| WEEK # | TOPICS | LECTURE SUMMARIES |
|---|---|---|
| 1 | Introduction and Course Overview |
Introduction
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| Topic 1: Fixer Uppers: Parasite-mediated Remodeling of the Host Cell and its Disease Implications: During infection, intracellular microorganisms tailor host cell pathways to their own needs, enabling them to control cell responses, avoid host defenses and establish a niche in which to grow. The themes covered in this topic will include mechanisms of parasite protein export, subversion of host signaling cascades, remodeling of the host actin cytoskeleton by the parasite and manipulation of the host environment at large. | ||
| 2 | Fixer Uppers: Parasite-Mediated Remodeling of the Host Cell and its Disease Implications I |
Peixoto, L., F. Chen, et al. "Integrative Genomic Approaches Highlight a Family of Parasite-specific Kinases that Regulate Host Responses." Cell Host Microbe 8, no. 2 (2010): 208–18. This paper describes a phylogenomic approach to characterize the kinome of Toxoplasma gondii, a protozoan parasite. This paper includes methods of identification and characterization of new virulence factors and how to use microarray technology to measure the expression levels of large numbers of genes simultaneously as a way to examine the effects of parasite gene expression on the host cell. Ong, Y. C., M. L. Reese, et al. "Toxoplasma Rhoptry Protein 16 (ROP16) Subverts Host Function by Direct Tyrosine Phosphorylation of STAT6." The Journal of Biological Chemistry 285, no. 37 (2010): 28731–40. This work exemplifies the generation of parasite knockout strains to define the molecular function of specific genes. We will discuss approaches to the biochemical characterization of a parasite kinase and identification of its host cell targets as well as the role of host STAT6, a transcription factor, in infection. |
| 3 | Fixer Uppers: Parasite-Mediated Remodeling of the Host Cell and its Disease Implications II |
Cyrklaff, M., C. P. Sanchez, et al. "Hemoglobins S and C Interfere with Actin Remodeling in Plasmodium falciparum—infected Erythrocytes." Science 334, no. 6060 (2011): 1283–6. This paper reports a cell biological mechanism for the basis of host resistance to infection by Plasmodium falciparum (the disease-causing agent of malaria) in patients who display the sickle-cell hemoglobin trait. Grüring, C., A. Heiber, et al. "Uncovering Common Principles in Protein Export of Malaria Parasites." Cell Host and Microbe 12, no. 5 (2012): 717–29. Protein export from the Plasmodium parasite into the host cytoplasm is necessary for the acute stage of infection and the worst symptoms of malaria. The authors discover a newlayer of regulation of protein export that unifies what were thought to be divergent export pathways. This newly discovered protein export step is sufficient to distinguish exported from non-exported proteins. Thus, this work facilitates identification of novel exported proteins and identifies new targets for drug design. |
| Topic 2: Invasion of the Host Cell: Adhesion to host cells and invasion of the intracellular space are critical steps for the traversal of host barriers leading to organ infection and pathogen spread in the organism. Invasion involves an intimate association of the pathogen with the host cell. The entire process is highly orchestrated and driven by the pathogen. We will discuss papers showing how pathogens have the ability to build its own anchorage site or take advantage of cell surface receptors to invade and disseminate to multiple organs. | ||
| 4 | Invasion of the Host Cell I |
Alexander, D. L., J. Mital., et al. "Identification of the Moving Junction Complex of Toxoplasma gondii: A Collaboration between Distinct Secretory Organelles." PLoS Pathogens 1, no. 2 (2005): e17. This work demonstrates pathogen-driven invasion of the host cell through the orchestrated secretion of proteins from specialized secretory organelles, rhoptries and micronemes. Rhoptry and micronemal proteins promote contact between parasite and host plasma membranes in the form of a ring-shaped moving junction that begins at the anterior end of the parasite and then migrates posteriorly. Straub, K. W., E. D. Peng, et al. "The Moving Junction Protein RON8 Facilitates Firm Attachment and Host Cell Invasion in Toxoplasma gondii." PLoS Pathogens 7, no. 3 (2011): e1002007. Another example of pathogen-driven invasion of the host cell. This paper shows the importance of targetting of proteins to their subcellular localizations. How invasion of the host cell translates into virulence in the mouse model will be discussed. |
| 5 | Invasion of the Host Cell II |
