Supporting information Click here for additional data file. Contributor Information Katherine Kedzierska, Email: ua. References 1. Vaccination in the elderly: an immunological perspective. Trends Immunol ; 30 : — Front Immunol ; 8 : Open Forum Infect Dis ; 6 : ofz Aging Albany NY ; 12 : — Immunol Cell Biol ; 96 : — J Immunol ; : — J Leukoc Biol ; : — J Clin Invest ; : — B and C viruses.
Nat Immunol ; 20 : — Pizzolla A, Wakim LM. Memory T cell dynamics in the lung during influenza virus infection. Science ; : — Nat Immunol ; 19 : — T cell memory. Resident memory CD8 T cells trigger protective innate and adaptive immune responses. Science ; : 98— Cell Rep ; 29 : — Nat Immunol ; 14 : — Resident memory T cells T RM are abundant in human lung: diversity, function, and antigen specificity.
PLoS One ; 6 : e Nat Immunol ; 17 : — Sci Immunol ; 2 : eaag J Leukoc Biol ; 95 : — Cold Spring Harb Perspect Biol ; a No hemolysis was observed under either condition. BHA binding and insertion into cells did not affect the asymmetry of PS. Incubation of influenza virus fusion at pH 5, 0 degrees C resulted in complete fusion but no outward movement of PS was observed.
Nonhuman primates are susceptible to infection with a number of unadapted human influenza A isolates, including viruses of the H1N1 including pre seasonal [ 39 , — ] and swine-origin pandemic [ 39 ] strains, as well as the reconstructed pandemic virus [ , ] , H3N2 [ ], and H5N1 [ , , — ] subtypes. Within a decade of the first isolation of influenza virus from humans into ferrets, experimental inoculation of nonhuman primates had been performed.
In , Saslaw et al. No clinical signs of infection, including fever, anorexia, debility, or the respiratory distress were observed; however, infected monkeys demonstrated leukopenia, primarily manifesting as a decrease in neutrophils, and developed neutralizing antibodies to the inoculating strain between eight and 10 days post-infection.
However, in two monkeys inoculated by instillation of virus via syringe directly into the trachea, signs and symptoms consistent with influenza were observed, including listlessness and lethargy, facial flushing, and conjunctival injection. Symptoms persisted for two days, after which the animals returned to baseline.
In these animals too, neutropenia with reciprocal lymphocytosis was seen [ ]. A more pronounced clinical syndrome is observed in nonhuman primates infected with highly pathogenic human viruses, including avian influenza H5N1 strains.
One of four monkeys developed clinical signs consistent with the acute respiratory disease syndrome ARDS , including tachypnea, cough, lethargy, anorexia, and peripheral cyanosis. On necropsy of monkeys euthanized four or seven days after infection, high viral titers were isolated from lung tissue, which demonstrated necrotizing bronchointerstitial pneumonia, including extensive loss of alveolar and bronchiolar epithelium with alveolar exudates comprising edema, fibrin, cell debris, and peripheral blood cells.
This pathology is similar to that seen in primary influenza pneumonia in humans [ ]. Baskin et al. Macaques infected with the H5N1 virus demonstrated a more severe clinical syndrome than those infected with either Tx91 or the Tx reassortant; clinical obervations included anorexia, depression, coughing, diarrhea, and thrombocytopenia in H5N1-infected animals.
Both the H5N1 and Tx recombinant viruses produced severe pathology, a multi-lobar bronchopneumonia with consolidation and edema on gross inspection and bronchiolitis and alveolitis on microscopy, though pathology was worse in the H5N1 virus infected animals [ ].
A subsequent study by Cilloniz et al. They found that animals infected with the virus demonstrated more severe lung pathology within the first 24 hours of infection, with severe peribronchiolar alveolitis, edema, and hemorrage. By 48 hours post-inoculation hpi , similar lung pathology was seen with both viruses.
Lung titers were higher at 12 hpi in infected macaques, but titers equalized for both viruses by 24 hpi. Thus, although virus titers were similar at the hour time point, the virus had already caused greater tissue damage, which continued to worsen [ ]. Despite the genetic and physiologic similarities between human and nonhuman primates, there are likely subtle differences in influenza virus infection in these species.
Using virus histochemistry, Van Riel et al. Antivirals and vaccines against influenza virus have also been tested in the nonhuman primate model. Recently, Stittelaar et al. In the United States, zanamavir is currently licensed for use as an inhaled preparation; however, this dosing method is impractical for patients critically ill with avian influenza.
