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Ross River virus (RRV) is a mosquito-borne zoonotic arbovirus associated with high public health and economic burdens across Australia, but particularly in South East Queensland (SEQ). Despite this high burden, humans are considered incidental hosts. Transmission of RRV is maintained among mosquitoes and many nonhuman vertebrate reservoir hosts, although the relative contributions of each of these hosts are unclear. To clarify the importance of a range of vertebrates in RRV transmission in SEQ, a total of 595 serum samples from 31 species were examined for RRV exposure using a gold-standard plaque reduction neutralization test. Data were analyzed statistically using generalized linear models and a coefficient inference tree, and spatially. RRV exposure was highly variable between and within species groups. Critically, species group (“placental mammal,” “marsupial,” and “bird”), which has previously been used as a proxy for reservoir hosts, was a poor correlate for exposure. Instead, we found that generalized “diet” and greater “body mass” were most strongly correlated with seropositivity. We also identified significant differences in seropositivity between the two major possum species (ringtail possums and brushtail possums), which are ecologically and taxonomically different. Finally, we identified distinct hotspots and coldspots of seropositivity in nonhuman vertebrates, which correlated with human notification data. This is the largest diversity of species tested for RRV in a single study to date. The analysis methods within this study provide a framework for analyzing serological data in combination with species traits for other zoonotic disease, but more specifically for RRV highlight areas to target further public health research and surveillance effort.
Eloise B. Skinner; Penny A. Rudd; Alison J. Peel; Hamish McCallum; Simon A. Reid; Lara J. Herrero. Species Traits and Hotspots Associated with Ross River Virus Infection in Nonhuman Vertebrates in South East Queensland. Vector-Borne and Zoonotic Diseases 2021, 21, 50 -58.
AMA StyleEloise B. Skinner, Penny A. Rudd, Alison J. Peel, Hamish McCallum, Simon A. Reid, Lara J. Herrero. Species Traits and Hotspots Associated with Ross River Virus Infection in Nonhuman Vertebrates in South East Queensland. Vector-Borne and Zoonotic Diseases. 2021; 21 (1):50-58.
Chicago/Turabian StyleEloise B. Skinner; Penny A. Rudd; Alison J. Peel; Hamish McCallum; Simon A. Reid; Lara J. Herrero. 2021. "Species Traits and Hotspots Associated with Ross River Virus Infection in Nonhuman Vertebrates in South East Queensland." Vector-Borne and Zoonotic Diseases 21, no. 1: 50-58.
Over the last decade, an arbovirus surveillance system based on the preservation of nucleic acids (RNA/DNA) has been developed using Flinders Technology Associates (FTA®) cards. Soaked in honey, FTA® cards are applied in the field to detect arboviruses excreted during mosquito sugar feeding. This technique has been shown to be inexpensive and efficient, and the implementation of this system for detecting parasites could be of international importance. As Leishmania parasites are highly prevalent in developing countries, FTA® cards may offer an alternative inexpensive tool to enhance field surveillance activities for leishmaniasis. Not only will the simple approach of applying the cards in programs substitute the necessary extensive training of personnel, it can preclude the need to screen large samples and analysis of insect populations to provide evidence of disease transmission. In our hands, Leishmania macropodum DNA was shown to be stable on FTA® cards during a 10-week time course, supporting their suitability for projects where direct access to laboratories is unobtainable and samples require storage prior to processing. This may benefit programs in remote areas where accessibility to laboratory facilities are limited and samples need to be stored long-term. Overall, this study found that FTA® cards are a valuable tool in the surveillance of leishmaniasis. Download : Download high-res image (139KB)Download : Download full-size image
Elina Panahi; Martin Shivas; Sonja Hall-Mendelin; Nina Kurucz; Penny A. Rudd; Rachel De Araujo; Eloise B. Skinner; Lorna Melville; Lara J. Herrero. Utilising a novel surveillance system to enhance field screening activities for the leishmaniases. MethodsX 2020, 7, 101156 .
AMA StyleElina Panahi, Martin Shivas, Sonja Hall-Mendelin, Nina Kurucz, Penny A. Rudd, Rachel De Araujo, Eloise B. Skinner, Lorna Melville, Lara J. Herrero. Utilising a novel surveillance system to enhance field screening activities for the leishmaniases. MethodsX. 2020; 7 ():101156.
Chicago/Turabian StyleElina Panahi; Martin Shivas; Sonja Hall-Mendelin; Nina Kurucz; Penny A. Rudd; Rachel De Araujo; Eloise B. Skinner; Lorna Melville; Lara J. Herrero. 2020. "Utilising a novel surveillance system to enhance field screening activities for the leishmaniases." MethodsX 7, no. : 101156.
