Videos - 2018 CEND Symposium

<h3>Preventing Cholera Using Bacteriophages</h3><p>The biological factors that govern the dissemination and transmission of toxigenic Vibrio cholerae remain ill defined. By studying hundreds of cholera patient rice-water stools from clinics in Bangladesh and Haiti we found that most cholera patients shed high titers of at least one of three distinct species of V. cholerae-specific virulent (lytic) bacteriophage. We provide evidence that these phages prey extensively on V. cholerae within the human gastrointestinal tract, thus impacting the infection, dissemination, transmission and evolution of V. cholerae. Using genetic and phenotypic analyses we have begun to reveal the biology of these phages and important details of the ongoing arms race between each phage and V. cholerae. We have shown that the LPS O1 antigen and OmpU serve as receptors for these phages. V. cholerae phage-resistant escape mutants arise from mutations in the genes required for the production of these receptors, resulting in strains that are avirulent. By combining these phages we have developed a cocktail that, when administered to animals up to 24 hours prior to challenge, can prevent cholera. The combination of phages appears to prevent the appearance of mutants that can escape predation by all three phages. Ongoing studies seek to determine the frequency (or lower bound) at which escape mutants to the phage cocktail arise, as well as the impact, if any, of the phage cocktail on the gut microbiota in healthy animals.</p>

Andy Camilli, Tufts University

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<h3>Recurring Conflicts with a Single Predatory Phage Drive the Evolution of Vibrio cholerae</h3><p>The waterborne pathogen and causative agent of the diarrheal disease cholera, Vibrio cholerae, is antagonized by predatory phages in the environment as well as in human hosts during disease. The predatory phage ICP1 has been recovered from cholera patient stool and water samples over at least a 15-year period in Bangladesh and is consequently considered a persistent predator of epidemic V. cholerae in this region. The pervasiveness of ICP1 with continued cholera epidemics suggests that V. cholerae has strategies to limit ICP1 predation, and that ICP1 can evolve to overcome such defenses. Our work suggests that a key weapon for phage defense in epidemic V. cholerae are mobile genetic elements called PLEs (for phage-inducible chromosomal island-like elements). We have identified and characterized five unique PLEs in V. cholerae which all show specific anti-phage activity towards ICP1. Although the molecular basis for PLE-mediated anti-phage activity is not yet known, all PLEs exhibit a common, ICP1-dependent response, which initiates with the integrated PLE excising from the chromosome and circularizing. We demonstrate that PLE encodes a large serine recombinase that exploits an ICP1-specific protein, PexA, to trigger excision in response to infection. Our results uncover an aspect to the molecular specificity underlying the longstanding conflict between a single predatory phage and V. cholerae PLE and contribute to our understanding of the molecular arms race that drives long-term evolution between combatting phage and their bacterial hosts in nature.</p>

Kimberley Seed, University of California, Berkeley

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<h3>Drug Discovery at the Novartis Institutes for Biomedical Research</h3><p>The Novartis Institute for Tropical Diseases (NITD) is an independent research institute within NIBR that applies drug-discovery expertise to combat infectious tropical diseases. NITD is currently focused on parasitic pathogens, including malaria, cryptosporidiosis, and three major kinetoplastid diseases – human African trypanosomiasis (sleeping sickness), Chagas disease, and leishmaniasis. NITD scientists collaborate with academic and non-profit partners, including the Wellcome Trust, the Bill &amp; Melinda Gates Foundation, Medicines for Malaria Venture, and the Swiss Tropical Public Health Institute. NITD and collaborators have discovered two novel classes of antimalarials, which are currently in phase II clinical trials. One of these compounds, KAF156, has the potential to be a game-changer in malaria elimination. This presentation will provide an overview of NITD’s accomplishments in the discovery and development of novel therapies to treat and prevent neglected tropical diseases.</p>

