MICR 454L Emerging and Re-Emerging Infectious Diseases Lecture 11: SARS, Hantavirus (Reading: Emerging Viruses) Dr. Nancy McQueen & Dr. Edith Porter

Overview SARS Hantavirus Brief history Morphology Genome Replication cycle Diseases Pathogenesis Diagnosis Treatment Prevention Threat

SARS

SARS Brief History 2003 - an epidemic of severe and often fatal pneumonia broke out in Southeast China, Hong Kong, and Vietnam. The disease spread to Toronto, Canada. Air travel by infected individuals quickly spread the disease to 32 countries resulting in the first pandemic in the twenty-first century. Over a 6 month period there were 8,000 cases and 800 deaths The disease was named severe acute respiratory syndrome (SARS). The causative agent was quickly identified as a previously uncharacterized coronavirus

SARS Family Coronaviridae Coronaviruses - divided into 3 groups (I,II, and III) based on antigenic and genomic sequences SARS does not fit into any groups ? recombination between an ancestral group II mammalian and a group III avian virus. Humans - from contact with palm civets (a cat-like mammal related to the mongoose) Probably acquired during slaughter of the civet rather than from eating the civet. Palm civets - not the natural reservoir, but rather an intermediate or amplifier host Chinese horseshoe bats are the natural reservoir Spherical, enveloped with glycoprotein spikes Linear SS + RNA genome

Civet

Replication cycle of SARS Fusion at the plasma membrane Direct translation of genomic RNA mRNA synthesis and genome replication in cytoplasm Budding into intracytoplasmic vesicles

SARS Disease Transmission Mean incubation period: 6.4 days Symptoms From contact with infected civet Human to human transmission Through eyes, nose , and mouth Direct contact Fecal-oral Droplets produced by coughing and sneezing ? Contact with blood Mean incubation period: 6.4 days Symptoms Fever, dry cough, dyspnea (shortness of breath), headache,hypoxemia (low blood oxygen concentration) Other general influenza-like symptoms, including chills, malaise, loss of appetite, and myalgia. Gastrointestinal symptoms (less common), including diarrhea (27%), vomiting (14%), and abdominal pain (13%).

SARS Pathogenesis Virus initially infects ciliated epithelial cells Next infects macrophages, and T lymphocytes Immune cells bring the virus to pneumocytes and surface enterocytes of the small intestine as well as other organs The typical clinical course: improvement in symptoms during the first week of infection worsening of symptoms during the second week. may be due to combined effects of patient's immune responses (proinflammatory cytokines) and uncontrolled viral replication. Death may result from progressive respiratory failure due to diffuse alveolar damage (DAD). Pathologic lesions show inflammatory exudation in the alveoli and interstitial tissue with hyperplasia of fibrous tissue and fibrosis. Fatality rate is 13.2% for patients younger than 60 years and 43.3% for patients aged 60 years or older.

Proposed Role of Immune Cells in SARS Pathogenesis Dissemination to other organs Infection of immune cells SARS-CoV Infection of epithelial cells of respiratory tract (Transient) Immunosuppression ARDS Injury to respiratory tract

SARS Lung Pathology Normal lung tissue Diffuse alveolar damage pattern of lung injury in SARS patients. (a) Early exudative phase diffuse alveolar damage showing vascular congestion, with interstitial and airspace edema and inflammatory cell infiltrates (H&E, original magnification 200); (b) the same field showing fibrinous exudates by Martius scarlet blue stain (original magnification 200); (c, d) exudative phase diffuse alveolar damage, with hyaline membranes (c, H&E, original magnification 200; d, elastic trichrome, original magnification 200); (e, f) organizing phase diffuse alveolar damage (e, H&E, original magnification 100; f, elastic trichrome, original magnification 100). http://www.nature.com/modpathol/journal/v18/n1/images/3800247f1.jpg

SARS Laboratory Findings Lymphopenia - due to infection and destruction of T cells Extent of decrease correlates with severity of disease Mildly elevated aminotransferase indicating liver damage Histopathological changes in many organs

SARS Diagnosis Diagnostic tests for coronavirus infection fall into two types: Serological testing indirect fluorescent antibody testing ELISA Molecular testing RT-PCR

SARS Treatment Antiviral drugs such as Ribavirin and interferon  have been used There is no agreement that these antiviral drugs have been successful in treating SARS or any coronavirus infection. Some studies suggest that these treatments cause more harm than good for the patient.