Changes to Australia’s climate and land-use patterns could result in expanded spatial and temporal distributions of endemic mosquito vectors including Aedes and Culex species that transmit medically important arboviruses. Climate and land-use changes greatly influence the suitability of habitats for mosquitoes and their behaviors such as mating, feeding and oviposition. Changes in these behaviors in turn determine future species-specific mosquito diversity, distribution and abundance. In this review, we discuss climate and land-use change factors that influence shifts in mosquito distribution ranges. We also discuss the predictive and epidemiological merits of incorporating these factors into a novel integrated statistical (SSDM) and mechanistic species distribution modelling (MSDM) framework. One potentially significant merit of integrated modelling is an improvement in the future surveillance and control of medically relevant endemic mosquito vectors such as Aedes vigilax and Culex annulirostris, implicated in the transmission of many arboviruses such as Ross River virus and Barmah Forest virus, and exotic mosquito vectors such as Aedes aegypti and Aedes albopictus. We conducted a focused literature search to explore the merits of integrating SSDMs and MSDMs with biotic and environmental variables to better predict the future range of endemic mosquito vectors. We show that an integrated framework utilising both SSDMs and MSDMs can improve future mosquito-vector species distribution projections in Australia. We recommend consideration of climate and environmental change projections in the process of developing land-use plans as this directly impacts mosquito-vector distribution and larvae abundance. We also urge laboratory, field-based researchers and modellers to combine these modelling approaches. Having many different variations of integrated (SDM) modelling frameworks could help to enhance the management of endemic mosquitoes in Australia. Enhanced mosquito management measures could in turn lead to lower arbovirus spread and disease notification rates.
Eugene T. Madzokere; Willow Hallgren; Oz Sahin; Julie A. Webster; Cameron E. Webb; Brendan Mackey; Lara J. Herrero. Integrating statistical and mechanistic approaches with biotic and environmental variables improves model predictions of the impact of climate and land-use changes on future mosquito-vector abundance, diversity and distributions in Australia. Parasites & Vectors 2020, 13, 1 -13.
AMA StyleEugene T. Madzokere, Willow Hallgren, Oz Sahin, Julie A. Webster, Cameron E. Webb, Brendan Mackey, Lara J. Herrero. Integrating statistical and mechanistic approaches with biotic and environmental variables improves model predictions of the impact of climate and land-use changes on future mosquito-vector abundance, diversity and distributions in Australia. Parasites & Vectors. 2020; 13 (1):1-13.
Chicago/Turabian StyleEugene T. Madzokere; Willow Hallgren; Oz Sahin; Julie A. Webster; Cameron E. Webb; Brendan Mackey; Lara J. Herrero. 2020. "Integrating statistical and mechanistic approaches with biotic and environmental variables improves model predictions of the impact of climate and land-use changes on future mosquito-vector abundance, diversity and distributions in Australia." Parasites & Vectors 13, no. 1: 1-13.
Up until recently, Australia was considered free of Leishmania due to the absence of phlebotomine sandfly species (Diptera: Phlebotominae) known to transmit Leishmania parasites in other parts of the world. The discovery of Leishmania (Mundinia) macropodum (Kinetoplastida: Trypanosomatidae) in Northern Australia sparked questions as to the existence of alternative vectors of Leishmania. This has added to the complexity of fully understanding the parasite's interaction with its vector, which is known to be very specific. Previous findings demonstrated L. macropodum infection beyond the blood meal stage in the day-biting midges Forcipomyia (Lasiohelea) Kieffer (Diptera: Ceratopogonidae) implicating them in the parasite's life cycle. Currently, there is no conclusive evidence demonstrating this suspected vector to transmit L. macropodum to a naïve host. Therefore, this research aimed to investigate the vector competency of day-biting midge F. (Lasiohelea) to transmit L. macropodum utilising a novel technology that preserves nucleic acids. Honey-soaked Flinders Technology Associates (FTA®) filter-paper cards were used to obtain saliva expectorated from biting midges while sugar-feeding. F. (Lasiohelea) were aspirated directly off macropods from a known Leishmania-transmission site and were kept in a waxed-paper container holding a honey-coated FTA® card for feeding. Insect identification and Taqman quantitative real-time PCR (qPCR) screening assays revealed L. macropodum DNA in F. (Lasiohelea) up to 7 days post field-collection, and in an unidentified biting midge, previously known as F. (Lasiohelea) sp.1. Moreover, 7/145 (4.83%) of FTA® cards were confirmed positive with L. macropodum DNA after exposure to field-collected F. (Lasiohelea). Additionally, FTA® cards were found to be a valuable surveillance tool, given the ease of use in the field and laboratory. Overall, our findings support previous reports on L. macropodum transmission by an alternative vector to phlebotomine sandflies. Further studies identifying and isolating infective L. macropodum promastigotes is necessary to resolve questions on the L. macropodum vector.
Elina Panahi; Martin Shivas; Sonja Hall-Mendelin; Nina Kurucz; Penny A. Rudd; Rachel De Araujo; Eloise B. Skinner; Lorna Melville; Lara J. Herrero. Utilising a novel surveillance system to investigate species of Forcipomyia (Lasiohelea) (Diptera: Ceratopogonidae) as the suspected vectors of Leishmania macropodum (Kinetoplastida: Trypanosomatidae) in the Darwin region of Australia. International Journal for Parasitology: Parasites and Wildlife 2020, 12, 192 -198.
AMA StyleElina Panahi, Martin Shivas, Sonja Hall-Mendelin, Nina Kurucz, Penny A. Rudd, Rachel De Araujo, Eloise B. Skinner, Lorna Melville, Lara J. Herrero. Utilising a novel surveillance system to investigate species of Forcipomyia (Lasiohelea) (Diptera: Ceratopogonidae) as the suspected vectors of Leishmania macropodum (Kinetoplastida: Trypanosomatidae) in the Darwin region of Australia. International Journal for Parasitology: Parasites and Wildlife. 2020; 12 ():192-198.
Chicago/Turabian StyleElina Panahi; Martin Shivas; Sonja Hall-Mendelin; Nina Kurucz; Penny A. Rudd; Rachel De Araujo; Eloise B. Skinner; Lorna Melville; Lara J. Herrero. 2020. "Utilising a novel surveillance system to investigate species of Forcipomyia (Lasiohelea) (Diptera: Ceratopogonidae) as the suspected vectors of Leishmania macropodum (Kinetoplastida: Trypanosomatidae) in the Darwin region of Australia." International Journal for Parasitology: Parasites and Wildlife 12, no. : 192-198.
