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7.346 | Spring 2013 | Undergraduate

# Virus-host Interactions in Infectious Diseases

### Written Assignment (Due Week 7)

You will be provided with relevant parts of a research paper (materials and methods, figures, tables and results) minus the title and abstract. Using your knowledge, compose an original title and a 400–500 word abstract to describe the paper. Your abstract should be concise, must summarize the major results of the research paper in a language that non-specialists can understand, and should clearly state the significance and broader impact of the findings. This title and abstract must be your original work, and should not be a copy or modification of the published title and abstract (i.e. do not search literature databases for them). The most important component of this assignment is your critical thinking and interpretation of the conclusions that can be drawn from the data/experiments described in the paper.

### End of Term Oral Presentation (Presented in the Final Class Meeting)

By the end of this course, you should be able to freely browse the primary research literature and critically analyze experiments, results, and conclusions. To consolidate these skills, you will select an article from a list of primary research articles (provided by the instructors) related to host-virus interactions and critically analyze the article in a 20 minute presentation (about 15 slides) to the class. The presentation must highlight the relevance of the paper to virus invasion of the host cell by immune evasion, the rationale of the experiments and approach, the experiments and controls, any missing experimental controls, the results, and the overall conclusions. In your presentation you should communicate your critical assessment of the paper rather than present a summary of the data/figures. You should explicitly identify and discuss the key figure or table in the paper and the key control for that experiment, why you think that the conclusions of the paper are supported by the data, or what alternate explanations are possible.

### Course Overview

This page focuses on the course 7.346 Virus-Host Interactions in Infectious Diseases as it was taught by Dr. Sumana Sanyal and Dr. Joseph Ashour in Spring 2013.

This course is one of many Advanced Undergraduate Seminars offered by the Biology Department at MIT. In these pass/fail seminars, students draw upon primary research literature to discuss and learn about current biological research in a highly interactive, small-group setting. This particular seminar focuses on virus-host interactions in infectious diseases.

### Course Outcomes

This course is designed to encourage critical thinking skills in future scientists. Students learn how to read research articles and evaluate the strengths and weaknesses of the experiments presented.

### Student Information

#### Enrollment

8 students

#### Breakdown by Year

A mix of undergraduate juniors and seniors.

#### Breakdown by Major

3/4 biology majors, 1/4 engineering majors.

#### Typical Student Background

Students have typically taken introductory level courses in biology and chemistry.

#### Ideal Class Size

This class works best with fewer than ten students. Students must feel comfortable speaking in class, and that’s easier for the students in a smaller group.

### Curriculum Information

#### Prerequisites (Recommended)

- 7.03 Genetics
- 7.05 General Biochemistry
- 7.06 Cell Biology
- 7.28 Molecular Biology

#### Requirements Satisfied

None

#### Offered

Seminars are offered each semester and are topics based. This particular topic is not offered every semester.

### How Student Time Was Spent

During an average week, students were expected to spend 6 hours on the course, roughly divided as follows:

#### Seminar Meeting

The first ten minutes of class were spent on the students sharing their thoughts on the two research articles assigned as reading for the week. Were the papers interesting? Were they difficult to read? How strong were the experimental designs and conclusions?

The remainder of the time was spent discussing the papers in detail, one at a time. One student would give an overall summary of the article. Each figure would then be presented by a student, who would describe the methodology used, the findings, and the strengths and weaknesses of the conclusions.

Open discussion was encouraged amongst the students. The instructors intentionally remained outside the discussions. Occasionally if a major point of the paper was missed or misunderstood, or glaring weaknesses or strengths were not picked up by the students, the instructors asked open-ended questions to guide students toward these points.

#### Out of Class

- Reading assignments – two journal articles per week
- Written assignments

WEEK # | TOPICS | LECTURE SUMMARIES
--- | --- | ---

1 | Introduction and Course Overview | The first meeting will consist of introductions, both of the instructors and the students. The instructors will present a general overview of the course, discuss the format, and explain the preparation that will be expected of each student each week. The instructors will also provide an overview of the course material with an introduction to general aspects of viral infection and concepts of host innate immunity.

2 | Host Sensors of Viral Infection-I | Induction of the anti-viral innate immune response depends on recognition of viral components by sensors present in the host. One of the key cytoplasmic viral sensors is the RNA helicase that recognizes double-stranded RNA generated during a viral infection. In this class, we will discuss the mechanism of Retinoic acid Induced Gene-1 (RIG-I) mediated viral sensing and subsequent activation of interferon (IFN) responses along with a strategy adopted by influenza virus to evade detection by this anti-viral component. From paper 1, you will learn about the role of ubiquitin in activating RIG-I that is critical for the anti-viral response, and from paper 2 we will discuss the mechanism by which influenza Non-Structural protein 1 (NS1) interacts directly with RIG-I to inhibit production of interferons.