SARS Prevention Currently there is no vaccine, but several different vaccines are under development Isolation of infected individuals Hospital personnel must wear masks Wash hands Decontaminate all infectious wastes

SARS Threats No current threats However, because coronaviruses can undergo high rates of recombination, it is feared that other coronaviruses might cross the species barrier as a result of generation of recombinants containing both animal and human coronavirus genes. ~5% of bats in the U.S. carry coronaviruses

Take Home Message SARS SARS is a coronavirus which is enveloped and contains a SS +RNA genome The natural host for SARS is a bat and the disease was originally transmitted to humans from infected civets SARS is characterized by a fever, hypoxemia and a high mortality rate from respiratory failure. Currently no effective treatment or vaccines

Hantavirus

Hantavirus: Brief History (1) In 1993 in the four corners area of the United States, 24 cases of a severe influenza-like respiratory illness complicated by respiratory failure occurred in previously healthy young adults. Death occurred in 50-60% of the cases. A hantavirus was ultimately identified as the causative agent and transmission found to be from contact with infected rodents (deer mice) or their droppings. Why did this happen in the Four Corners area? Simply because there was a "bumper crop" of rodents there, due to heavy rains during the spring of 1993, which produced an extra-plentiful supply of the foods that rodents eat.

Hantavirus Brief History (2) A new type of hantavirus disease. Previously, hantavirus infections had been associated with hemorrhagic fevers, not respiratory disease. Documented as early as 1,000 years ago in China. Since the initial outbreak in the Four Corners Region, the disease has been confirmed in over half of the states in the US, with a total of nearly 500 people infected.

Hantavirus Classification Hantavirus belongs to the family Bunyaviridae, genus Hantavirus Hantavirus genus contains several viruses that infect humans Some cause a severe hemorrhagic fever with renal syndrome (HFRS) Some cause hantavirus pulmonary syndrome (HPS) All are zoonotic viruses of wild rodents Spherical, enveloped virus Linear SS, segmented, - RNA genome 3 segments - small, medium, and large

Hantavirus Replication Cycle Enter via receptor mediated endocytosis Fusion with endosomal membrane - uncoating mRNA synthesis and genome replication occur in cytoplasm Budding into the Golgi complex

Representative Pathogenic Hantaviruses Disease Distribution Mortality rate (%) Hantaan virus HFRS (severe) Asia 5-10 Dobrava virus Europe (Balkans) Seoul virus HFRS (moderate) Southeast Asia, Worldwide 1-2 Puumala virus HFRS (mild) North and Central Europe <1 Sin Nombre virus HPS (severe) North America >40 Bayou virus HPS (renal variant) North America (US) Andes virus South America (Argentina, Chile)

HFRS Disease/Pathogenesis Transmission via aerosols of viruses from rodent saliva, urine or feces Disease divided into five phases Acute febrile - fever, chills, headache, anorexia, vomiting, backache Hypotensive Oliguric Diuretic - suggests improvement Convalescent - may require 4 months Viral antigens are detected in brain, spleen, kidneys and liver. thrombocytopenia with hemorrhagic manifestations; kidney edema, proteinuria, renal failure; cardiovascular instability and shock Death

HPS Transmission to humans Aerosols of viruses from rodent saliva Rodent bites (rare) Oral after touching or eating something that has been contaminated with rodent urine, droppings, or saliva Human-to-human transmission via aerosols

HPS Disease/Pathogenesis Disease divided into four phases: Prodromal - non-specific symptoms such as fatigue, fever, chills, myalgias Cardiopulmonary - abrupt onset of respiratory failure which may proceed rapidly and lead to shock, non-cardiogenic pulmonary edema and hypotension. Symptoms include coughing and shortness of breath, with the sensation of, as one survivor put it, a "...tight band around my chest and a pillow over my face" as the lungs fill with fluid. 50% die in 24-48 hours Diuretic - coincides with rapid clinical improvement Convalescence - may last several months