Arthritogenic alphaviruses cause debilitating inflammatory disease, and current therapies are restricted to palliative approaches. Here, we show that following monocyte-driven muscle inflammation, tissue recovery is associated with the accumulation of CX 3 CR1 + macrophages in the muscle. Modulating inflammatory monocyte infiltration using immune-modifying microparticles (IMP) reduced tissue damage and inflammation and enhanced the formation of tissue repair-associated CX 3 CR1 + macrophages in the muscle. This shows that modulating key effectors of viral inflammation using microparticles can alter the outcome of disease by facilitating the accumulation of macrophage subsets associated with tissue repair.
Ali Zaid; Kothila Tharmarajah; Helen Mostafavi; Joseph R. Freitas; Kuo-Ching Sheng; Suan-Sin Foo; Weiqiang Chen; Jelena Vider; Xiang Liu; Nicholas P. West; Lara J. Herrero; Adam Taylor; Laura K. Mackay; Daniel R. Getts; Nicholas J. C. King; Suresh Mahalingam. Modulation of Monocyte-Driven Myositis in Alphavirus Infection Reveals a Role for CX 3 CR1 + Macrophages in Tissue Repair. mBio 2020, 11, 1 .
AMA StyleAli Zaid, Kothila Tharmarajah, Helen Mostafavi, Joseph R. Freitas, Kuo-Ching Sheng, Suan-Sin Foo, Weiqiang Chen, Jelena Vider, Xiang Liu, Nicholas P. West, Lara J. Herrero, Adam Taylor, Laura K. Mackay, Daniel R. Getts, Nicholas J. C. King, Suresh Mahalingam. Modulation of Monocyte-Driven Myositis in Alphavirus Infection Reveals a Role for CX 3 CR1 + Macrophages in Tissue Repair. mBio. 2020; 11 (2):1.
Chicago/Turabian StyleAli Zaid; Kothila Tharmarajah; Helen Mostafavi; Joseph R. Freitas; Kuo-Ching Sheng; Suan-Sin Foo; Weiqiang Chen; Jelena Vider; Xiang Liu; Nicholas P. West; Lara J. Herrero; Adam Taylor; Laura K. Mackay; Daniel R. Getts; Nicholas J. C. King; Suresh Mahalingam. 2020. "Modulation of Monocyte-Driven Myositis in Alphavirus Infection Reveals a Role for CX 3 CR1 + Macrophages in Tissue Repair." mBio 11, no. 2: 1.
By identifying natural Ross River virus (RRV) amino acid determinants for type I interferon (IFN) modulation, this study gives further insight into the mechanism of type I IFN modulation by alphaviruses. Here, the crucial role of type I IFN in the early stages of RRV disease pathogenesis is further demonstrated. This study also provides a comparison of the roles of different parts of the RRV nonstructural region in type I IFN modulation, highlighting the importance of nonstructural protein 1 (nsP1) and nsP2 in this process. Three substitutions in nsP1 and nsP2 were found to be independently associated with enhanced type I IFN sensitivity, and four independent substitutions in nsP2 were important in elevated type I IFN induction. Such evidence has clear implications for RRV immunobiology, persistence, and pathology. The identification of viral proteins that modulate type I IFN may also have importance for the pathogenesis of other alphaviruses.
Xiang Liu; Margit Mutso; Liubov Cherkashchenko; Eva Zusinaite; Lara J. Herrero; Stephen L. Doggett; John Haniotis; Andres Merits; Belinda L. Herring; Adam Taylor; Suresh Mahalingam. Identification of Natural Molecular Determinants of Ross River Virus Type I Interferon Modulation. Journal of Virology 2020, 94, 1 .
AMA StyleXiang Liu, Margit Mutso, Liubov Cherkashchenko, Eva Zusinaite, Lara J. Herrero, Stephen L. Doggett, John Haniotis, Andres Merits, Belinda L. Herring, Adam Taylor, Suresh Mahalingam. Identification of Natural Molecular Determinants of Ross River Virus Type I Interferon Modulation. Journal of Virology. 2020; 94 (8):1.
Chicago/Turabian StyleXiang Liu; Margit Mutso; Liubov Cherkashchenko; Eva Zusinaite; Lara J. Herrero; Stephen L. Doggett; John Haniotis; Andres Merits; Belinda L. Herring; Adam Taylor; Suresh Mahalingam. 2020. "Identification of Natural Molecular Determinants of Ross River Virus Type I Interferon Modulation." Journal of Virology 94, no. 8: 1.
