Infectious Diseases - Research Publications

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    Antibody to Plasmodium falciparum Variant Surface Antigens, var Gene Transcription, and ABO Blood Group in Children With Severe or Uncomplicated Malaria
    Barua, P ; Duffy, MF ; Manning, L ; Laman, M ; Davis, TME ; Mueller, I ; Haghiri, A ; Simpson, JA ; Beeson, JG ; Rogerson, SJ (OXFORD UNIV PRESS INC, 2023-10-18)
    BACKGROUND: Antibodies to variant surface antigens (VSAs) such as Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) may vary with malaria severity. The influence of ABO blood group on antibody development is not understood. METHODS: Immunoglobulin G antibodies to VSAs in Papua New Guinean children with severe (n = 41) or uncomplicated (n = 30) malaria were measured by flow cytometry using homologous P falciparum isolates. Isolates were incubated with ABO-matched homologous and heterologous acute and convalescent plasma. RNA was used to assess var gene transcription. RESULTS: Antibodies to homologous, but not heterologous, isolates were boosted in convalescence. The relationship between antibody and severity varied by blood group. Antibodies to VSAs were similar in severe and uncomplicated malaria at presentation, higher in severe than uncomplicated malaria in convalescence, and higher in children with blood group O than other children. Six var gene transcripts best distinguished severe from uncomplicated malaria, including UpsA and 2 CIDRα1 domains. CONCLUSIONS: ABO blood group may influence antibody acquisition to VSAs and susceptibility to severe malaria. Children in Papua New Guinea showed little evidence of acquisition of cross-reactive antibodies following malaria. Var gene transcripts in Papua New Guinean children with severe malaria were similar to those reported from Africa.
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    Correction: Does Malaria Affect Placental Development? Evidence from In Vitro Models
    Umbers, AJ ; Stanisic, DI ; Ome, M ; Wangnapi, R ; Hanieh, S ; Unger, HW ; Robinson, LJ ; Lufele, E ; Baiwog, F ; Siba, PM ; King, CL ; Beeson, JG ; Mueller, I ; Aplin, JD ; Glazier, JD ; Rogerson, SJ ; Hviid, L (Public Library of Science (PLoS), 2013)
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    Asia-Pacific ICEMR: Understanding Malaria Transmission to Accelerate Malaria Elimination in the Asia Pacific Region
    Mueller, I ; Vantaux, A ; Karl, S ; Laman, M ; Witkowski, B ; Pepey, A ; Vinit, R ; White, M ; Barry, A ; Beeson, JG ; Robinson, LJ (AMER SOC TROP MED & HYGIENE, 2022-10)
    Gaining an in-depth understanding of malaria transmission requires integrated, multifaceted research approaches. The Asia-Pacific International Center of Excellence in Malaria Research (ICEMR) is applying specifically developed molecular and immunological assays, in-depth entomological assessments, and advanced statistical and mathematical modeling approaches to a rich series of longitudinal cohort and cross-sectional studies in Papua New Guinea and Cambodia. This is revealing both the essential contribution of forest-based transmission and the particular challenges posed by Plasmodium vivax to malaria elimination in Cambodia. In Papua New Guinea, these studies document the complex host-vector-parasite interactions that are underlying both the stunning reductions in malaria burden from 2006 to 2014 and the significant resurgence in transmission in 2016 to 2018. Here we describe the novel analytical, surveillance, molecular, and immunological tools that are being applied in our ongoing Asia-Pacific ICEMR research program.