Fernandes, M. C., M. Cortez, et al. "Trypanosoma cruzi Subverts the Sphingomyelinase-mediated Plasma Membrane Repair Pathway for Cell Invasion." Journal of Experimental Medicine 208, no. 5 (2011): 909–21. Trypanosoma cruzi is the protozoan pathogen that causes Chagas disease, which can develop over many years into a potentially life-threatening chronic illness affecting the digestive system and heart. This report describes how T. cruzi is able to mimic a form of membrane damage to the extracellular surface of the host cell, thereby gaining entry by co-opting the host membrane repair machinery. Calderón, J., E. Maganto-Garcia, et al. "The Receptor Slamf1 on the Surface of Myeloid Lineage Cells Controls Susceptibility to Infection by Trypanosoma cruzi." PLoS Pathogens 8, no. 7 (2012): e1002799. This work reports the discovery of a molecular basis for T. cruzi's ability to infect myocardial (heart) tissue. The authors identify Slamf1, which is a host cell surface marker found in myocardial tissue, as a determining factor of infection of these tissues, thus providing a potential drug target to treat the chronic phase of Chagas disease. |
| 6 | Invasion of the Host Cell III |
Nikitas, G., C. Deschamps, et al. "Transcytosis of Listeria monocytogenes Across the Intestinal Barrier upon Specific Targeting of Goblet Cell Accessible E-cadherin." Journal of Experimental Medicine 208, no. 11 (2011): 2263–77. Listeria is a gram-positive food-borne bacterium. This paper sheds light on the interaction between InlA (a bacterial irulence factor) and E-cadherin, a host cell surface protein. The interaction between InlA and E-cadherin is crucial for Listeria oral infectivity. This report demonstrates the interaction of pathogen surface proteins with host cell receptors to promote translocation across the intestinal epithelium and cause systemic infection. Also, it shows the importance of choosing the right target cells for infection. Bou Ghanem, E. N., G. S. Jones, et al. "InlA Promotes Dissemination of Listeria monocytogenes to the Mesenteric Lymph Nodes during Food Borne Infection of Mice." PLoS Pathogens 8, no. 11 (2012): e1003015. This paper describes a new role for InlA in facilitating systemic spread via the lymphatic system after invasion of the gut mucosa. We will discuss the importance of appropriate animal models and routes of inoculation to study infection. |
| Topic 3: Determinants of Pathogen Proliferation within the Host Cell: Intracellular pathogens are presented with a rich but challenging environment within their host cell niche. To survive, they must actively procure host nutrients for which they might be autotrophic but at the same time they must also avoid intracellular host defenses. We will examine how both eukaryotic and prokaryotic pathogens can subvert or be destroyed by the host autophagy pathway. We will also study how pathogens can alter host cell biology to facilitate nutrient uptake and conversely how the host can restrict nutrient access to starve the pathogen. | ||
| 7 | Determinants of Pathogen Proliferation within the Host Cell I |
Jaramillo, M., M. A. Gomez, et al. "Leishmania Repression of Host Translation Through mTOR Cleavage is Required for Parasite Survival and Infection." Cell Host Microbe 9, no. 4 (2011): 331–41. Leishmaniasis is a disease caused by several species of the genus Leishmania, which are protists (single cell eukaryotes). Leishmaniasis is largely confined to the skin and produces skin lesions, but can rarely affect vital organs and be fatal to the patient. This report presents a molecular basis for how Leishmania disrupts host protein synthesis by disabling the pro-growth mTORC1 kinase complex, which enables intracellular proliferation. Wilson, J., C. Huynh, et al. "Control of Parasitophorous Vacuole Expansion by LYST/Beige Restricts the Intracellular Growth of Leishmania amazonensis." PLoS Pathogens 4, no. 10 (2008): e1000179. Inside the host cell, Leishmania resides within a vacuole it forms called the parasitophorous vacuole. This paper characterizes the effect of a host protein on parasitophorous vacuole size in Leishmania and its concordant effect on growth. This work provides insight into the relationship between vacuole size and growth. |
| 8 | Determinants of Pathogen Proliferation within the Host Cell II |
Checroun, C., T. D. Wehrly, et al. "Autophagy-mediated Reentry of Francisella tularensis into the Endocytic Compartment after Cytoplasmic Replication." Proceedings of National Academy of Sciences of the United States of America 103, no. 39 (2006): 14578–83. This work studies the interaction between an intracellular bacterium, Francisella, and the endocytic pathway and demonstrates how bacterial pathogens cycle through different host cell compartments during their intracellular cycles. Chong, A., T. D. Wehrly, et al. "Cytosolic Clearance of Replication-deficient Mutants Reveals Francisella tularensis Interactions with the Autophagic Pathway." Autophagy 8, no. 9 (2012): 1342–56. Life-death balance in the cytosol of the host cell can be mediated by autophagy, a process that involves cell degradation of unnecessary or dysfunctional cellular components. The authors describe the capture of replication-deficient Francisella strains and show how replication-competent bacteria interfere with autophagic recognition, therefore ensuring survival and proliferation. |
| 9 | Determinants of Pathogen Proliferation within the Host Cell III |