Recently the anti-viral effects of prophylactic treatment with the low-molecular-weight heparan sulfate mimetic PG545 in Ross River virus (RRV) infected mice were reported. We further investigated the related, transient pathophysiology of PG545 drug treatment in RRV-infected and mock-infected PG545-treated mice. PG545 treatment resulted in mild lethargy and piloerection, on days after the drug administration. Mice were treated with two or three doses of PG545 within a ten-day period and were subsequently culled at peak disease or at disease resolution. The treatment responses of the spleen and liver were assessed through histology, flow cytometry, gene arrays and serum biochemistry. Microscopy showed an expanded red pulp in the spleen following either two or three treatments with PG545. The red pulp expansion was further demonstrated by the proliferation of megakaryocytes and erythrocyte precursors within the spleen. In addition, flow cytometry and gene array analyses revealed a reduction of lymphocytes within the spleens of PG545-treated mice. Previously unreported, RRV-induced elevations of aspartate aminotransferase (AST) and alanine transaminase (ALT) enzymes and creatinine were also noted in the RRV-infected mice. However, PG545 only reduced AST and ALT levels but not the creatinine levels in infected mice during treatment. Mice treated with three doses of PG545 also showed hepatosplenomegaly and anaemia, which were reversed upon discontinuation of the treatment. In summary, this study demonstrates that dose and frequency related haemopoietic pathophysiology such as hepatosplenomegaly and anaemia, occurred in C57BL/6 mice treated with PG545. However, this effect was reversible once drug administration is terminated.
Aroon Supramaniam; Helle Bielefeldt-Ohmann; Penny A. Rudd; Julie Webster; Vito Ferro; Lara J. Herrero. PG545 treatment reduces RRV-induced elevations of AST, ALT with secondary lymphoid organ alterations in C57BL/6 mice. PLOS ONE 2019, 14, e0217998 .
AMA StyleAroon Supramaniam, Helle Bielefeldt-Ohmann, Penny A. Rudd, Julie Webster, Vito Ferro, Lara J. Herrero. PG545 treatment reduces RRV-induced elevations of AST, ALT with secondary lymphoid organ alterations in C57BL/6 mice. PLOS ONE. 2019; 14 (6):e0217998.
Chicago/Turabian StyleAroon Supramaniam; Helle Bielefeldt-Ohmann; Penny A. Rudd; Julie Webster; Vito Ferro; Lara J. Herrero. 2019. "PG545 treatment reduces RRV-induced elevations of AST, ALT with secondary lymphoid organ alterations in C57BL/6 mice." PLOS ONE 14, no. 6: e0217998.
Mosquito-borne diseases are associated with major global health burdens. Aedes spp. and Culex spp. are primarily responsible for the transmission of the most medically important mosquito-borne viruses, including dengue virus, West Nile virus and Zika virus. Despite the burden of these pathogens on human populations, the interactions between viruses and their mosquito hosts remain enigmatic. Viruses enter the midgut of a mosquito following the mosquito’s ingestion of a viremic blood meal. During infection, virus recognition by the mosquito host triggers their antiviral defense mechanism. Of these host defenses, activation of the RNAi pathway is the main antiviral mechanism, leading to the degradation of viral RNA, thereby inhibiting viral replication and promoting viral clearance. However, whilst antiviral host defense mechanisms limit viral replication, the mosquito immune system is unable to effectively clear the virus. As such, these viruses can establish persistent infection with little or no fitness cost to the mosquito vector, ensuring life-long transmission to humans. Understanding of the mosquito innate immune response enables the discovery of novel antivectorial strategies to block human transmission. This review provides an updated and concise summary of recent studies on mosquito antiviral immune responses, which is a key determinant for successful virus transmission. In addition, we will also discuss the factors that may contribute to persistent infection in mosquito hosts. Finally, we will discuss current mosquito transmission-blocking strategies that utilize genetically modified mosquitoes and Wolbachia-infected mosquitoes for resistance to pathogens.
Wai-Suet Lee; Julie A. Webster; Eugene T. Madzokere; Eloise B. Stephenson; Lara J. Herrero. Mosquito antiviral defense mechanisms: a delicate balance between innate immunity and persistent viral infection. Parasites & Vectors 2019, 12, 1 -12.
AMA StyleWai-Suet Lee, Julie A. Webster, Eugene T. Madzokere, Eloise B. Stephenson, Lara J. Herrero. Mosquito antiviral defense mechanisms: a delicate balance between innate immunity and persistent viral infection. Parasites & Vectors. 2019; 12 (1):1-12.
Chicago/Turabian StyleWai-Suet Lee; Julie A. Webster; Eugene T. Madzokere; Eloise B. Stephenson; Lara J. Herrero. 2019. "Mosquito antiviral defense mechanisms: a delicate balance between innate immunity and persistent viral infection." Parasites & Vectors 12, no. 1: 1-12.
Objective Arthritogenic alphaviruses, such as Ross River virus (RRV), chikungunya virus (CHIKV), Sindbis virus (SINV), Barmah Forest virus, o'nyong‐nyong virus and Mayaro virus cause sporadic and sometimes large outbreaks worldwide. These viruses particularly affect joints of the extremities and can lead to debilitating and potentially chronic polyarthritis/polyarthralgia. The host's innate immune response plays a crucial role in inducing pro‐inflammatory host factors, leading to tissue destruction and bone loss in the joints. This study tested the effect of inhibiting IL‐1 β signaling using the clinical RA drug anakinra on bone loss during arthritogenic alphavirus infections. Methods Mice were infected with RRV or CHIKV and treated with anakinra. Weight gain and disease score was measured, tissue viral titers were determined, and histological changes in joint tissues were assessed. Results Anakinra reduced RRV‐ and CHIKV‐induced bone loss in the mouse model. In histological analysis of the knee joint, treatment with anakinra decreased epiphyseal growth plate thinning, the loss of epiphyseal bone volume and osteoclastogenesis in the tibia. Importantly, pharmacologic IL‐1 receptor blockade did not enhance other clinical signs including disease score, weight loss or viremia. Conclusion The present experimental data suggest consideration of the further testing of anakinra for patients with arthritogenic alphavirus disease. This article is protected by copyright. All rights reserved.