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    Impact of Environmental Modifications on the Ecology, Epidemiology, and Pathogenesis of Plasmodium falciparum and Plasmodium vivax Malaria in East Africa
    Yan, G ; Lee, M-C ; Zhou, G ; Jiang, A-L ; Degefa, T ; Zhong, D ; Wang, X ; Hemming-Schroeder, E ; Mukabana, WR ; Dent, AE ; King, CL ; Hsu, K ; Beeson, J ; Githure, JI ; Atieli, H ; Githeko, AK ; Yewhalaw, D ; Kazura, JW (AMER SOC TROP MED & HYGIENE, 2022-10)
    Food insecurity, recurrent famine, and poverty threaten the health of millions of African residents. Construction of dams and rural irrigation schemes is key to solving these problems. The sub-Saharan Africa International Center of Excellence for Malaria Research addresses major knowledge gaps and challenges in Plasmodium falciparum and Plasmodium vivax malaria control and elimination in malaria-endemic areas of Kenya and Ethiopia where major investments in water resource development are taking place. This article highlights progress of the International Center of Excellence for Malaria Research in malaria vector ecology and behavior, epidemiology, and pathogenesis since its inception in 2017. Studies conducted in four field sites in Kenya and Ethiopia show that dams and irrigation increased the abundance, stability, and productivity of larval habitats, resulting in increased malaria transmission and a greater disease burden. These field studies, together with hydrological and malaria transmission modeling, enhance the ability to predict the impact of water resource development projects on vector larval ecology and malaria risks, thereby facilitating the development of optimal water and environmental management practices in the context of malaria control efforts. Intersectoral collaborations and community engagement are crucial to develop and implement cost-effective malaria control strategies that meet food security needs while controlling malaria burden in local communities.
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    Targeting malaria parasites with novel derivatives of azithromycin
    Burns, AL ; Sleebs, BE ; Gancheva, M ; McLean, KT ; Siddiqui, G ; Venter, H ; Beeson, JG ; O'Handley, R ; Creek, DJ ; Ma, S ; Froelich, S ; Goodman, CD ; McFadden, G ; Wilson, DW (FRONTIERS MEDIA SA, 2022-11-30)
    INTRODUCTION: The spread of artemisinin resistant Plasmodium falciparum parasites is of global concern and highlights the need to identify new antimalarials for future treatments. Azithromycin, a macrolide antibiotic used clinically against malaria, kills parasites via two mechanisms: 'delayed death' by inhibiting the bacterium-like ribosomes of the apicoplast, and 'quick-killing' that kills rapidly across the entire blood stage development. METHODS: Here, 22 azithromycin analogues were explored for delayed death and quick-killing activities against P. falciparum (the most virulent human malaria) and P. knowlesi (a monkey parasite that frequently infects humans). RESULTS: Seventeen analogues showed improved quick-killing against both Plasmodium species, with up to 38 to 20-fold higher potency over azithromycin after less than 48 or 28 hours of treatment for P. falciparum and P. knowlesi, respectively. Quick-killing analogues maintained activity throughout the blood stage lifecycle, including ring stages of P. falciparum parasites (<12 hrs treatment) and were >5-fold more selective against P. falciparum than human cells. Isopentenyl pyrophosphate supplemented parasites that lacked an apicoplast were equally sensitive to quick-killing analogues, confirming that the quick killing activity of these drugs was not directed at the apicoplast. Further, activity against the related apicoplast containing parasite Toxoplasma gondii and the gram-positive bacterium Streptococcus pneumoniae did not show improvement over azithromycin, highlighting the specific improvement in antimalarial quick-killing activity. Metabolomic profiling of parasites subjected to the most potent compound showed a build-up of non-haemoglobin derived peptides that was similar to chloroquine, while also exhibiting accumulation of haemoglobin-derived peptides that was absent for chloroquine treatment. DISCUSSION: The azithromycin analogues characterised in this study expand the structural diversity over previously reported quick-killing compounds and provide new starting points to develop azithromycin analogues with quick-killing antimalarial activity.