Thierry Diagana, Novartis Institutes for Biomedical Research

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<h3>BLASTOFF – Keeping Up With A Cereal Killer</h3><p>Infectious plant diseases cause havoc to world agriculture and threaten to slow laudable efforts to launch a second green revolution to meet the food security needs of a booming world population. Filamentous pathogens such as the rice blast fungus, wheat stripe and stem rust, the Irish potato famine pathogen, and many others continue to trigger recurrent epidemics with far reaching consequences. In this talk, I will discuss how it is possible to perform cutting-edge research and significantly advance knowledge on economically important pathosystems, particularly in the post-genomics era. I will focus on the blast fungus Magnaporthe oryzae, a devastating cereal killer that infects the crops wheat, barley and rice, which are staple food for a majority of the world population. Together with collaborators Ryohei Terauchi (Kyoto University, Japan) and Mark Banfield (John Innes Centre, UK), we gained an unprecedented level of detail of the molecular interactions that define host-pathogen recognitions by solving the crystal structures of fungal effectors in complex with plant proteins and reconstructing the evolutionary history of these molecular interactions. Our aim is to build on these discoveries to drive both basic and applied plant pathology. We have started to develop a thorough understanding of the biophysical properties of pathogen effector binding to host proteins and their consequences on pathogenesis and immunity. Ultimately, we will deliver traits and non-transgenic cultivars for breeding disease resistance in crops.</p>

Sophien Kamoun, The Sainsbury Laboratory

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<h3>Combating the Cereal Killer: Investigating the Biology of Rice Blast Disease</h3><p>Rice blast is one of the most serious diseases affecting global rice production and each year destroys enough rice to feed 60 million people. Rice blast is caused by the fungus Magnaporthe oryzae, which is also the causal agent of wheat blast, a disease that now threatens wheat production in South America and South Asia. My research group is investigating the biology of plant infection by the blast fungus and using this information to develop new strategies to control blast diseases. During plant infection, M. oryzae forms a specialised infection structure called an appressorium. The infection cell generates enormous turgor, of up to 80 atmospheres, which is focused as mechanical force to breach the rice cuticle and enable entry of the fungus into plant tissue. Appressorium function depends on precise cell cycle control and autophagic recycling of the contents of the fungal spore into the developing infection cell. Re-polarisation of the appressorium requires a hetero-oligomeric septin GTPase complex that organises a toroidal F-actin network at the base of the appressorium. This allows protrusion of a rigid penetration hypha to invade epidermal cells, enabling the fungus to colonise rise tissue and cause disease. Once tissue is invaded the fungus undergoes differential expression and secretion of a large repertoire of effector proteins that can be directed into plant cells to suppress plant immunity. The fungus then uses primary pit fields to move from cell-to-cell within the host plant. We have identified key determinants of appressorium function and tissue colonisation, which are potential targets for disease intervention. We are also using knowledge of the population dynamics of the rice blast fungus to guide marker-assisted plant breeding strategies in Sub-Saharan Africa to provide more durable combinations of disease resistance genes into high yielding, locally adapted rice cultivars. I will present an overview of the biology of plant infection by the rice blast fungus, recent progress in understanding fungal pathogenicity, and describe how this knowledge is being utilised to guide disease control strategies.</p>