HPS Disease progression

Hantavirus Pathophysiology Hantaviruses preferentially infect endothelial cells Viruses target the pulmonary capillary walls (HPS) or the capillary walls in the kidney (HFRS) initiating a cascade of events culminating in a massive, pulmonary or kidney-specific inflammatory response endothelial damage and edema (TNF and IL-1) The damage to pulmonary/kidney microvascular endothelium increases capillary permeability and leads to even more fulminant pulmonary/kidney edema. In HFRS - DIC, and hemorrhagic manifestations may follow

Hantavirus Diagnosis Serology Immunohistochemistry RT-PCR ELISA Western immunoblot Immunohistochemistry RT-PCR

Hantavirus Treatment Ribavirin may reduce mortality if given early in disease - May increase error rate of the RNA polymerase Attentive and supportive therapy HPS - if infected individuals are recognized early and receive medical care in an intensive care unit, they may do better. In intensive care, patients are intubated and given oxygen therapy to help them through the period of severe respiratory distress.

Hantavirus Prevention Eliminate or minimize contact with rodents Vaccines are in development

Hantavirus Threats 60,000 to 150,000 are hospitalized/year due to HPS or HFRS Genomic reassortment by RNA viruses with segmented genomes is well documented and has the potential to produce viruses with altered biological activity, host range, and disease potential. Genomic reassortment among hantaviruses is known to occur in nature, but the precise role of genomic reassortment in the epidemiology of hantavirus infections is unknown. HPS causing hantviruses have potential use as biological weapons Aerosol infection Highly lethal

Take Home Message Hantavirus Hantaviruses are enveloped and contain a segmented SS - RNA genome. The natural host for hantaviruses is rodents and man usually acquires the disease via inhalation after contact with infected rodents or their droppings. Hantaviruses cause two different types of disease - Hemorrhagic fever with renal syndrome (HFRS) characterized by fever, renal failure, hemorrhaging and shock with a 5-10% mortality rate Hantavirus pulmonary syndrome (HPS) characterized by flu symptoms, coughing, and shortness of breath as the lungs fill with fluid. The mortality rate is over 50%. There is potential for new hantaviruses through shift and drift

Resources The Microbial Challenge, by Krasner, ASM Press, Washington DC, 2002. Brock Biology of Microorganisms, by Madigan and Martinko, Pearson Prentice Hall, Upper Saddle River, NJ, 11th ed, 2006. Microbiology: An Introduction, by Tortora, Funke and Case; Pearson Prentice Hall; 9th ed, 2007. Fundamentals of Molecular Virology, by Nicholas Acheson; Wiley and Sons; 2007 Human Virology by Collier and Oxford, Oxford University Press; 2nd edition, 2000. www.chinadaily.com.cn/english/doc/2004-06/28/xin_11060128103408705697.jpg www.stanford.edu/~siegelr/RSA/civet.jpg

Resources http://www.emedicine.com/emerg/topic861.htm www.math.tu-berlin.de/aktMath/site/pics/SARS-Virus.jpg www.savi-info.ca/SARS_Virus.JPG www.cdc.gov http://www.emedicine.com/emerg/topic861.htm Samuel, Melanie A. and Michael S. Diamond (2006). Pathogenesis of West Nile Virus Infection: a Balance between Virulence, Innate and Adaptive Immunity, and Viral Evasion, J Virol. 80(19): 9349-9360. Amy C. Simsa, Susan E. Burkett, Boyd Yount, Raymond J. Pickles (2008). SARS-CoV replication and pathogenesis in an in vitro model of the human conducting airway epithelium. Virus Research 133:33–44 Yong Guo, Christine Korteweg, Michael A. McNutt, Jiang Gu (2008). Review - Pathogenetic mechanisms of severe acute respiratory syndrome. Virus Research 133:4–12. Colleen B. Jonsson, Brook G. Milligan, Jeffrey B. Arterburn (2005) Potential importance of error catastrophe to the development of antiviral strategies for hantaviruses. Virus Research 107:195–205