Stefan Wolf; Adam Taylor; Ali Zaid; Joseph Freitas; Lara J. Herrero; Shambhavi Rao; Andreas Suhrbier; Mark R. Forwood; Richard Bucala; Suresh Mahalingam. Inhibition of Interleukin‐1β Signaling by Anakinra Demonstrates a Critical Role of Bone Loss in Experimental Arthritogenic Alphavirus Infections. Arthritis & Rheumatology 2019, 71, 1185 -1190.
AMA StyleStefan Wolf, Adam Taylor, Ali Zaid, Joseph Freitas, Lara J. Herrero, Shambhavi Rao, Andreas Suhrbier, Mark R. Forwood, Richard Bucala, Suresh Mahalingam. Inhibition of Interleukin‐1β Signaling by Anakinra Demonstrates a Critical Role of Bone Loss in Experimental Arthritogenic Alphavirus Infections. Arthritis & Rheumatology. 2019; 71 (7):1185-1190.
Chicago/Turabian StyleStefan Wolf; Adam Taylor; Ali Zaid; Joseph Freitas; Lara J. Herrero; Shambhavi Rao; Andreas Suhrbier; Mark R. Forwood; Richard Bucala; Suresh Mahalingam. 2019. "Inhibition of Interleukin‐1β Signaling by Anakinra Demonstrates a Critical Role of Bone Loss in Experimental Arthritogenic Alphavirus Infections." Arthritis & Rheumatology 71, no. 7: 1185-1190.
Infection with Ross River virus (RRV) causes debilitating polyarthritis and arthralgia in individuals. Alphaviruses are highly sensitive to type I interferon (IFN). Mutations at the conserved P3 position of the cleavage site between nonstructural protein 1 (nsP1) and nsP2 (1/2 site) modulate type I IFN induction for both RRV and Sindbis virus (SINV). We constructed and characterized RRV-T48 A534V , a mutant harboring an A534V substitution in the P1 position of the 1/2 site, and compared it to parental RRV-T48 and to RRV-T48 A532V , SINV I538 and SINV T538 harboring different substitutions in the same region. A534V substitution resulted in impaired processing of RRV nonstructural polyprotein and in elevated production of replicase-generated pathogen-associated molecular pattern (PAMP) RNAs that induce expression of type I IFN. Both A532V and A534V substitutions affected synthesis of viral RNAs, though the effects of these closely located mutations were drastically different affecting mostly either the viral negative-strand RNA or genomic and subgenomic RNA levels, respectively. Synthesis of PAMP RNAs was also observed for SINV replicase, and it was increased by I538T substitution. In comparison to RRV-T48, RRV-T48 A534V was attenuated in vitro and in vivo . Interestingly, when type I IFN-deficient cells and type I IFN receptor-deficient mice were infected with RRV-T48 or RRV-T48 A534V , differences between these viruses were no longer apparent. Compared to RRV-T48, RRV-T48 A534V infection was associated with increased upregulation of type I IFN signaling proteins. We demonstrate novel mechanisms by which the A534V mutation affect viral nonstructural polyprotein processing that can impact PAMP RNA production, type I IFN induction/sensitivity, and disease. IMPORTANCE This study gives further insight into mechanisms of type I IFN modulation by the medically important alphaviruses Ross River virus (RRV) and Sindbis virus (SINV). By characterizing attenuated RRV mutants, the crucial role of amino acid residues in P1 and P3 positions (the first and third amino acid residues preceding the scissile bond) of the cleavage site between nsP1 and nsP2 regions was highlighted. The study uncovers a unique relationship between alphavirus nonstructural polyprotein processing, RNA replication, production of different types of pathogen-associated molecular pattern (PAMP) RNAs, type I IFN induction, and disease pathogenesis. This study also highlights the importance of the host innate immune response in RRV infections. The viral determinants of type I IFN modulation provide potential drug targets for clinical treatment of alphaviral disease and offer new approaches for rational attenuation of alphaviruses for construction of vaccine candidates.
Xiang Liu; Margit Mutso; Age Utt; Anni Lepland; Lara J. Herrero; Adam Taylor; Jayaram Bettadapura; Penny A. Rudd; Andres Merits; Suresh Mahalingam. Decreased Virulence of Ross River Virus Harboring a Mutation in the First Cleavage Site of Nonstructural Polyprotein Is Caused by a Novel Mechanism Leading to Increased Production of Interferon-Inducing RNAs. mBio 2018, 9, e00044-18 .
AMA StyleXiang Liu, Margit Mutso, Age Utt, Anni Lepland, Lara J. Herrero, Adam Taylor, Jayaram Bettadapura, Penny A. Rudd, Andres Merits, Suresh Mahalingam. Decreased Virulence of Ross River Virus Harboring a Mutation in the First Cleavage Site of Nonstructural Polyprotein Is Caused by a Novel Mechanism Leading to Increased Production of Interferon-Inducing RNAs. mBio. 2018; 9 (4):e00044-18.
Chicago/Turabian StyleXiang Liu; Margit Mutso; Age Utt; Anni Lepland; Lara J. Herrero; Adam Taylor; Jayaram Bettadapura; Penny A. Rudd; Andres Merits; Suresh Mahalingam. 2018. "Decreased Virulence of Ross River Virus Harboring a Mutation in the First Cleavage Site of Nonstructural Polyprotein Is Caused by a Novel Mechanism Leading to Increased Production of Interferon-Inducing RNAs." mBio 9, no. 4: e00044-18.
