Influenza virus is an ever-evolving human pathogen that presents a constant threat to global public and animal health. Therefore, there is an undeniable need to identify the missing links – both host and viral – that are important for influenza virus pathogenesis to develop alternative, effective and long-lasting anti-influenza strategies. We have discovered that human histone deacetylases, HDAC1 and HDAC2 possess anti-influenza properties and are a component of host innate response against influenza. We found that RNA interference-mediated knockdown of HDAC1 and 2 expression augmented the influenza A virus (IAV) growth in A549 cells by more than 3- and 4-fold, respectively. Further, both HDAC1 and 2 exert their anti-IAV function via viperin, an interferon-stimulated gene known to inhibit IAV infection. We found that the expression of viperin was reduced by 58% and 53% in HDAC1- and 2-depleted cells, respectively, in response to IAV infection. However, like other antiviral host factors, influenza antagonizes HDAC1 and 2, and by using the same pathway, to undermine their antiviral function. We found that IAV downregulates the level of HDAC1 and 2, primarily at polypeptide level in A549 cells that can be recovered to almost 100% level in the presence of a proteasome inhibitor. The HDAC1 and 2 are prototypic members of class I HDACs and are closely related in structure and function. Hence, in many heterologous conditions, HDAC1 and 2 behave practically like “twins”. The data generated so far indicate that, in IAV-infected cells, HDAC1 and 2 also behave in a similar fashion. Interestingly, IAV also antagonizes them both in a similar manner. Nevertheless, future investigations will reveal further similarities and differences in anti-influenza viral mechanisms of host HDAC1 and 2.

Recorded During the Keystone Symposia Conference on:

Framing the Response to Emerging Virus Infections (S2), Oct 14-18, 2018 | HKU, Hong Kong

This Keystone Symposia Virtual Access was made possible by a grant from the Croucher Foundation and The University of Hong Kong.

Recorded During the Keystone Symposia Conference on:

Framing the Response to Emerging Virus Infections (S2), Oct 14-18, 2018 | HKU, Hong Kong

This Keystone Symposia Virtual Access was made possible by a grant from the Croucher Foundation and The University of Hong Kong.

The limited protection of current commercial vaccines necessitates the investigation of novel vaccine strategies for unpredictable outbreaks. To investigate the feasibility of using vaccines derived from Group 1 influenza A virus to induce broadly cross-reactive immune responses against multiple influenza subtypes, we tested a panel of sequential 4-dose immunization regimens in mice. Mice were treated with inactivated (seasonal H1N1, pandemic H1N1 and H5N1) and vaccinia virus-based H5N1 live-attenuated vaccines in different combinations.

Mice were then challenged by viruses of either Group 1 (H1N1) or Group 2 (H3N2, H7N7) influenza virus. All studied sequential 4-dose vaccinations could induce some degrees of heterosubtypic protection in mice. Amongst all these regimens, the combined use of inactivated and live-attenuated vaccines could achieve the best heterologous protection. These results highlight the synergistic effect of combining different vaccine platforms to enhance heterosubtypic protection against influenza viruses.

Recorded During the Keystone Symposia Conference on:

Framing the Response to Emerging Virus Infections (S2), Oct 14-18, 2018 | HKU, Hong Kong

This Keystone Symposia Virtual Access was made possible by a grant from the Croucher Foundation and The University of Hong Kong.

Recorded During the Keystone Symposia Conference on:

Framing the Response to Emerging Virus Infections (S2), Oct 14-18, 2018 | HKU, Hong Kong

This Keystone Symposia Virtual Access was made possible by a grant from the Croucher Foundation and The University of Hong Kong.

Title: Immune genes are primed for robust transcription by proximal lncRNAs located in nuclear compartments

Accumulation of H3K4me3 epigenetic marks on immune-related gene promoters underlies robust transcription during trained immunity. However, the molecular basis for this remains unknown. Here we show 3D chromatin topology enables immune genes to engage in chromosomal contacts with a new subset of lncRNAs we have defined as immune-gene priming lncRNAs (IPLs).

We show that the prototypical IPL, UMLILO, acts in cis to direct the WDR5/MLL1 complex across the chemokine promoters facilitating their H3K4me3 epigenetic priming. This mechanism is shared amongst several trained immune genes. β-glucan-mediated training epigenetically reprograms immune genes by upregulating IPLs in an NFAT-dependent manner. The murine chemokine TAD lacks an IPL and the Cxcl genes are not trained. Strikingly, the insertion of UMLILO into the chemokine TAD in murine macrophages resulted in training of Cxcl genes. This provides strong evidence that lncRNA-mediated regulation is central to the establishment of trained immunity.

