Montana had always been athletic and considered herself to be very healthy and in great shape. Even during finals week she had managed her daily 5 mile run. By mid-June, however, she noticed that she was exhausted after her normal run. As the summer went on, running for even short distances caused chest pain and dizziness. At first she blamed the hot Tucson weather even though she was running at dawn, but finally she visited her family doctor for a checkup. Her physician immediately sent her to a cardiologist, who diagnosed dilated cardiomyopathy (DCM) and put her on the heart transplant registry. Montana was fortunate to receive a new heart approximately six months after she was diagnosed. She was able to resume her studies and her running.
Figure 1: Left image: diagram of a normal heart and one with dilated cardiomyopathy (DCM). From the National Institute of Alcohol Abuse and and Alcoholism. http://www.niaaa.nih.gov/ Right image: Echocardiograms of normal and DCM hearts, showing the enlarged size of the latter. From The Pathology of Systolic and Diastolic Heart Failure. Kisslo and Adams. http://www.echoincontext.com/ 2002tele/pathologySupp.asp
Dilated cardiomyopathy (DCM) is a condition in which the heart becomes enlarged and pumps blood very inefficiently (Figure 1). Many of the 9,000-20,000 cases of DCM diagnosed in the U. S. each year are classified as idiopathic, meaning of unknown cause. Half of these patients die within two years. Treatment is heart transplantation; about half of all heart transplants are done to treat DCM. It is estimated that 10-20% of all idiopathic DCM is the result of an infection with Coxsackievirus B (CVB).
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Figure 2 Coxsackievirus B structure. Coxsackieviruses are approximately 30 nanometers in diameter. Their positive sense RNA genome is surrounded by a protein capsid composed of 32 capsomeres made up of four structural proteins (VP1-4). CVB are not enveloped. In addition to capsid proteins, the viral genome encodes an RNA-dependent RNA polymerase for viral replication and several viral proteases for assembly. From the Enterovirus Research Laboratory, University of Nebraska, http://www.unmc.edu/Pathology/Enteroviruslab/default.htm |
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Coxsackieviruses are members of the Picornavirus family. They are small (pico), RNA (rna)-containing icosahedral viruses (Figure 2). Other members of the same family include the viruses that cause colds, polio, meningitis, skin rashes, and hepatitis A (Figure 3). Picornaviruses are transmitted by the fecal-oral route. To date, six serotypes of CVB have been identified; all are able in infect and kill heart cells in tissue culture. CVB3 is the most common serotype associated with myocarditis (inflammation of the heart muscle). Other pathogens that can cause myocarditis include bacteria (streptococcus, pneumococcus, staphylococcus, cholera), fungi (aspergillis, candida), protozoan parasites (trypanosomes), helminth worms (ascarid, filaria) and viruses (CVB, adenovirus, HIV, influenza, cytomegaolvirus). Infection with CVB is often asymptomatic or associated with mild disease. Often myocarditis occurs during CVB infection but the heart soon recovers with no lasting effects. DCM may occur weeks to months following CVB infection.
Figure 3: Pathology of enteroviruses. From Dr. Richard Hunt, University of South Carolina, http://pathmicro.med.sc.edu/virol/picorna.htm
Final Exam Questions
1. (50 points) Describe the immune mechanisms that could damage the heart muscle in response to infection with Coxsackievirus B (CVB). Your answer should include cells and molecules from both innate and adaptive immunity and should be specific for a virus infection of the heart.
2. (25 points) In addition to immunopathology, heart muscle damage caused by the immune response to CVB, it is also thought that DCM may be the result of an autoimmune disease triggered by CVB infection. However, DCM might also be caused by a persistent virus infection resulting in a prolonged immune response. Describe two properties of the immune system that you could need to detect in DCM patients that would convince you that the DCM was an autoimmune disease, and tell me how you would detect (measure) them. You have access to DCM patient blood and heart tissue (the heart is removed when a transplant is done).
3. (25 points) Brainstorm a vaccine for CVB. Include the type of vaccine you would develop, what immune response would be protective against CVB, who you would vaccinate, and any possible risks associated with vaccination. Explain your choices.
REMEMBER:
This exam is designed to evaluate your knowledge of immunology as well as your ability to analyze and evaluate immunology information. EXPLAIN all your answers.
There are several possible answers to these questions (especially #3); your detailed explanations are more important that the specific vaccine you choose.
This exam is to be completed INDIVIDUALLY. Evidence of cheating will provoke a grade of 0 on this exam and possible failure of the course. Answers copied verbatim from web sites (including course tutorials) will not receive credit.
Optional Sources [You do not need to consult these sources to score well on this exam; material you need has been covered in class and in the textbooks.]
Fujinami, R. S. et al. Molecular mimicry, bystander activation, or viral persistence: infections and autoimmune disease. Clinical Microbiology Reviews 19(1): 80-94, January 2006.
Huber, S. A. Autoimmunity in coxsackievirus B3 induced myocarditis. Autoimmunity 39(1): 55-61, February 2006.
What are Coxsackie Virus? http://www.safewater.org/facts/cox.htm