Aroon Supramaniam; Hayman Lui; Bernadette M. Bellette; Penny A. Rudd; Lara J. Herrero. How myeloid cells contribute to the pathogenesis of prominent emerging zoonotic diseases. Journal of General Virology 2018, 99, 953 -969.
AMA StyleAroon Supramaniam, Hayman Lui, Bernadette M. Bellette, Penny A. Rudd, Lara J. Herrero. How myeloid cells contribute to the pathogenesis of prominent emerging zoonotic diseases. Journal of General Virology. 2018; 99 (8):953-969.
Chicago/Turabian StyleAroon Supramaniam; Hayman Lui; Bernadette M. Bellette; Penny A. Rudd; Lara J. Herrero. 2018. "How myeloid cells contribute to the pathogenesis of prominent emerging zoonotic diseases." Journal of General Virology 99, no. 8: 953-969.
Recently we reported on the efficacy of pentosan polysulfate (PPS), a heparan sulfate mimetic, to reduce the recruitment of inflammatory infiltrates and protect the cartilage matrix from degradation in Ross River virus (RRV)-infected PPS-treated mice. Here, we describe both prophylactic and therapeutic treatment with PG545, a low-molecular-weight heparan sulfate mimetic, for arthritogenic alphaviral infection. We first assessed antiviral activity in vitro through a 50% plaque reduction assay. Increasing concentrations of PG545 inhibited plaque formation prior to viral adsorption in viral strains RRV T48, Barmah Forest virus 2193, East/Central/South African chikungunya virus (CHIKV), and Asian CHIKV, suggesting a strong antiviral mode of action. The viral particle-compound dissociation constant was then evaluated through isothermal titration calorimetry. Furthermore, prophylactic RRV-infected PG545-treated mice had reduced viral titers in target organs corresponding to lower clinical scores of limb weakness and immune infiltrate recruitment. At peak disease, PG545-treated RRV-infected mice had lower concentrations of the matrix-degrading enzyme heparanase in conjunction with a protective effect on tissue morphology, as seen in the histopathology of skeletal muscle. Enzyme-linked immunosorbent assay quantification of cartilage oligomeric matrix protein and cross-linked C-telopeptides of type II collagen as well as knee histopathology showed increased matrix protein degradation and cartilage erosion in RRV-infected phosphate-buffered saline-treated mice compared to their PG545-treated RRV-infected counterparts. Taken together, these findings suggest that PG545 has a direct antiviral effect on arthritogenic alphaviral infection and curtails RRV-induced inflammatory disease when administered as a prophylaxis.
Aroon Supramaniam; Xiang Liu; Vito Ferro; Lara J. Herrero. Prophylactic Antiheparanase Activity by PG545 Is Antiviral In Vitro and Protects against Ross River Virus Disease in Mice. Antimicrobial Agents and Chemotherapy 2018, 62, 1 .
AMA StyleAroon Supramaniam, Xiang Liu, Vito Ferro, Lara J. Herrero. Prophylactic Antiheparanase Activity by PG545 Is Antiviral In Vitro and Protects against Ross River Virus Disease in Mice. Antimicrobial Agents and Chemotherapy. 2018; 62 (4):1.
Chicago/Turabian StyleAroon Supramaniam; Xiang Liu; Vito Ferro; Lara J. Herrero. 2018. "Prophylactic Antiheparanase Activity by PG545 Is Antiviral In Vitro and Protects against Ross River Virus Disease in Mice." Antimicrobial Agents and Chemotherapy 62, no. 4: 1.
Arthritogenic alphavirus infections often result in debilitating musculoskeletal disorders that affect the joints, muscle, and bone. In order to evaluate the infection profile of primary human skeletal muscle and chondrocyte cells to Ross River virus (RRV) in vitro, cells were infected at a multiplicity of infection (MOI) of 1 over a period of two days. Viral titers were determined by plaque assay and cytokine expression by Bio-Plex® assays using the supernatants harvested. Gene expression studies were conducted using total RNA isolated from cells. Firstly, we show that RRV RNA is detected in chondrocytes from infected mice in vivo. Both human primary skeletal muscle and chondrocyte cells are able to support productive RRV infection in vitro. We also report the production of soluble host factors including the upregulation of heparanase (HPSE) and inflammatory host factors such as interleukin-6 (IL-6), monocyte chemoattractant protein 1 (MCP-1), RANTES (regulated on activation, normal T cell expressed and secreted), interferon gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α), which are also present during clinical disease in humans. Our study is the first to demonstrate that human chondrocyte cells are permissive to RRV infection, support the production of infectious virus, and produce soluble factors including HPSE, which may contribute to joint degradation and the pathogenesis of disease.
Elisa X. Y. Lim; Aroon Supramaniam; Hayman Lui; Peta Coles; Wai Suet Lee; Xiang Liu; Penny A. Rudd; Lara J. Herrero. Chondrocytes Contribute to Alphaviral Disease Pathogenesis as a Source of Virus Replication and Soluble Factor Production. Viruses 2018, 10, 86 .
AMA StyleElisa X. Y. Lim, Aroon Supramaniam, Hayman Lui, Peta Coles, Wai Suet Lee, Xiang Liu, Penny A. Rudd, Lara J. Herrero. Chondrocytes Contribute to Alphaviral Disease Pathogenesis as a Source of Virus Replication and Soluble Factor Production. Viruses. 2018; 10 (2):86.
