PMC:2700745 / 1093-7510 JSONTXT

{"project":"2_test","denotations":[{"id":"19176218-16319291-3579160","span":{"begin":871,"end":875},"obj":"16319291"},{"id":"19176218-16319291-3579160","span":{"begin":871,"end":875},"obj":"16319291"},{"id":"19176218-18328578-3579161","span":{"begin":1780,"end":1784},"obj":"18328578"},{"id":"19176218-18328578-3579161","span":{"begin":1780,"end":1784},"obj":"18328578"},{"id":"T55972","span":{"begin":871,"end":875},"obj":"16319291"},{"id":"T71107","span":{"begin":871,"end":875},"obj":"16319291"},{"id":"T5223","span":{"begin":1780,"end":1784},"obj":"18328578"},{"id":"T96466","span":{"begin":1780,"end":1784},"obj":"18328578"}],"text":"1 Introduction\nInfluenza A viruses infecting humans are responsible for a gamut of illnesses ranging from inapparent infections to pneumonia and severe acute respiratory syndrome. The typical infection one associates with seasonal influenza is a mild, self-limited febrile syndrome. As with other respiratory viruses, influenza viruses can cause more severe infections in infants, the elderly, and immunodeficient persons. In those individuals whose immune system is compromised or not fully developed, influenza-associated disease will often lead to severe viral pneumonitis or be complicated by bacterial superinfection, leading to pneumonia and sepsis. Seasonal influenza also occasionally results in neurologic complications. Even in non-pandemic years, more than 40,000 deaths annually are attributable to influenza infections in the United States (Dushoff et al., 2006). Much more rarely, humans can become infected by viruses that have spread directly from wild birds to domestic poultry. Such “avian influenza” can range in severity from mild conjunctivitis through the rapidly lethal disease seen in persons infected with the recently emerged Southeast Asian H5N1 virus. However, the potential for such highly virulent, lethal viruses to spread globally, as in the 1918 “Spanish Flu” pandemic, has resulted in a tremendous effort to develop vaccines and antiviral drugs to block the spread of virus and to treat the disease in humans, so as to prevent death.\nThe basic virology, clinical syndromes, epidemiology, and approved antiviral drugs for influenza virus infections are presented in Table 1 . Efforts have intensified in recent years to understand the pathogenesis of the various forms of influenza virus infection and to develop new treatments (Beigel and Bray, 2008). To develop effective antiviral therapies for this wide range of diseases, it is essential to have laboratory animal models that replicate the major features of illness in humans and provide selective, sensitive and reproducible results. Selecting the appropriate laboratory animal infection is very important in the drug development process. Some animals, such as pigs and ferrets, are naturally susceptible to infection by influenza viruses, but some of the other species that have been used for influenza studies are not. For the latter, the virus requires adaptation before it can replicate in the animal and/or cause disease (e.g., human seasonal influenza viruses in mice, rats). Once influenza viruses infect an animal, the virus may cause nonlethal disease or lethal disease. The type of disease that is induced can be manipulated by the investigator and is dependent on a variety of factors including virus strain, amount of virus in the inoculum, route of inoculation, time allowed for the disease to develop and the animal's immune status.\nTable 1 Influenza A virus infections: the basics.\nClassification and structure Influenza viruses are spherical or pleomorphic, single-stranded, negative-sense RNA viruses belonging to the family Orthomyxoviridae. Influenza A and B viruses contain eight separate ribonucleoprotein (RNP) segments, while influenza C virus contains seven, each of which encodes 1 or 2 proteins. The internal antigens (M1 and NP proteins) are the type-specific antigens used to determine if a particular virus is A, B or C, while the external hemagglutinin (HA) and neuraminidase (NA) are the subtype- and strain-specific antigens.\n\u2028\u2028\nInfection cycle Influenza virus binds to receptors on the surface of the host cell via the HA protein. It is internalized into endosomes, after which pH-dependent fusion and uncoating release the viral RNPs into the cytoplasm, where they are transported into the nucleus for replication. Viral messenger RNAs are exported out of the nucleus for protein synthesis, and some of the resulting proteins are transported back into the nucleus to assist in replication and RNP assembly. New RNPs assemble with other virus proteins at the M1 matrix to form virions, which bud from the plasma membrane.\n\u2028\u2028\nEpidemiology Influenza A viruses cause chronic, asymptomatic infection in the gastrointestinal tracts of wild birds, but are also able to infect and cause disease in a variety of mammals. Such avian viruses cause a range of illness in humans, ranging from conjunctivitis through the fulminant illness caused by the recently emerged H5N1 virus. On rare occasions, an influenza A virus is introduced into human populations and spreads rapidly to cause a global pandemic. This can occur either when an avian virus with a novel HA protein adapts to human-to-human transmission, or when an avian virus undergoes genomic reassortment during co-infection of an influenza virus-infected mammal such as a pig. As a pandemic virus circulates, it undergoes progressive antigenic drift in its HA and NA proteins, permitting to re-infect the same populations in regular outbreaks of “seasonal” influenza.\n\u2028\u2028\nClinical syndromes Symptoms of seasonal influenza typically include high fever, chills, headache, sore throat, dry cough, myalgia, anorexia, and malaise. Complications include primary viral pneumonia, secondary bacterial pneumonia, or combined bacterial and viral pneumonia. Severe infections caused by the recently emerged avian influenza A H5N1 virus are characterized by rapid development of diffuse interstitial pneumonia, viremia and shock leading to death.\n\u2028\u2028\nVaccines Inactivated vaccines (Fluzone®, Fluvirin™) obtained from infected chicken embryos are most commonly used. Attenuated vaccines include FluMist®.\n\u2028\u2028\nApproved therapeutics Approved therapeutics for seasonal influenza A virus infections include the neuraminidase inhibitors oseltamivir phosphate (Tamiflu®) and zanamivir (Relenza®) and the M2 ion channel blockers amantadine (Symmetrel®) and rimantadine (Flumadine®).\nThis paper reviews animal models currently in use for the study of influenza pathogenesis and immune responses to influenza virus infections and to assess vaccine and antiviral drug efficacy. Models that will be reviewed will include: models of benign influenza, typical severe seasonal influenza and pneumonia, influenza-associated sepsis, models using H5N1 viruses, models in which acute respiratory distress syndrome (ARDS) is induced, models of influenza-associated neurologic disease, models for virus transmission studies, immunocompromised models, and models of host resistance."}