade remains unknown. Here, we show that infection-derived lipids 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPG) and 1-palmitoyl-2-oleoyl diacylglycerol (PODAG) stimulate the IMD pathway of ticks. The tick IMD network protects against colonization by three distinct bacteria, that is the Lyme disease spirochete Borrelia burgdorferi and the rickettsial agents Anaplasma phagocytophilum and A...
February 14, 2017: Nature Communications
Yani Hu, Kaitlin O'Boyle, Jim Auer, Sagar Raju, Fuping You, Penghua Wang, Erol Fikrig, Richard E Sutton
UBXN proteins likely participate in the global regulation of protein turnover, and we have shown that UBXN1 interferes with RIG-I-like receptor (RLR) signaling by interacting with MAVS and impeding its downstream effector functions. Here we demonstrate that over-expression of multiple UBXN family members decreased lentivirus and retrovirus production by several orders-of-magnitude in single cycle assays, at the level of long terminal repeat-driven transcription, and three family members, UBXN1, N9, and N11 blocked the canonical NFκB pathway by binding to Cullin1 (Cul1), inhibiting IκBα degradation...
February 2017: PLoS Pathogens
Nabil M Abraham, Lei Liu, Brandon Lyon Jutras, Akhilesh K Yadav, Sukanya Narasimhan, Vissagan Gopalakrishnan, Juliana M Ansari, Kimberly K Jefferson, Felipe Cava, Christine Jacobs-Wagner, Erol Fikrig
Arthropods transmit diverse infectious agents; however, the ways microbes influence their vector to enhance colonization are poorly understood. Ixodes scapularis ticks harbor numerous human pathogens, including Anaplasma phagocytophilum, the agent of human granulocytic anaplasmosis. We now demonstrate that A. phagocytophilum modifies the I. scapularis microbiota to more efficiently infect the tick. A. phagocytophilum induces ticks to express Ixodes scapularis antifreeze glycoprotein (iafgp), which encodes a protein with several properties, including the ability to alter bacterial biofilm formation...
January 31, 2017: Proceedings of the National Academy of Sciences of the United States of America
Kara Fikrig, Brian J Johnson, Durland Fish, Scott A Ritchie
BACKGROUND: The viruses transmitted by Aedes aegypti, including dengue and Zika viruses, are rapidly expanding in geographic range and as a threat to public health. In response, control programs are increasingly turning to the use of sterile insect techniques resulting in a need to trap male Ae. aegypti to monitor the efficacy of the intervention. However, there is a lack of effective and cheap methods for trapping males. Thus, we attempted to exploit the physiological need to obtain energy from sugar feeding in order to passively capture male and female Ae...
January 17, 2017: Parasites & Vectors
Michael K Simoni, Kellie Ann Jurado, Vikki M Abrahams, Erol Fikrig, Seth Guller
Recent studies have linked antenatal infection with Zika virus (ZIKV) with major adverse fetal and neonatal outcomes, including microcephaly. There is a growing consensus for the existence of a congenital Zika syndrome (CZS). Previous studies have indicated that non-placental macrophages play a key role in the replication of dengue virus (DENV), a closely related flavivirus. As the placenta provides the conduit for vertical transmission of certain viruses, and placental Hofbauer cells (HBCs) are fetal-placental macrophages located adjacent to fetal capillaries, it is not surprising that several recent studies have examined infection of HBCs by ZIKV...
February 2017: American Journal of Reproductive Immunology: AJRI
Amber M Paul, Dhiraj Acharya, Linda Le, Penghua Wang, Dobrivoje S Stokic, A Arturo Leis, Lena Alexopoulou, Terrence Town, Richard A Flavell, Erol Fikrig, Fengwei Bai
West Nile virus (WNV) is a neurotropic ssRNA flavivirus that can cause encephalitis, meningitis, and death in humans and mice. Human TLR7 and TLR8 and mouse TLR7 recognize viral ssRNA motifs and induce antiviral immunity. However, the role of mouse TLR8 in antiviral immunity is poorly understood. In this article, we report that TLR8-deficient (Tlr8(-/-)) mice were resistant to WNV infection compared with wild-type controls. Efficient WNV clearance and moderate susceptibility to WNV-mediated neuronal death in Tlr8(-/-) mice were attributed to overexpression of Tlr7 and IFN-stimulated gene-56 expression, whereas reduced expression of the proapoptotic gene coding Bcl2-associated X protein was observed...