Nguitragool, W., A. A. Bokhari, et al. "Malaria Parasite Clag3 Genes Determine Channel-Mediated Nutrient Uptake by Infected Red Blood Cells." Cell 145, no. 5 (2011): 665–77. The authors present a mechanistic explanation of how Plasmodium alters the membrane permeability of the host erythrocyte to access certain nutrients. Nutrient acquisition by the parasite is an important target for anti-malarial drug research. Zhao, H., A. Konishi, et al. "Lipocalin 2 Bolsters Innate and Adaptive Immune Responses to Blood-stage Malaria Infection by Reinforcing Host Iron Metabolism." Cell and Host Microbe 12, no. 5 (2012): 705–16. Lipocalin 2 is an innate immune factor secreted by a neutrophil (a type of white blood cell) upon encountering an infected cell. This report describes a central role of Lipocalin 2 in the host’s fight against Plasmodium infection by regulating cellular iron homeostasis. |
| 10 | Field Trip | For their field trip, students will choose a seminar from a local academic institution, focusing on infectious disease research or drug design. |
| Topic 4: Both Sides of the Battle: Innate Immunity versus Virulence Factors: There is fierce selection pressure driving the co-evolution between specific host innate immune molecules and the pathogenic factors that oppose them. In many cases, genetic variation of either of these types of molecules can determine the severity of infection and ultimately disease outcomes. In the next 3 weeks, we will study specific pathogenic mechanisms for immune avoidance and how the host specifically recognizes and targets certain pathogens for destruction. | ||
| 11 | Both Sides of the Battle: Innate Immunity versus Virulence Factors I |
Yoshikawa, Y., M. Ogawa, et al. "Listeria monocytogenes ActA-mediated Escape from Autophagic Recognition." Nature Cell Biology 11, no. 10 (2009): 1233–40. A wolf in sheep's skin—Listeria avoids autophagic recognition by exploiting the ability of its surface virulence factor, ActA, to recruit host cell cytoskeletal proteins, disguising itself as a host cell organelle. Ribet, D., M. Hamon, et al. "Listeria monocytogenes Impairs SUMOylation for Efficient Infection." Nature 464, no. 7292 (2010): 1192–5. This work exemplifies how to take advantage of the comparison of phenotypes between pathogenic and non-pathogenic strains of the same bacterial species to investigate the effects of infection on the host cell. This paper describe how bacterial targeting of the SUMO pathway, an ubiquitin-like pathway that regulates a wide range of cellular events, can be used to modify simultaneously the activities of many different proteins of the host cell. |
| 12 | Both Sides of the Battle: Innate Immunity versus Virulence Factors II |
Vanhollebeke, B., G. De Muylder, et al. "A Haptoglobin-Hemoglobin Receptor Conveys Innate Immunity to Trypanosoma brucei in Humans." Science 320, no. 5876 (2008): 677–81. This paper unravels the mechanism through which host HDL-lipoprotein (a form of cholesterol) is internalized by the parasite. This process is required for parasite survival in mice but has the opposite effect in humans, in whom it leads to parasite destruction through internalization of a toxic component of human HDL. Jones, J. W., N. Kayagaki, et al. "Absent in Melanoma 2 is Required for Innate Immune Recognition of Francisella tularensis." Proceedings of National Academy of Sciences of the United States of America 107, no. 21 (2010): 9771–6. This paper discusses the role of the inflammasome, a component of the innate immune system responsible for activation of inflammatory processes, in infection. This study identifies AIM2, a DNA-sensing inflammasome component, as a crucial sensor of Francisella infection and provides genetic proof of the critical role of AIM2 in host innate immunity to intracellular pathogens. |
| Topic 5: Virus Meets Parasite: How Viruses and Parasites Interact, Affecting Host Fitness: This final week will focus on two exciting examples of the interaction between a virus and the parasite Leishmania. In one case, a viral pathogen of the parasite itself affects the disease outcome of the host. The second case demonstrates that the virulence of HIV is affected by the presence of Leishmania infecting the same host. These studies reflect a trend in infectious disease research to examine how different pathogens interact within the same host and affect host fitness in a model more representative of the real world. | ||
| 13 | Virus Meets Parasite: How Viruses and Parasites Interact, Affecting Host Fitness |
Ives, A., C. Ronet, et al. "Leishmania RNA Virus Controls the Severity of Mucocutaneous Leishmaniasis." Science 331, no. 6018 (2011): 775–8. This report describes how a virus that infects Leishmania itself causes a more severe disease outcome in the host by affecting the host’s immediate, partially specific immune response to infection. Mock, D. J., J. A. Hollenbaugh, et al. "Leishmania Induces Survival, Proliferation and Elevated Cellular dNTP Levels in Human Monocytes Promoting Acceleration of HIV Co-infection." PLoS Pathogens 8, no. 4 (2012). The authors characterize molecular processes induced by Leishmania that increase virulence of HIV in co-infected individuals. |
| 14 | Oral Presentations and Discussion of the Course | Oral Presentations |