PMC:2700745 / 7535-16364 JSONTXT

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Models of benign influenza\nInfluenza is usually an acute, self-limited respiratory tract infection that begins with the sudden onset of high fever, followed by inflammation of the upper respiratory tree and trachea, with coryza, cough, headache, prostration, malaise and other signs and symptoms that persist for 7–10 days (Taubenberger and Morens, 2008). The virus replicates in both the upper and lower respiratory tract. In experimental infections in healthy volunteers, influenza A viral replication peaks approximately 48 h after inoculation into the nasopharynx, declining thereafter, with usually little or no virus shed after 6 days. However, viral antigen can still be detected in cells from the respiratory tract and secretions of infected individuals by enzyme immunoassay for several days after infectious virus can no longer be recovered (Wright et al., 2007). A summary of current animal models available for studying benign seasonal influenza is presented in Table 2 .\nTable 2 Summary of current animal models available for studying benign disease associated with seasonal influenza.\nVirus Disease Model Animal Model References\nInfluenza A strains Mild Pathogenesis Mouse Gambaryan et al. (2005)\nAichi/2/68 (H3N2) BALB/cJCitMoise (B/c)\nA/NIB/26/90M (H3N2) A/SnJCitMoise\nA/NIB/23/89M (H1N1) CBA/CaLacSto\nA/NIB/23/89-MA (mouse adapted) C57BL/6LacSto\n\u2028\u2028\nInfluenza A/Aichi/2/68 (H3N2) Mild Pathogenesis Ferret Svitek et al. (2008)\nInfluenza A/Port/ Chalmers/173 (rat adapted after 11 passages in rats Mild Pathogenesis Rat (Rattus) Brown Norway Fischer-344 Sprague–Dawley Daniels et al. (2003)\n\u2028\u2028\nSwine influenza A strains Mild Pathogenesis Pig Vincent et al. (2007)\nX98 H3N2\nA/SW/CO/23619/ 99 H3N2\nA/SW/IA/00239/2004 rH1N1\n\u2028\u2028\nInfluenza A H1N1 Mild Pathogenesis/Pneumonia Pigtailed macaque Baas et al. (2006)\nA/Texas/36/91\n\n2.1.1 Mice\nIn mice infected with influenza viruses of low pathogenicity, a mild illness occurs with few of the signs and symptoms that are seen in humans. The major parameters of mild to moderate disease are weight loss and the detection of virus, primarily in the lungs (Sidwell and Smee, 2004). In such a model, a polymer-bound 6′sialyl-N-acetyllactosamine was found to ameliorate weight loss in treated animals (Gambaryan et al., 2005).\n\n2.1.2 Ferrets\nLess virulent strains of influenza virus cause mild influenza-like symptoms in ferrets that rarely end in death. For example ferrets infected with A/Aichi/2/68 (H3N2) did not lose weight (Svitek et al., 2008). Only mild respiratory disease occurred in Aichi-infected animals with occasional sneezing and little serous nose exudate expressed. Virus infection elicits a rapid and strong upregulation of IFN-α, IFN-γ, and TNF-α, while more virulent strains induced significantly lower levels of IFN-α during the first 2 days after infection. During the first 4 days after infection, only IL-8 was detected in samples from animals inoculated with A/Aichi/2/68, whereas IL-6 expression was associated with the more virulent viruses (Svitek et al., 2008).\nThe utility of a ferret model in which a benign infection was induced is illustrated by the results from the following vaccine study. Ferrets immunized with virosome-based intranasal influenza vaccine consisting of hemagglutinins from influenza A/Beijing/262/95like (H1N1), A/Sydney/5/97 (H3N2), and influenza B/Harbin/7/94 and then challenged with the A/Sydney/5/97 (H3N2) strain had less viral shedding in nasal secretions and the vaccine elicited a vaccine-specific antibody response (Lambkin et al., 2004). In addition, the vaccine regimen protected against fever, weight loss, and infiltration of inflammatory cells.\n\n2.1.3 Rats\n“True” rat species have been evaluated to determine their suitability as models for influenza disease and to ascertain whether genetic background impacts their susceptibility to infection. In one study, Brown Norway (BN), Fischer-344 (F344) and Sprague–Dawley (SD) rats were challenged with a rat-adapted influenzaA/Port/Chalmers/173 (H3N2) virus (Daniels et al., 2003). The virus was adapted to rats by 11 successive passages thorough infected lung homogenate. The F344 and SD rats were most sensitive to the infection, with 100-fold higher lung virus titers than seen in the BN rats. Alveolar macrophages, lactate dehydrogenase activity, and total lung protein concentrations (an indicator of pulmonary edema) were higher in the BN rats. Neutrophil numbers, interleukin 6 levels, and TNF-α activity were greatest in the bronchoalveolar lavage fluids from F344 and SD rats. Nevertheless, the infection was not lethal and few pathologic abnormalities were noted in the lungs. Although the study provided insights into factors of importance in protecting the host from influenza virus infections, rat models probably have not been characterized well enough to be recommended for use in evaluating anti-influenza therapies.