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    Fc engineered ACE2-Fc is a potent multifunctional agent targeting SARS-CoV2 (vol 13, 889372, 2022)
    Wines, BD ; Kurtovic, L ; Trist, HM ; Esparon, S ; Lopez, E ; Chappin, K ; Chan, L-J ; Mordant, FL ; Lee, WS ; Gherardin, NA ; Patel, SK ; Hartley, GE ; Pymm, P ; Cooney, JP ; Beeson, JG ; Godfrey, DI ; Burrell, LM ; van Zelm, MC ; Wheatley, AK ; Chung, AWW ; Tham, W-H ; Subbarao, K ; Kent, SJ ; Hogarth, PM (FRONTIERS MEDIA SA, 2023-01-10)
    [This corrects the article .].
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    The Plasmodium falciparum parasitophorous vacuole protein P113 interacts with the parasite protein export machinery and maintains normal vacuole architecture
    Bullen, HE ; Sanders, PR ; Dans, MG ; Jonsdottir, TK ; Riglar, DT ; Looker, O ; Palmer, CS ; Kouskousis, B ; Charnaud, SC ; Triglia, T ; Gabriela, M ; Schneider, MP ; Chan, J-A ; de Koning-Ward, TF ; Baum, J ; Kazura, JW ; Beeson, JG ; Cowman, AF ; Gilson, PR ; Crabb, BS (WILEY, 2022-05)
    Infection with Plasmodium falciparum parasites results in approximately 627,000 deaths from malaria annually. Key to the parasite's success is their ability to invade and subsequently grow within human erythrocytes. Parasite proteins involved in parasite invasion and proliferation are therefore intrinsically of great interest, as targeting these proteins could provide novel means of therapeutic intervention. One such protein is P113 which has been reported to be both an invasion protein and an intracellular protein located within the parasitophorous vacuole (PV). The PV is delimited by a membrane (PVM) across which a plethora of parasite-specific proteins are exported via the Plasmodium Translocon of Exported proteins (PTEX) into the erythrocyte to enact various immune evasion functions. To better understand the role of P113 we isolated its binding partners from in vitro cultures of P. falciparum. We detected interactions with the protein export machinery (PTEX and exported protein-interacting complex) and a variety of proteins that either transit through the PV or reside on the parasite plasma membrane. Genetic knockdown or partial deletion of P113 did not significantly reduce parasite growth or protein export but did disrupt the morphology of the PVM, suggesting that P113 may play a role in maintaining normal PVM architecture.
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    Induction, decay, and determinants of functional antibodies following vaccination with the RTS,S malaria vaccine in young children
    Feng, G ; Kurtovic, L ; Agius, PA ; Aitken, EH ; Sacarlal, J ; Wines, BD ; Hogarth, PM ; Rogerson, SJ ; Fowkes, FJ ; Dobano, C ; Beeson, JG (BMC, 2022-08-25)
    BACKGROUND: RTS,S is the first malaria vaccine recommended for implementation among young children at risk. However, vaccine efficacy is modest and short-lived. Antibodies play the major role in vaccine-induced immunity, but knowledge on the induction, decay, and determinants of antibody function is limited, especially among children. Antibodies that promote opsonic phagocytosis and other cellular functions appear to be important contributors to RTS,S immunity. METHODS: We studied a phase IIb trial of RTS,S/AS02 conducted in young children in malaria-endemic regions of Mozambique. We evaluated the induction of antibodies targeting the circumsporozoite protein (CSP, vaccine antigen) that interact with Fcγ-receptors (FcRγs) and promote phagocytosis (neutrophils, monocytes, THP-1 cells), antibody-dependent respiratory burst (ADRB) by neutrophils, and natural killer (NK) cell activity, as well as the temporal kinetics of responses over 5 years of follow-up (ClinicalTrials.gov registry number NCT00197041). RESULTS: RTS,S vaccination induced CSP-specific IgG with FcγRIIa and FcγRIII binding activity and promoted phagocytosis by neutrophils, THP-1 monocytes, and primary human monocytes, neutrophil ADRB activity, and NK cell activation. Responses were highly heterogenous among children, and the magnitude of neutrophil phagocytosis by antibodies was relatively modest, which may reflect modest vaccine efficacy. Induction of functional antibodies was lower among children with higher malaria exposure. Functional antibody magnitude and the functional activity of antibodies largely declined within a year post-vaccination, and decay were highest in the first 6 months, consistent with the decline in vaccine efficacy over that time. Decay rates varied for different antibody parameters and decay was slower for neutrophil phagocytosis. Biostatistical modelling suggested IgG1 and IgG3 contribute in promoting FcγR binding and phagocytosis, and IgG targeting the NANP-repeat and C-terminal regions CSP were similarly important for functional activities. CONCLUSIONS: Results provide new insights to understand the modest and time-limited efficacy of RTS,S in children and the induction of antibody functional activities. Improving the induction and maintenance of antibodies that promote phagocytosis and cellular functions, and combating the negative effect of malaria exposure on vaccine responses are potential strategies for improving RTS,S efficacy and longevity.