Read the Paper in Nature Genetics

Emerging infectious diseases are relatively little understood. Their periodic, unpredictable outbreaks can quickly transform into global pandemics, as was the case with SARS and avian influenza. They tend to be zoonotic (deriving from an animal source), infect thousands of people at a time, engender significant fear and panic, and have high mortality rates, which is frequently because the public infrastructure to diagnose, prevent and treat them is lacking. Newer examples of these diseases include MERS and Ebola, both of which are RNA viruses with the ability to mutate from one outbreak to the next, making them that much deadlier.

This thought-provoking epanel broadcast will discuss a range of questions and challenges surrounding emerging infectious diseases, including:

• How do emerging infectious diseases differ from regular infectious diseases?
• What drives the emergence of these diseases?
• What are optimal ways to respond to emerging infectious disease outbreaks and is a new paradigm needed?
• How have societal changes such as international travel, livestock practices and social media changed the nature of pandemics, such as by amplifying disease transmission and sowing panic?
• Which newly emerging infectious diseases represent the greatest coming threats?
• How can we provide incentives for vaccinating animal carriers, some of whom don’t fall sick from the virus they are carrying?
• What is the role of big pharma in responding to these threats and who will fund the development of vaccines and other therapeutics?

Following the panel discussion broadcast, audience members watching the live event will be able to participate in a live Q&A with the panelists. Questions can be submitted during the broadcast via Twitter or the chat room, or in advance when registering for the event.

This epanel was filmed during the Keystone Symposia conference on “Framing the Response to Emerging Virus Infections” at the Lee Shau Kee Lecture Centre of The University of Hong Kong, October 14-18, 2018, and was made possible with funding from both The University of Hong Kong and the Croucher Foundation.

Event Hashtag: #VKSpandemic

Jorge da Rocha2, Dr Zané Lombard1, Prof Michèle Ramsay2,

1Division of Human Genetics, University of the Witwatersrand; 2Sydney Brenner Institute for Molecular Bioscience, University of the Witwatersrand

Cancer is a critical health burden in Africa, and mortality rates are rising rapidly. Treatments are severe and expensive, and often cause adverse-drug-reactions (ADRs). Pharmacogenomics (PGx) aims to increase drug safety and efficacy by aligning drugs to known responses based on genomic variants, but data is sparse for African populations. Thirteen genes linked with ADRs to medicines used for treating major cancer types were identified: ABCB1, DPYD, TYMS, CYP19A1, GSTP1, CYP1B1, CYP3A4, CYP3A5, ESR1, CYP2D6, SLC19A1 and XRCC1/5. Public domain whole-genome-sequencing data from the 1000-Genomes-Project and the African-Genome-Variation-Project were mined to assess variants in eight African populations. Functional annotation was performed with a series of bioinformatics-based scoring tools to assess potential likelihood of deleterious impact. Two key African specific variants were identified: the CYP3A5 frameshift variant, rs41303343, which is highly likely to knockout gene function, and the CYP2D6 missense variant rs59421388, which was scored highly likely deleterious by all tools. Both variants are common in Africans, but lack clinical investigation into their PGx impact. For missense variants with known PGx effects, such as CYP2D6 - rs1065852 and DPYD - rs2297595, intra-African frequencies are significantly distinct, with rs1065852 being more common in West Africans, while rs2297595 is more common in East Africans. Many known variants are less common in Africans than other populations. These data indicate that guidelines for cancer drug safety based on African data are essential for use in Africa, and novel region-specific guidelines should be developed to ensure that Africans could benefit from a precision medicine approach.

Chiaka Anumudu1, Olugbenga Onile2, Adewale Adebayo1,3, Henrietta Awobode4, Raphael Isokpehi5

1Cellular Parasitology Programme, Department of Zoology, University of Ibadan, Ibadan Nigeria; 2Elizade University, Ilara Mokin, Ondo State Nigeria; 3King’s College London UK; 4Parasitology Unit, Department of Zoology, University of Ibadan, Ibadan, Nigeria; 5College of Engineering and Sciences, Bethune Cookman University, Daytona Beach, Florida, USA

Validated diagnostic markers are key to the early detection and treatment of cancer. Indeed, if these biomarkers can be readily extracted and detected in bodily fluids, a simple, diagnostic test can be developed that would be of extreme value to patients especially in rural and resource-poor settings. 