3 | Host Sensors of Viral Infection-II: The Road to IFN Production Runs through the Mitochondria | The type-I interferon response constitutes one of the first lines of defense against virus infections. In the first paper you will learn that the signaling pathway for inducing IFN production after detection of virus relies on the Mitochondrial Anti-Viral Signaling protein (MAVS). In the second paper we will read about the discovery of the first viral protein known to directly target MAVS and inhibit its function by cleaving it from the mitochondrial membrane— Hepatitis C Virus Non-Structural 3–4a protein (NS3-4A) protein.

4 | Secreted IFN – In the Extracellular Space, No One Can Hear You Scream | Vaccinia virus (VV) is the prototypic member of the poxvirus family of cytoplasmic DNA viruses. VV and other poxviruses have evolved clever strategies to evade the anti-viral effects of IFNs. The first paper we will discuss is one of the classics describing the initial discovery of the IFN cytokine. From the second paper, you will learn how VV employs mimicry to block the anti-viral activity of IFNs by expressing a decoy receptor that binds the cytokine.

5 | Vaccines: We Win, Finally. Not So Fast | Successful vaccines, which prevent viral infection, generate neutralizing antibodies. Our first paper presents the most promising approach in vaccine development for dengue virus (DENV). We will discuss why vaccines against dengue virus might do more harm than good. The second paper will look at the clinical development of a neutralizing antibody to treat human Cytomegalovirus Virus (hCMV) infection, which was aborted due to lack of efficiency, followed by the discovery of a bizarre solution hCMV has employed to evade neutralizing antibodies.

6 | Trip to Sanofi/Pasteur | We will visit the Sanofi/Pasteur Research Institute in Cambridge, which is actively involved in developing vaccines for viruses such as influenza. This visit will allow the students to appreciate the translational aspect of the research topics that we discuss in class and see the laboratory setting in an institute dedicated to fighting against infectious diseases and the equipment and the techniques that are routinely used.

7 | A New Player in the Puzzle of Filovirus Entry into Host Cells | Viruses of the genera Ebola virus and Marburg virus are filoviruses that cause haemorrhagic fever in primates, with extremely high fatality rates. Studies have focused on elucidating how these viruses enter host cells, with the aim of developing therapeutics. From the first paper, you will learn about how Ebola virus utilization of host cathepsins for cellular entry permits the virus to evade immune recognition while also providing a new target for therapeutics. From paper 2, we will discuss a novel screening strategy to identify host factors required for Ebola viral infection. This method resulted in identification of NPC1 as a necessary host protein that mediates Ebola virus entry.

8 | IFN Signaling: United STATs and the Rule of V | IFN binding to the IFN receptor leads to stimulation of the IFN signaling pathway and subsequent creation of the antiviral state, as an endpoint of signal transduction through the Janus Kinase-Signal Transduction and Activator of Transcription (JAK-STAT) pathway. Our first paper, a classic, studies how the pathway was characterized using chemical mutagenesis. From the second paper we will look at how one virus family (paramyxovirus) has particular expertise in blocking the IFN signaling pathway and focus on the Nipah virus V protein which binds and sequesters the STAT proteins.

9 | Mechanisms of Human Cytomegalovirus Infection and Restriction | Little is known about the mechanism by which IFNs inhibit human Cytomegalovirus (hCMV) replication. Viperin is an interferon-inducible protein that is expressed during infection by hCMV. Despite being a protein of an anti-viral innate immune response, Viperin can enhance infection in host cells. In this class we will discuss the two distinct modes of operation of Viperin. Paper 1 describes how Viperin functions to restrict viral infection. Paper 2 describes a novel strategy that hCMV employs to coopt the function of Viperin to facilitate the infectious process.

10 | HIV Restriction Factors and Mechanism of Evasion | Interferon-induced genes function to inhibit viral infection at a number of steps. Tetherin is an example of an interferon-induced gene that blocks release of Human Immune-deficiency Virus (HIV) and other enveloped viruses. In this session we will discuss the opposing modes of action on Tetherin by HIV and the host cell. Paper 1 describes the mechanism through which Tetherin acts to block release of viral particles by directly tethering nascent enveloped virions to the surface of infected cells. Paper 2 describes subsequent strategies that HIV has evolved to counteract this anti-viral activity through degradation of Tetherin in the lysosomes.