Chicago/Turabian StyleElisa X. Y. Lim; Aroon Supramaniam; Hayman Lui; Peta Coles; Wai Suet Lee; Xiang Liu; Penny A. Rudd; Lara J. Herrero. 2018. "Chondrocytes Contribute to Alphaviral Disease Pathogenesis as a Source of Virus Replication and Soluble Factor Production." Viruses 10, no. 2: 86.
Viruses: Friends and Foes | InTechOpen, Published on: 2018-02-14. Authors: Penny A. Rudd and Lara J. Herrero
Penny A. Rudd; Lara J. Herrero. Viruses: Friends and Foes. Cartilage Repair and Regeneration 2018, 1 .
AMA StylePenny A. Rudd, Lara J. Herrero. Viruses: Friends and Foes. Cartilage Repair and Regeneration. 2018; ():1.
Chicago/Turabian StylePenny A. Rudd; Lara J. Herrero. 2018. "Viruses: Friends and Foes." Cartilage Repair and Regeneration , no. : 1.
Alphaviruses are arthropod-borne viruses and are predominantly transmitted via mosquito vectors. This vector preference by alphaviruses raises the important question of the determinants that contribute to vector competence. There are several tissue barriers of the mosquito that the virus must overcome in order to establish a productive infection. Of importance are the midgut, basal lamina and the salivary glands. Infection of the salivary glands is crucial for virus transmission during the mosquito’s subsequent bloodfeed. Other factors that may contribute to vector competence include the microflora and parasites present in the mosquito, environmental conditions, the molecular determinants of the virus to adapt to the vector, as well as the effect of co-infection with other viruses. Though mosquito innate immunity is a contributing factor to vector competence, it will not be discussed in this review. Detailed understanding of these factors will be instrumental in minimising transmission of alphaviral diseases.
Elisa X. Y. Lim; Wai Suet Lee; Eugene T. Madzokere; Lara J. Herrero. Mosquitoes as Suitable Vectors for Alphaviruses. Viruses 2018, 10, 84 .
AMA StyleElisa X. Y. Lim, Wai Suet Lee, Eugene T. Madzokere, Lara J. Herrero. Mosquitoes as Suitable Vectors for Alphaviruses. Viruses. 2018; 10 (2):84.
Chicago/Turabian StyleElisa X. Y. Lim; Wai Suet Lee; Eugene T. Madzokere; Lara J. Herrero. 2018. "Mosquitoes as Suitable Vectors for Alphaviruses." Viruses 10, no. 2: 84.
Transmitted by mosquitoes; chikungunya virus (CHIKV) is responsible for frequent outbreaks of arthritic disease in humans. CHIKV is an arthritogenic alphavirus of the Togaviridae family. Capsid protein, a structural protein encoded by the CHIKV RNA genome, is able to translocate to the host cell nucleus. In encephalitic alphaviruses nuclear translocation induces host cell shut off; however, the role of capsid protein nuclear localisation in arthritogenic alphaviruses remains unclear. Using replicon systems, we investigated a nuclear export sequence (NES) in the N-terminal region of capsid protein; analogous to that found in encephalitic alphavirus capsid but uncharacterised in CHIKV. The chromosomal maintenance 1 (CRM1) export adaptor protein mediated CHIKV capsid protein export from the nucleus and a region within the N-terminal part of CHIKV capsid protein was required for active nuclear targeting. In contrast to encephalitic alphaviruses, CHIKV capsid protein did not inhibit host nuclear import; however, mutating the NES of capsid protein (∆NES) blocked host protein access to the nucleus. Interactions between capsid protein and the nucleus warrant further investigation.
Susan C. Jacobs; Adam Taylor; Lara J. Herrero; Suresh Mahalingam; John K. Fazakerley. Mutation of a Conserved Nuclear Export Sequence in Chikungunya Virus Capsid Protein Disrupts Host Cell Nuclear Import. Viruses 2017, 9, 306 .
AMA StyleSusan C. Jacobs, Adam Taylor, Lara J. Herrero, Suresh Mahalingam, John K. Fazakerley. Mutation of a Conserved Nuclear Export Sequence in Chikungunya Virus Capsid Protein Disrupts Host Cell Nuclear Import. Viruses. 2017; 9 (10):306.
Chicago/Turabian StyleSusan C. Jacobs; Adam Taylor; Lara J. Herrero; Suresh Mahalingam; John K. Fazakerley. 2017. "Mutation of a Conserved Nuclear Export Sequence in Chikungunya Virus Capsid Protein Disrupts Host Cell Nuclear Import." Viruses 9, no. 10: 306.
The expansion of mosquito-borne viral (arboviral) arthritis poses a significant threat to human health worldwide. Clinical reports show that arboviral arthritis can be persistent and debilitating, with evidence of bone pathology. As part of the Togaviridae family, alphaviruses are mosquito-borne viruses that are widely distributed throughout the globe causing extensive morbidity and mortality. Despite this, very little is known about the pathogenesis of disease caused by alphaviruses. It has been shown that macrophages play a crucial role in the development of alphaviral arthritis. Infection causes macrophage activation and the release of macrophage inhibitory factor (MIF), which subsequently plays a pivotal role in alphavirus-induced arthritis by regulating the expression of pro-inflammatory factors. This chapter discusses the role of the MIF-CD74 axis in the development of alphavirus arthritis and the therapeutic potential of antagonists in the treatment of alphaviral arthropathies.
Lara Herrero; Ali Zaid; Margit Mutso; Suresh Mahalingam. The MIF-CD74 Inflammatory Axis in Alphaviral Infection. MIF Family Cytokines in Innate Immunity and Homeostasis 2017, 175 -187.