In addition, zanamivir is the only currently available neuraminidase inhibitor effective against H1N1 viruses with the NA-HY mutation. Stittelaar et al. Additionally, fewer zanamivir-treated animals developed lung lesions than did those in the placebo group, and, in treated animals that developed pneumonia, the pathology was generally less severe [ ].
Because of the genetic and physiologic similarities between humans and nonhuman primates, several studies [ , , , ] have explored gene expression during influenza virus infection in macaques. Such a study in rhesus macaques found that oseltamivir prophylaxis, prior to infection with a seasonal H1N1 influenza isolate, significantly reduced virus titers in the trachea and also increased mRNA levels of the interferon-stimulated gene MxA ; from this data, the authors hypothesized that, in primates, influenza virus protein expression actively suppresses expression of this antiviral gene [ ].
Nonhuman primates have also been used to assess the immunogenicity and efficacy of vaccines against influenza virus infection. These experiments have shown efficacy — measured either by the induction of protective antibody and cellular immune responses or the reduction of disease in vaccinated, virus-challenged animals — of a number of novel vaccine candidates.
Some of these novel strategies include modifications of existing vaccines, such as a cold-adapted live-attenuated influenza virus vaccine LAIV directed against highly pathogenic avian influenza viruses [ ].
A novel LAIV rendered replication-deficient not by cold-adaptation, but by the deletion of a viral gene that antagonizes the protective interferon response, has also been tested [ ]. Other novel strategies include intradermal or intramuscular electroporation of plasmid DNA-encoded antigens [ ] or intramuscular administration of replication-deficient vaccinia virus as a vector to deliver influenza virus genes [ ].
Several animal species have been used in influenza virus research, each with particular advantages and disadvantages. Symptoms of influenza virus infection in humans are most closely mimicked by the ferret, in which influenza virus disease is manifested by fever, nasal discharge, lethargy, weakness, anorexia, and sneezing.
Depending on the virus strain, macaques can also display a human-like symptomatology, and, like humans, infection with highly pathogenic avian influenza viruses can induce ARDS and multi-organ system dysfunction in primate models.
Mice and cotton rats, while less overtly symptomatic, can display hypothermia and weight loss, while guinea pigs and hamsters show no overt clinical signs of influenza virus infection.
Thus, the use of antivirals to prevent symptoms cannot be studied adequately in the rodent models. Ferrets, guinea pigs, cotton rats, hamsters, and nonhuman primates are all susceptible to infection with human influenza virus strains, without the need for prior adaptation to the species. Mice, however, are resistant to infection with most primary human virus isolates; thus, they are less useful when studying non-adapted strains.
Important exceptions include the H1N1 pandemic strain, highly pathogenic avian influenza viruses, some low pathogenic avian influenza viruses, and the H1N1 pandemic strain, which have been demonstrated to be infectious in mice without prior passaging. Efficient transmission of influenza virus has been shown only in ferrets, guinea pigs, and, to a lesser extent, hamsters.
While nonhuman primates would be expected to transmit human strains like humans, the large numbers of animals required for these experiments would be cost-prohibitive. Thus, for studies on mammalian transmission of influenza virus and interventions aimed at preventing spread, most of the models discussed in this review, with the exception of ferrets and guinea pigs, would be unsuitable. In terms of size, cost, and husbandry requirements, the smaller rodents — mice, cotton rats, hamsters, and guinea pigs — are readily accessible to most researchers, and statistically robust data may be obtained with large numbers of animals.
Ferrets and nonhuman primates are more expensive, require larger caging and facilities, and have greater husbandry demands than the smaller models, thus limiting their use in some research settings. The heightened interest of the public and funding bodies in influenza in recent years has led to the expansion of the field and, correspondingly, a greater need for well characterized animal models of disease and transmission.
While, as discussed above, significant progress has been achieved in this regard, challenges remain. One important topic which has been difficult to fully address in either humans or animal models is the relative contributions of small droplet aerosols, larger respiratory droplets, and contact with contaminated surfaces to influenza virus transmission. Technological hurdles related to the isolation and quantification of viable influenza viruses from dilute aerosols have hampered progress on this issue.
If these can be overcome, the insight gained will be of great value in informing public health responses to influenza virus outbreaks. Keck Foundation. National Center for Biotechnology Information , U. Journal List Viruses v. Published online Jul Nicole M. Bouvier 1, 2 and Anice C. Anice C. Author information Article notes Copyright and License information Disclaimer. This article has been cited by other articles in PMC. Abstract Influenza virus infection of humans results in a respiratory disease that ranges in severity from sub-clinical infection to primary viral pneumonia that can result in death.