11 | Interferon-Induced Transmembrane (IFITM) Proteins as Restriction Factors for Influenza Virus | The host expresses a number of interferon-induced genes to defend against influenza virus infection. The IFITM proteins are such a class of restriction factors that function to inhibit a number of viruses, such as influenza, dengue virus and West Nile virus. From paper 1, we will discuss a screening strategy for identification of anti-viral host proteins and the initial discovery of this family of proteins that mediate cellular innate immunity. From paper 2, you will learn about IFITM3 mutations discovered in the human population and linked to increased morbidity and mortality during influenza infection.

12 | End-term final assignment | See “Assignments” for a description of what is expected. The students will receive written evaluations of their presentations from the instructor. Discussion of final assignment. We will conclude with a general discussion to summarize what we covered in the course and address any questions that the students might have. Students are encouraged to provide feedback about any aspect of the course.

WEEK # | TOPICS | READINGS
--- | --- | ---

1 | Host Sensors of Viral Infection-I See the Lecture Summary | No readings

2 | Introduction and Course Overview See the Lecture Summary | Zeng, W., L. Sun, et al. “Reconstitution of the RIG-I Pathway Reveals a Signaling Role of Unanchored Polyubiquitin Chains in Innate Immunity.” Cell 141, no. 2 (2010): 315–30. Mibayashi, M., L. Martinez-Sobrido, et al. “Inhibition of Retinoic Acid-Inducible Gene I-Mediated Induction of Beta Interferon by the NS1 Protein of Influenza A Virus.” Journal of Virology 81, no. 2 (2007): 514–24.

3 | Host Sensors of Viral Infection-II: The Road to IFN Production Runs through the Mitochondria. See the Lecture Summary | Kawai, T., K. Takahashi, et al. “IPS-1, An Adaptor Triggering RIG-I and Mda5-Mediated Yype-I Interferon Induction.” Nature Immunology 6, no. 10 (2005): 981–8. Li, XD., L. Sun, et al. “Hepatitis C Virus Protease NS3/4A Cleaves Mitochondrial Antiviral Signaling Protein Off the Mitochondria to Evade Innate Immunity.” Proceedings of the National Academy of Sciences 102, no. 49 (2005): 17717–22.

4 | Secreted IFN – In the Extracellular Space, No One Can Hear You Scream See the Lecture Summary | Smith, T. J., and R. R. Wagner. “Rabbit Macrophage Interferons I. Conditions For Biosynthesis By Virus-Infected And Uninfected Cells.” Journal of Experimental Medicine 125, no. 4 (1967): 559–77. Alcamí, A., J. A. Symons, et al. “The Vaccinia Virus Soluble Alpha/Beta Interferon (IFN) Receptor Binds to the Cell Surface and Protects Cells from the Antiviral Effects of IFN.” Journal of Virology 74, no. 23 (2000): 11230–9.

5 | Vaccines: We Win, Finally. Not So Fast See the Lecture Summary | Guirakhoo, F., J. Arroyo, et al. “Construction, Safety, and Immunogenicity in Nonhuman Primates of a Chimeric Yellow Fever-Dengue Virus Tetravalent Vaccine.” Journal of Virology 75, no. 16 (2001): 7290–304. Manley K., J. Anderson, et al. “Human Cytomegalovirus Escapes a Naturally Occurring Neutralizing Antibody by Incorporating It into Assembling Virions.” C_ell Host and Microbe_ 10, no. 3 (2011): 197–209.

6 | Trip to Sanofi/Pasteur See the Lecture Summary | Field Trip—No Readings

7 | A New Player in the Puzzle of Filovirus Entry into Host Cells See the Lecture Summary | Chandran, K., N. J. Sullivan, et al. “Endosomal Proteolysis of the Ebola Virus Glycoprotein Is Necessary for Infection.” Science 308, no. 5728 (2005): 1643–5. Carette, J. E., M. Raaben, et al. “Ebola Virus Entry Requires Cholesterol Transporter Niemann Pick-C1.” Nature 477, no. 7364 (2011): 340–3.

8 | IFN Signaling: United STATs and the Rule of V See the Lecture Summary | Leung, S., S. A. Qureshi, et al. “Role of STAT2 in the Alpha Interferon Signaling Pathway.” Molecular and Cellular Biology 15, no. 3 (1995): 1312–7. Rodriguez, J. J., J. P. Parisien, et al. “Nipah Virus V Protein Evades Alpha and Gamma Interferons by Preventing STAT1 and STAT2 Activation and Nuclear Accumulation.” Journal of Virology 76, no. 22 (2002): 11476–83.