December 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Dhiraj Acharya, Penghua Wang, Amber M Paul, Jianfeng Dai, David Gate, Jordan E Lowery, Dobrivoje S Stokic, A Arturo Leis, Richard A Flavell, Terrence Town, Erol Fikrig, Fengwei Bai
CD8(+) T cells are crucial components of immunity and play a vital role in recovery from West Nile virus (WNV) infection. Here, we identify a previously unrecognized function of interleukin-17A (IL-17A) in inducing cytotoxic-mediator gene expression and promoting CD8(+) T cell cytotoxicity against WNV infection in mice. We find that IL-17A-deficient (Il17a(-/-)) mice are more susceptible to WNV infection and develop a higher viral burden than wild-type (WT) mice. Interestingly, the CD8(+) T cells isolated from Il17a(-/-) mice are less cytotoxic and express lower levels of cytotoxic-mediator genes, which can be restored by supplying recombinant IL-17A in vitro and in vivo Importantly, treatment of WNV-infected mice with recombinant IL-17A, as late as day 6 postinfection, significantly reduces the viral burden and increases survival, suggesting a therapeutic potential for IL-17A...
January 1, 2017: Journal of Virology
Michael J Conway, Berlin Londono-Renteria, Andrea Troupin, Alan M Watson, William B Klimstra, Erol Fikrig, Tonya M Colpitts
Aedes aegypti is the primary vector of several medically relevant arboviruses including dengue virus (DENV) types 1-4. Ae. aegypti transmits DENV by inoculating virus-infected saliva into host skin during probing and feeding. Ae. aegypti saliva contains over one hundred unique proteins and these proteins have diverse functions, including facilitating blood feeding. Previously, we showed that Ae. aegypti salivary gland extracts (SGEs) enhanced dissemination of DENV to draining lymph nodes. In contrast, HPLC-fractionation revealed that some SGE components inhibited infection...
September 2016: PLoS Neglected Tropical Diseases
Kellie Ann Jurado, Michael K Simoni, Zhonghua Tang, Ryuta Uraki, Jesse Hwang, Sarah Householder, Mingjie Wu, Brett D Lindenbach, Vikki M Abrahams, Seth Guller, Erol Fikrig
The strong association of Zika virus infection with congenital defects has led to questions of how a flavivirus is capable of crossing the placental barrier to reach the fetal brain. Here, we demonstrate permissive Zika virus infection of primary human placental macrophages, commonly referred to as Hofbauer cells, and placental villous fibroblasts. We also demonstrate Zika virus infection of Hofbauer cells within the context of the tissue ex vivo using term placental villous explants. In addition to amplifying infectious virus within a usually inaccessible area, the putative migratory activities of Hofbauer cells may aid in dissemination of Zika virus to the fetal brain...
August 18, 2016: JCI Insight
Laila Heringer, Brian J Johnson, Kara Fikrig, Bruna A Oliveira, Richard D Silva, Michael Townsend, Roberto Barrera, Álvaro E Eiras, Scott A Ritchie
The Gravid Aedes Trap (GAT) uses visual and olfactory cues to attract gravid Aedes aegypti (L.) that are then captured when knocked down by a residual pyrethroid surface spray. However, the use of surface sprays can be compromised by poor availability of the spray and pesticide resistance in the target mosquito. We investigated several "alternative" insecticide and insecticide-free killing agents for use in the GAT. This included long-lasting insecticide-impregnated nets (LLINs), vapor-active synthetic pyrethroids (metofluthrin), canola oil, and two types of dry adhesive sticky card...
July 2016: Journal of Medical Entomology
Andrea Troupin, Berlin Londono-Renteria, Michael J Conway, Erin Cloherty, Samuel Jameson, Stephen Higgs, Dana L Vanlandingham, Erol Fikrig, Tonya M Colpitts
BACKGROUND: Dengue virus (DENV) is a mosquito-borne flavivirus that causes significant human disease and mortality in the tropics and subtropics. By examining the effects of virus infection on gene expression, and interactions between virus and vector, new targets for prevention of infection and novel treatments may be identified in mosquitoes. We previously performed a microarray analysis of the Aedes aegypti transcriptome during infection with DENV and found that mosquito ubiquitin protein Ub3881 (AAEL003881) was specifically and highly down-regulated...