Keywords: influenza virus, transmission, pathogenicity, animal model, antiviral drug, influenza vaccine. Influenza in the human host 1. Disease Uncomplicated influenza is characterized by an acute onset of symptoms within one to two days of infection with influenza virus. Transmission When considering influenza in humans, viral shedding is often used as a proxy measure of contagiousness. Animal models of influenza Laboratory animal models are widely used in the preclinical evaluation of potential vaccines and antiviral compounds, to investigate the safety of the vaccine or compound and its efficacy in preventing or moderating infection, disease or secondary transmission.
Mice Mus musculus Mice are the most widely used animal model for influenza virus research. Susceptibility of mice to human and other influenza viruses The susceptibility of mice to influenza viruses depends both on the strain of mouse and on the strain of influenza virus. Table 1. Open in a separate window.
Signs of disease in mice When an appropriate pairing of viral and mouse strains are selected, the mouse model represents a convenient means of assessing influenza virus pathogenicity and its reduction through the use of vaccines and antiviral drugs. Ferrets Mustela putorius The ferret has been used to model human influenza virus infection since the virus was first isolated from humans in the s.
Susceptibility of ferrets to human and other influenza viruses Ferrets, like mice, have been used in studies of influenza virus pathogenesis since the initial isolation of influenza viruses from swine and humans in the early s [ — ]. Signs of disease in ferrets Early experiments demonstrated that ferrets inoculated with human influenza virus exhibit overt disease, including fever, nasal congestion and discharge, anorexia, lethargy, and sneezing [ , ]; this symptomatology is similar to influenza in humans [ 1 ].
Guinea Pig Cavia porcellus Outbred Hartley strain guinea pigs are used most commonly for influenza virus research. Susceptibility of guinea pigs to human and other influenza viruses Like ferrets, guinea pigs are highly susceptible to infection with human influenza viruses, including seasonal strains of the H3N2 [ , — ] and H1N1 [ , ] subtypes; pandemic strains [ ]; the pandemic strain [ ]; and highly pathogenic H5N1 viruses [ , — ].
Signs of disease in guinea pigs Despite the high viral titers reached in the respiratory tract, influenza viruses do not cause severe overt disease in guinea pigs.
Transmission of influenza viruses among guinea pigs Human influenza viruses transmit efficiently from guinea pig-to-guinea pig. Cotton Rat Sigmodon hispidus A well-established model for respiratory syncitial virus, the cotton rat has also been characterized as a model for human influenza viruses. Syrian Golden Hamsters Mesocricetus auratus In the s, experiments showed that hamsters inoculated with influenza viruses demonstrated no clinical signs of disease, yet they mounted a specific antibody response to the infection [ ].
Susceptibility of hamsters to human and other influenza viruses Like ferrets, guinea pigs and cotton rats, hamsters are naturally susceptible to unadapted human influenza virus isolates, including influenza A subtypes H1N1 [ — ], H2N2 [ , , ], and H3N2 [ — , — ], and influenza B viruses [ , ]. Signs of disease in hamsters In early studies [ , ], hamsters inoculated with influenza viruses did not show signs or symptoms of infection, but influenza virus-specific antibodies could be serologically demonstrated after infection.
Transmission of influenza viruses in hamsters In , Ali et al. Table 2. Nonhuman Primates: Rhesus macaque Macaca mulatta , Pig-tailed macaque Macaca nemestrina , and Cynomolgus macaque Macaca fascicularis Because of the genetic and physiological similarities between human and nonhuman primates, macaques are thought to more closely model the human response to influenza virus infection than do more distantly related mammalian species like mice and ferrets.
Susceptibility of nonhuman primates to human and other influenza viruses Nonhuman primates are susceptible to infection with a number of unadapted human influenza A isolates, including viruses of the H1N1 including pre seasonal [ 39 , — ] and swine-origin pandemic [ 39 ] strains, as well as the reconstructed pandemic virus [ , ] , H3N2 [ ], and H5N1 [ , , — ] subtypes.
Signs of disease in nonhuman primates Within a decade of the first isolation of influenza virus from humans into ferrets, experimental inoculation of nonhuman primates had been performed. Conclusions Several animal species have been used in influenza virus research, each with particular advantages and disadvantages. Future Perspectives The heightened interest of the public and funding bodies in influenza in recent years has led to the expansion of the field and, correspondingly, a greater need for well characterized animal models of disease and transmission.
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