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    Antibody responses to the RTS,S/AS01E vaccine and Plasmodium falciparum antigens after a booster dose within the phase 3 trial in Mozambique (vol 5, 46, 2020)
    Sanchez, L ; Vidal, M ; Jairoce, C ; Aguilar, R ; Ubillos, I ; Cuamba, I ; Nhabomba, AJ ; Williams, NA ; Diez-Padrisa, N ; Cavanagh, D ; Angov, E ; Coppel, RL ; Gaur, D ; Beeson, JG ; Dutta, S ; Aide, P ; Campo, JJ ; Moncunill, G ; Dobano, C (NATURE PORTFOLIO, 2022-08-08)
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    Assessment of IgG3 as a serological exposure marker for Plasmodium vivax in areas with moderate-high malaria transmission intensity
    Tayipto, Y ; Rosado, J ; Gamboa, D ; White, MTT ; Kiniboro, B ; Healer, J ; Opi, DH ; Beeson, JGG ; Takashima, E ; Tsuboi, T ; Harbers, M ; Robinson, L ; Mueller, I ; Longley, RJJ (FRONTIERS MEDIA SA, 2022-08-09)
    A more sensitive surveillance tool is needed to identify Plasmodium vivax infections for treatment and to accelerate malaria elimination efforts. To address this challenge, our laboratory has developed an eight-antigen panel that detects total IgG as serological markers of P. vivax exposure within the prior 9 months. The value of these markers has been established for use in areas with low transmission. In moderate-high transmission areas, there is evidence that total IgG is more long-lived than in areas with low transmission, resulting in poorer performance of these markers in these settings. Antibodies that are shorter-lived may be better markers of recent infection for use in moderate-high transmission areas. Using a multiplex assay, the antibody temporal kinetics of total IgG, IgG1, IgG3, and IgM against 29 P. vivax antigens were measured over 36 weeks following asymptomatic P. vivax infection in Papua New Guinean children (n = 31), from an area with moderate-high transmission intensity. IgG3 declined faster to background than total IgG, IgG1, and IgM. Based on these kinetics, IgG3 performance was then assessed for classifying recent exposure in a cohort of Peruvian individuals (n = 590; age 3-85 years) from an area of moderate transmission intensity. Using antibody responses against individual antigens, the highest performance of IgG3 in classifying recent P. vivax infections in the prior 9 months was to one of the Pv-fam-a proteins assessed (PVX_125728) (AUC = 0.764). Surprisingly, total IgG was overall a better marker of recent P. vivax infection, with the highest individual classification performance to RBP2b1986-2653 (PVX_094255) (AUC = 0.838). To understand the acquisition of IgG3 in this Peruvian cohort, relevant epidemiological factors were explored using a regression model. IgG3 levels were positively associated with increasing age, living in an area with (relatively) higher transmission intensity, and having three or more PCR-detected blood-stage P. vivax infections within the prior 13 months. Overall, we found that IgG3 did not have high accuracy for detecting recent exposure to P. vivax in the Peruvian cohort, with our data suggesting that this is due to the high levels of prior exposure required to acquire high IgG3 antibody levels.