AMA StyleLara Herrero, Ali Zaid, Margit Mutso, Suresh Mahalingam. The MIF-CD74 Inflammatory Axis in Alphaviral Infection. MIF Family Cytokines in Innate Immunity and Homeostasis. 2017; ():175-187.
Chicago/Turabian StyleLara Herrero; Ali Zaid; Margit Mutso; Suresh Mahalingam. 2017. "The MIF-CD74 Inflammatory Axis in Alphaviral Infection." MIF Family Cytokines in Innate Immunity and Homeostasis , no. : 175-187.
Wai Suet Lee; Aroon Supramaniam; Elisa Xin Ying Lim; Peta Coles; Lara J Herrero. Alphaviral targeted antivirals: evaluating the old, planning the future. Future Virology 2017, 12, 49 -54.
AMA StyleWai Suet Lee, Aroon Supramaniam, Elisa Xin Ying Lim, Peta Coles, Lara J Herrero. Alphaviral targeted antivirals: evaluating the old, planning the future. Future Virology. 2017; 12 (2):49-54.
Chicago/Turabian StyleWai Suet Lee; Aroon Supramaniam; Elisa Xin Ying Lim; Peta Coles; Lara J Herrero. 2017. "Alphaviral targeted antivirals: evaluating the old, planning the future." Future Virology 12, no. 2: 49-54.
Re-emergence of chikungunya virus, a mosquito-transmitted pathogen, is of serious public health concern. In the past 15 years, after decades of infrequent, sporadic outbreaks, the virus has caused major epidemic outbreaks in Africa, Asia, the Indian Ocean, and more recently the Caribbean and the Americas. Chikungunya virus is mainly transmitted by Aedes aegypti mosquitoes in tropical and subtropical regions, but the potential exists for further spread because of genetic adaptation of the virus to Aedes albopictus, a species that thrives in temperate regions. Chikungunya virus represents a substantial health burden to affected populations, with symptoms that include severe joint and muscle pain, rashes, and fever, as well as prolonged periods of disability in some patients. The inflammatory response coincides with raised levels of immune mediators and infiltration of immune cells into infected joints and surrounding tissues. Animal models have provided insights into disease pathology and immune responses. Although host innate and adaptive responses have a role in viral clearance and protection, they can also contribute to virus-induced immune pathology. Understanding the mechanisms of host immune responses is essential for the development of treatments and vaccines. Inhibitory compounds targeting key inflammatory pathways, as well as attenuated virus vaccines, have shown some success in animal models, including an attenuated vaccine strain based on an isolate from La Reunion incorporating an internal ribosome entry sequence that prevents the virus from infecting mosquitoes and a vaccine based on virus-like particles expressing envelope proteins. However, immune correlates of protection, as well as the safety of prophylactic and therapeutic candidates, are important to consider for their application in chikungunya infections. In this Review, we provide an update on chikungunya virus with regard to its epidemiology, molecular virology, virus-host interactions, immunological responses, animal models, and potential antiviral therapies and vaccines.
Felicity J Burt; Weiqiang Chen; Jonathan J Miner; Deborah J Lenschow; Andres Merits; Esther Schnettler; Alain Kohl; Penny A Rudd; Adam Taylor; Lara Herrero; Ali Zaid; Lisa Ng; Suresh Mahalingam. Chikungunya virus: an update on the biology and pathogenesis of this emerging pathogen. The Lancet Infectious Diseases 2017, 17, e107 -e117.
AMA StyleFelicity J Burt, Weiqiang Chen, Jonathan J Miner, Deborah J Lenschow, Andres Merits, Esther Schnettler, Alain Kohl, Penny A Rudd, Adam Taylor, Lara Herrero, Ali Zaid, Lisa Ng, Suresh Mahalingam. Chikungunya virus: an update on the biology and pathogenesis of this emerging pathogen. The Lancet Infectious Diseases. 2017; 17 (4):e107-e117.
Chicago/Turabian StyleFelicity J Burt; Weiqiang Chen; Jonathan J Miner; Deborah J Lenschow; Andres Merits; Esther Schnettler; Alain Kohl; Penny A Rudd; Adam Taylor; Lara Herrero; Ali Zaid; Lisa Ng; Suresh Mahalingam. 2017. "Chikungunya virus: an update on the biology and pathogenesis of this emerging pathogen." The Lancet Infectious Diseases 17, no. 4: e107-e117.
The majority of medical advances have been made using animals. Studies using mouse models of chikungunya-induced disease have proven invaluable for dissecting the intricate nature of the immune response to this viral infection and identifying potential targets for the development of treatment strategies. Herein we describe the common mouse models used to research the pathobiology of chikungunya virus infection to date.
Lara J. Herrero; Penny A. Rudd; Xiang Liu; Stefan Wolf; Suresh Mahalingam. Mouse Models of Chikungunya Virus. Methods in Molecular Biology 2016, 1426, 211 -224.
AMA StyleLara J. Herrero, Penny A. Rudd, Xiang Liu, Stefan Wolf, Suresh Mahalingam. Mouse Models of Chikungunya Virus. Methods in Molecular Biology. 2016; 1426 ():211-224.
Chicago/Turabian StyleLara J. Herrero; Penny A. Rudd; Xiang Liu; Stefan Wolf; Suresh Mahalingam. 2016. "Mouse Models of Chikungunya Virus." Methods in Molecular Biology 1426, no. : 211-224.