\nRecently Alarcon et al. (2007) demonstrated the use of the Brown Norway rat in evaluating influenza vaccines. Using microneedle technology for i.d. administration of three different types of influenza vaccines (Fluzone® 2003–2004 formulations and DNA plasmid-based vaccine) the investigators demonstrated in a rat model, that a whole inactivated virus elicited antibody responses to the corresponding wild type parent H3N2 and B strains. Animals treated with multiple doses of DNA plasmid vaccine also responded with antibody response to the parent strains.\n\n2.1.4 Pigs\nBecause influenza A viruses frequently adapt to efficient transmission among pigs, these animals have occasionally been used as a model for testing vaccines (van der Laan et al., 2008). Signs of illness include fever, loss of appetite, labored breathing and coughing. However, the animals rarely die from the disease unless virus is directly inoculated into the trachea, in which case they exhibit signs of pneumonia. Pigs have been found to have low susceptibility to recently emerged H5N1 strains (Lipatov et al., 2008). To date, the main use of the pig has been in the development of vaccines against swine influenza (reviewed by van der Laan et al., 2008).\nProblems that may preclude the use of pigs for influenza studies include caging, the complexities of animal husbandry and waste management. Thus, the recent development of a model in Ellegaard Göttingen minipigs appears to offer an alternative, if these animals can be shown to develop a fulminant pneumonia using a less intrusive route than intratracheal inoculation. However, as in the case of common pigs, minipigs were not susceptible to infection with H5N1 strains such as A/chicken/Yamaguchi/7/04 (Isoda et al., 2006). As with normal pigs one must always be cautious to obtain animals with no previous exposure to influenza viruses, since minipigs can be hosts for swine influenza A viruses (Hansen et al., 1997).\n\n2.1.5 Nonhuman primates\nBecause nonhuman primates are much more closely related to humans than small animals typically used to study influenza, they have been used as models for human disease. In particular, rhesus macaques have been used to study pathogenesis and evaluate therapeutic and prophylactic strategies (see Baas et al., 2006 for review). In addition, the suitability of pigtailed macaques as models of influenza in the context of transcriptional studies has been evaluated (Baskin et al., 2004). A recent study examined the innate immune response in affected lung tissue with viral genetic material present (Baas et al., 2006). The authors used histopathological analysis of lung tissue, immunohistochemistry, viral and host gene expression by microarray analysis, proteomics, gene expression in circulating blood cells, and quantitative real-time RT-PCR to study individual animal responses until the end of the experiment. The infections were mild, without pneumonia or significant lung pathology. The investigators were able to demonstrate significant differences in gene expression within regions in influenza virus-induced lesions, based on the presence or absence of viral mRNA, and correlated them with transcriptional markers of early disease in peripheral white blood cells (Baas et al., 2006).\nThe use of viruses causing benign infections in macaques has primarily been used for vaccine studies. For example, Rimmelzwaan et al. (2001) demonstrated that protective immunity induced by immune stimulating complex (ISCOM)-based vaccines consisting of the membrane glycoproteins of A/Philippines/2/82 did not protect macaques from a challenge infection with A/Netherlands/18/94. However, vaccination of monkeys, which had had a prior infection with an influenza A/Philippines/2/82-like virus with a single dose of ISCOM vaccine, induced long-lasting protective antibody immunity against challenge infection with the homologous virus A/Netherlands/18/94."}