Nick Talbot, University of Exeter

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<h3>Follow the Effectors: Understanding Ancient and Emerging Blast Diseases on Rice and Wheat</h3><p>The ascomyceteous fungus, Magnaporthe oryzae (synonym of Pyricularia oryzae), causes disease on diverse grass host plants including the world’s major cereal crops. M. oryzae occurs as host-adapted populations including the Oryza pathotype (MoO), causing the ancient rice blast disease, and the Triticum pathotype (MoT), causing the recently emerged wheat blast disease. Wheat blast has spread and restricted wheat production within South America since it was first reported in Brazil in 1985. Movement and establishment of this explosive disease in Bangladesh in 2016 underscores the importance of developing sustainable control strategies for blast diseases. The hemibiotrophic rice blast fungus repeatedly invades living rice cells as it spreads within host tissue for 4 to 5 days before macroscopic lesions appear. During biotrophic invasion, the MoO fungus specifically expresses genes encoding dozens of effectors, termed cytoplasmic effectors, which are delivered inside living rice cells to take control. In contrast to effectors that remain in the host extracellular space, the fungus secretes cytoplasmic effectors using a nonconventional secretion system and concentrates them into a specialized interfacial structure, the biotrophic interfacial complex (BIC). So far, at least 30 of the BIC-localized effectors that are translocated into the cytoplasm of invaded rice cells move into neighboring rice cells through plasmodesmata, the natural communication channels between plant cells, presumably to prepare these host cells before further fungal invasion. New higher-resolution live cell imaging shows that cytoplasmic effectors are packaged in vesicles in BICs and the surrounding rice cytoplasm, leading to our current working hypothesis that the fungus manipulates plant endocytosis mechanisms for internalizing effectors inside living rice cells. Initial results suggest that the wheat blast fungus shares the same cytoplasmic effectors and infection strategies identified for the rice blast fungus. Current status and interesting contrasts between the ancient and emerging blast diseases will be discussed.</p>

Barbara Valent, Kansas State University

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<h3>Coming to Grips with Flu Drift</h3><p>Influenza A virus (IAV) imposes a significant socio-economic burden on humanity, killing hundreds of thousands, and costing tens of billions of dollars worldwide each year. Vaccination, the best hope for reducing the impact of influenza, is effective in only 60% of individuals even under optimal circumstances. The difficulty stems from the remarkable ability of influenza A virus (IAV) to evade existing immunity. To address antibody response questions, my laboratory has developed a unique panel of viruses that allows us to quantitate mouse anti-HA Ab and germinal center B cell responses at the level of individual antigenic sites. Our findings show that B cell responses demonstrate a characteristic immunodominance hierarchy that changes dynamically among the sites as as the response progresses, and is influenced in a complex manner by many of the variables listed above. I will also present recent analysis from my lab demonstrating the remarkable clock like addition of glycans to the HA head that forms the basis for several simple rules that appear to govern glycan addition.</p>

Jonathan Yewdell, NIAID

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<h3>Repurposing Canonical Antiviral Responses to Promote Viral Infection</h3><p>Cells infected by influenza virus mount a large-scale antiviral response and most ultimately initiate cell death pathways in an attempt to suppress viral replication. During a CRISPR knockout screen designed to query post-entry steps during infection, we identified a large class of presumptive antiviral factors, including IFIT2, as important enhancers of influenza virus replication. IFIT2 is an interferon stimulated gene with well-established antiviral function for some viruses. Contrary to expectations, we show here that IFIT2 is instead repurposed by influenza virus to support viral replication. IFIT2 interacts with viral RNAs, the viral nucleoprotein, and translating ribosomes to enhance viral gene expression and replication. IFIT2 also stimulates virally-induced apoptosis. Cells lacking IFIT2 fail to undergo apoptosis and survive infection. Remarkably, genetic and chemical ablation of apoptosis further reduced viral yield. Our results suggest that influenza virus has evolved to exploit the antiviral and apoptotic cellular environment, redirecting these classically antiviral events into pro-viral effectors, a process we termed “going pro.” Moreover, it is highly unlikely that the re-purposing of antiviral genes is specific to influenza A virus, but rather is generalizable to additional viruses and other antiviral viral proteins defining a new interface between the virus and host.</p>

Andrew Mehle, University of Wisconsin-Madison

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<h3>100 Years and Counting: Influenza Continues to Stump Us</h3><p>This year will mark the 100th anniversary of the 1918 influenza pandemic. What have we learned during this time? What questions still remain? Is influenza still a threat and if so, what/who/where should we be focusing our surveillance efforts? And what’s up with our vaccine? Is it possible to create a universal flu vaccine? In this talk, Dr. Schultz-Cherry will present a brief background on influenza viruses, introduce the audience to influenza surveillance including the CEIRS and WHO networks, discuss influenza vaccines, and present new work on how changes in the host population could impact influenza disease severity, transmission and thwart the production of more effective vaccines.</p>

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