9 | Mechanisms of Human Cytomegalovirus Infection and Restriction See the Lecture Summary | Chin, K., and P. Cresswell. “Viperin (cig5), An IFN-inducible Antiviral Protein Directly Induced By Human Cytomegalovirus.” Proceedings of the National Academy of Sciences 98, no. 26 (2001): 15125–30. Seo, J., R. Yaneva, et al. “Human Cytomegalovirus Directly Induces the Antiviral Protein Viperin to Enhance Infectivity.” Science 332, no. 6033 (2011):1093–7.

10 | HIV Restriction Factors and Mechanism of Evasion See the Lecture Summary | Perez-Caballero, D., T. Zang, et al. “Tetherin Inhibits HIV-1 Release by Directly Tethering Virions to Cells.” Cell 139, no. 3 (2009): 499–511. Mitchell, R. S., C. Katsura, et al. “Vpu Antagonizes BST-2–Mediated Restriction of HIV-1 Release via β-TrCP and Endo-Lysosomal Trafficking.” PLoS Pathogens 5, no. 5 (2009): e1000450.

11 | Interferon-Induced Transmembrane (IFITM) Proteins as Restriction Factors for Influenza Virus See the Lecture Summary | Brass, A. L., I. Huang, et al. “The IFITM Proteins Mediate Cellular Resistance to Influenza A H1N1 Virus, West Nile Virus, and Dengue Virus.” Cell 139, no. 7 (2009): 1243–54. Everitt A. R., S. Clare, et al. “IFITM3 Restricts The Morbidity and Mortality Associated With Influenza.” Nature 484, no. 7395 (2012): 519–23.

12 | End-Term Final Assignment See the Lecture Summary | Final Assignment Due—No Readings

### Course Meeting Times

Lectures: 1 session / week, 2 hours / session

### Prerequisites

Recommended prerequisites are:

7.03 Genetics

7.05 General Biochemistry

7.06 Cell Biology

7.28 Molecular Biology

### Course Description

Co-evolution and adaptation between viruses and humans are often portrayed as a zero-sum biological arms race. Viruses enter host cells equipped with an array of mechanisms to evade the host defense responses and replicate. The rapid rate of mutation of viruses permits evolution of various methodologies for infection, which in turn drive development of non-specific but highly effective host mechanisms to restrict infection.

This class will discuss the varied solutions each side has developed as a means for survival. Focus will be on protein-protein interactions, host mimicry, intra-cellular trafficking, hijacking of host-cell machinery and up-regulation of multiple signaling pathways and subsequent induction of antiviral proteins. We will use examples drawn from human disease-causing pathogens that contribute seriously to the global health burden, including HIV, influenza and dengue virus. Primary research papers will be discussed to help students learn to pose scientific questions and design and conduct experiments to answer the questions and critically interpret data. We will visit a local biotechnology company to learn how the knowledge and techniques discussed in class are being applied towards vaccine development.

### Format

The course will meet weekly, and two original papers from the research literature will be discussed each week. Students are expected to read both papers in advance and to be prepared for a round-table discussion (with the exception of week 1, when the instructors will provide an overview of the course material). The emphasis will be on critical reading of key papers in the field of protein virus-host interactions, both at the data and conceptual levels. At the end of each session, the instructors will present an introduction to the topic of the following week’s assigned reading.

### Grading

This course is graded pass/fail. The grading will be based on regular participation in the weekly meetings as well as on the midterm written assignment and the end of term oral presentation.

### Calendar

WEEK # | TOPICS | KEY DATES
--- | --- | ---

1 | Introduction and Course Overview |

2 | Host Sensors of Viral Infection-I |

3 | Host Sensors of Viral Infection-II: The Road to Interferon (IFN) Production Runs through the Mitochondria |

4 | Secreted IFN – In the Extracellular Space, No One Can Hear You Scream |

5 | Vaccines: We Win, Finally. Not So Fast |

6 | Trip to Sanofi/Pasteur | Field Trip to Sanofi/Pasteur

7 | A New Player in the Puzzle of Filovirus Entry into Host Cells | Written Assignment Due

8 | IFN Signaling: United STATs and the Rule of V |

9 | Mechanisms of Human Cytomegalovirus Infection and Restriction |

10 | HIV Restriction Factors and Mechanism of Evasion |

11 | Interferon-Induced Transmembrane (IFITM) Proteins as Restriction Factors for Influenza Virus |

12 | End-Term Final Assignment | End of Term Final Assignment

## Course Info

##### Instructors

- Dr. Sumana Sanyal
- Dr. Joseph Ashour

##### Departments

- Biology

##### As Taught In

Spring 2013

##### Level

Undergraduate

##### Topics

- Science
  - Biology
    - Cell Biology
    - Molecular Biology
    - Virology

##### Learning Resource Types

co_present Instructor Insights

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