September 2016: Biochimica et Biophysica Acta
Jesse Hwang, Kellie Ann Jurado, Erol Fikrig
Arboviruses have made unexpected reappearances in recent years. Unlike viruses that undergo direct transmission, arboviruses utilize an arthropod vector (e.g., mosquitos, sandflies, and ticks) to spread throughout human populations. Here, we provide a snapshot of mosquito susceptibility to viral infection using flaviviruses, alphaviruses, and bunyaviruses as examples of emerging pathogens of global health relevance.
May 11, 2016: Cell Host & Microbe
Alex Wagemakers, Joris Koetsveld, Sukanya Narasimhan, Melvin Wickel, Kathleen Deponte, Boris Bleijlevens, Seta Jahfari, Hein Sprong, Lyudmila S Karan, Denis S Sarksyan, Tom van der Poll, Linda K Bockenstedt, Adriaan D Bins, Alexander E Platonov, Erol Fikrig, Joppe W Hovius
Borrelia miyamotoi is a relapsing fever spirochete in Ixodes ticks that has been recently identified as a human pathogen causing hard tick-borne relapsing fever (HTBRF) across the Northern Hemisphere. No validated serologic test exists, and current serologic assays have low sensitivity in early HTBRF. To examine the humoral immune response against B. miyamotoi, we infected C3H/HeN mice with B. miyamotoi strain LB-2001 expressing variable small protein 1 (Vsp1) and demonstrated that spirochetemia was cleared after 3 d, coinciding with anti-Vsp1 IgM production...
May 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Jeroen Coumou, Sukanya Narasimhan, Jos J Trentelman, Alex Wagemakers, Joris Koetsveld, Jasmin I Ersoz, Anneke Oei, Erol Fikrig, Joppe W Hovius
The causative agent of Lyme borreliosis, Borrelia burgdorferi, is transmitted by Ixodes ticks. During tick feeding, B. burgdorferi migrates from the tick gut to the salivary glands from where transmission to the host occurs. B. burgdorferi-interacting tick proteins might serve as vaccine targets to thwart B. burgdorferi transmission. A previous screening for B. burgdorferi-interacting Ixodes scapularis gut proteins identified an I. scapularis putative dystroglycan protein (ISCW015049). Here, we describe the ISCW015049's protein structure and its cellular location in the tick gut in relation to B...
March 2016: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
Penghua Wang, Shu Zhu, Long Yang, Shuang Cui, Wen Pan, Ruaidhri Jackson, Yunjiang Zheng, Anthony Rongvaux, Qiangming Sun, Guang Yang, Shandian Gao, Rongtuan Lin, Fuping You, Richard Flavell, Erol Fikrig
The nucleotide-binding oligomerization domain-like receptor (Nlrp) 6 maintains gut microbiota homeostasis and regulates antibacterial immunity. We now report a role for Nlrp6 in the control of enteric virus infection. Nlrp6(-/-) and control mice systemically challenged with encephalomyocarditis virus had similar mortality; however, the gastrointestinal tract of Nlrp6(-/-) mice exhibited increased viral loads. Nlrp6(-/-) mice orally infected with encephalomyocarditis virus had increased mortality and viremia compared with controls...
November 13, 2015: Science
Berlin Londono-Renteria, Andrea Troupin, Michael J Conway, Diana Vesely, Michael Ledizet, Christopher M Roundy, Erin Cloherty, Samuel Jameson, Dana Vanlandingham, Stephen Higgs, Erol Fikrig, Tonya M Colpitts
Dengue virus (DENV) is a mosquito-borne flavivirus that causes serious human disease and mortality worldwide. There is no specific antiviral therapy or vaccine for DENV infection. Alterations in gene expression during DENV infection of the mosquito and the impact of these changes on virus infection are important events to investigate in hopes of creating new treatments and vaccines. We previously identified 203 genes that were ≥5-fold differentially upregulated during flavivirus infection of the mosquito...
October 2015: PLoS Pathogens
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