For urinary schistosomiasis, we are looking for such a marker, which can be used for the detection of Schistosoma associated bladder damage and schistosomiasis, in a low-tech-test. We have used proteomics and microbiome methods to search for such markers in our previous works, and identified a large number of targets. Using a cross sectional study design, we collected 371 blood and urine samples from adults resident in Eggua. The urine was screened by centrifugation for eggs of the parasite Schistosoma haematobium and later 49 samples by proteomics methods for molecules that could be uniquely indicative of schistosomiasis and bladder damage. Participants were also tested by ultrasound for bladder pathologies. Microbiome analysis was performed on 70 blood and urine samples using NGS and bioinformatics pipeline. A total of 1306 proteins, and 9701 unique peptides were observed, and 54 human proteins were found to be potential biomarkers for schistosomiasis and bladder pathologies. Due to the interesting biomarkers identified from these proteomic and microbiome studies, we are currently engaged in a research collaboration to repeat the studies and validate the results with a larger sample. Further work may be of interest in to make a comparative analysis of the usefulness of each of the 54 identified biomarkers for the diagnosis of schistosomiasis.

Farai C. Muchadeyi1, Khanyisile Hadebe1, Edgar F. Dzomba2

1Agricultural Research Council, Biotechnology Platform, Onderstepoort, South Africa; 2Discipline of Genetics, School of Life Sciences, University of KwaZulu-Natal, Scottsville, South Africa

*Correspondence: MuchadeyiF@arc.agric.za

Local indigenous animal genetic resources play an important role in sustaining the livelihoods of rural and resource-limited farmers. These local breeds thrive on adaptation to unfavourable environment stressors such as extreme temperatures, worsening droughts and disease challenges that characterise most low input production systems. Livestock improvement programs strive to develop genotypes that are adapted to local conditions and are able to produce optimally and sustainably under constrained environments. Genetic mechanisms underlying biological traits for environmental adaptation are unclear but unravelling them would be essential when designing methods to improve and sustain these breeds. It is important to study the interaction between production environments and genetics of animal populations so as to establish selection priorities and develop suitable improvement strategies. Efforts to initiate improvement programs have historically been hindered by absence of performance data and pedigree records compounded by factors such as animals randomly mating within and between flocks on communal pastures. Landscape genomics merges the competing effects of the production system, geographical, and environment landscapes with adaptive genetic variation. Advances in livestock genomics have enabled production of large amounts of genetic data of genome-wide coverage which, when combined with environmental data, enables in-depth studies on the patterns of genetic diversity, identification of genes and elucidating processes underlying genetic adaptation in various indigenous animal populations. In this study, case studies are presented on the use of landscape genomics as a tool to understand the genetics of adaption in indigenous chickens and goat populations of Southern Africa.

Keywords: Livestock, rural farming communities, genetic adaptation; landscape genomics

Ijomanta, J.1,+, Asala, O.1, Bitrus, M.1, Musa, A.2, Shittu, I.1, Joannis, T.1, Nwosuh, C.1 and 1Meseko, C.*

1Regional Centre for Animal Influenza, National Veterinary Research Institute, Vom Nigeria; 2Veterinary Department, Plateau State Ministry of Agriculture, Jos Nigeria

+presenting author

*Corresponding author: cameseko@yahoo.com

Influenza virus A belongs to the family Orthomyxoviridae and is divided into subtypes H1-18. The virus affects a wide range of avian and mammalian hosts, subtypes H1; H3; H5; H7 and H9 have been reported to cause fatal infections that can adversely affect socio-economics and public health. In April 2009, WHO declared influenza pandemic when H1N1pdm09 spread to 214 countries and an estimated 151,700 –575 400 deaths were recorded. The virus was subsequently transmitted to pigs and had remained enzootic being detected in many countries including Nigeria.

In this study, a total of 143 tracheal swabs were collected during a targeted active surveillance of apparently healthy pigs in Jos abattoir, Plateau state from December 2017 through February 2018. The samples were analyzed for Influenza A by conventional One-step RT-PCR protocol targeting the matrix. To subtype the Influenza A viruses, multiplex RT-qPCR assays targeting the Hemagglutinin (H1pdm, H1avian, H1human and H3) and neuraminidase (N1, N2, N1pdm) were used. In all, 51 (35%) samples were positive for Influenza A while four of the ten selected samples for subtyping were identified as H1N1pdm09.

In a previous study carried out at the human-animal interface, circulation of H1N1pdm09 was reported in southwest Nigeria. Also, follow up studies revealed seroprevalence ranging from 20-60% in pigs. Here, we report a more recent and continuous circulation of the virus in pigs in North central Nigeria since it was first declared a pandemic in 2009. The virus in human is now seasonal and can easily be managed with vaccination. Currently, there is no vaccination programme for swine influenza in Nigeria therefore maintaining H1N1pdm09 in pigs poses great public health risk. Possible mutations and reassortments may result in emergence of novel virus with pandemic potential.

Keywords: surveillance; Influenza A virus; Nigeria; Pandemics; Pigs