Differential Distribution of Virus and Histological Damage in the Lower Respiratory Tract of Ferrets Infected with Influenza Viruses of Differing Virulence

Abstract

SUMMARYThe distribution of four strains of influenza virus [A/PR/8/34 (HON 1) and clone 64d (attenuated for ferrets) and clones 64c and 7a (virulent for ferrets) of the recombinant virus A/PR/8/34-A/England/939/69 (H3N2)] in the lower respiratory tract (trachea, bronchi and the hilar, intermediate and outer alveolar zones of the lung) of ferrets was monitored daily for 4 days after intranasal inoculation. On day 1, some animals had high virus titres in all the tissues but in other animals virus was undetectable, irrespective of the virus strain. Two days after inoculation increase of virus contents of all tissues tended to be restricted. On days 3 and 4, the virulent clones (64c and 7a), in contrast to the attenuated strains (A/PR/8/34 and clone 64d), consistently infected the lower respiratory tissues. However, for all infected animals the virus contents of the hilar zones of the lungs were higher than those in the intermediate zones, while the alveolar zones were relatively free from virus. Quantitative estimations of the mild histological damage occurring in the lower respiratory tract 3 to 6 days after inoculation also indicated that bronchial and bronchiolar tissue were more susceptible to influenza virus than alveolar tissue and that clones 64c and 7a produced more damage than the other two strains. In agreement with the relative viral contents of clones 64c and 7a in the bronchi and in the hilar and intermediate zones of the lung, clone 64c produced more damage than clone 7a in the bronchi and less in the bronchioles of the lung parenchyma.

Distribution of Viral Antigen within the Lower Respiratory Tract of Ferrets Infected with a Virulent Influenza Virus: Production and Release of Virus from Corresponding Organ Cultures

“…This suggested that influenza virus replicated mainly in areas where bronchial and bronchiolar epithelium predominated. Quantitative estimation of histological damage in the various areas supported this view; lung damage was minimal, but it was localized in the airways and not in the alveoli (Sweet et al, 1981).…”

“…Respiratory infection in ferrets inoculated with human strains of influenza virus mimics that in man, predominating in the upper respiratory tract with some involvement of the lower tract especially for virulent strains (Matsuyama et al, 1980;Sweet et al, 1981).…”

“…The pathogenesis of influenza in the lower respiratory tract (LRT) of the ferret has been studied in more detail by assessing the distribution in the tract of two virulent (clones 7a and 64c) and two attenuated (A/PR/8/34 and clone 64d) strains of the recombinant virus A/PR[8/34-A/England/939/69 (H3N2) (Sweet et al, 1981). Virus isolations from homogenates of trachea, the main bronchi, and the hilar, intermediate and alveolar zones of the lung on days 1 to 4 following intranasal inoculation showed that the virulent clones, in contrast to the attenuated ones, consistently infected the LRT.…”

“…Previous work suggested a possible explanation. Comparison of virus yields from organ cultures of nasal turbinates and lung tissue taken from a mixture of the intermediate and alveolar zones as defined by Sweet et al (1981), showed that the turbinates produced about tenfold more virus per cell than the lung tissue and released a much greater proportion (about 30%) of the virus yield than did lung cultures (about 6%); observations with fluorescent antibody showed that ciliated cells were the predominant cell type infected in the turbinate cultures, and alveolar type I and type II cells in the lung cultures (Kingsman et al, 1977a, b;Cavanagh et al, 1979;Matsuyama et al, 1980). Hence, one factor contributing to the higher susceptibility of nasal mucosa compared with lung tissue appeared to be a higher capacity of the ciliated cells of the former to produce and release influenza virus compared with the alveolar cells of the latter.…”

“…However, the greater susceptibility of airway epithelium may, like that of nasal turbinates, reflect a high capacity to produce and release virus. Hence virus production and release and median infectious doses of clone 7a have been examined in organ cultures of ferret nasal turbinates, trachea, main bronchi and the hilar, intermediate and alveolar zones of the lung (Sweet et al, 1981). With regard to the alveolar zone, care was taken to exclude bronchi and large bronchioles from the organ culture pieces so as to obtain a better estimate of virus production and release from alveolar tissue than had been achieved previously when the tissue pieces contained some large bronchioles and even small bronchi (Kingsman et al, 1977a, b;Cavanagh et al, 1979;Matsuyama et al, 1980).…”