Effects of Low- and High-Passage Influenza Virus Infection in Normal and Nude Mice

Abstract

A human isolate of type A Hong Kong influenza virus (H3N2) was adapted to mice by serial passage. Lung homogenates from mice who received low passage levels contained about the same quantity of virus (10 6.2−6.95 50% tissue culture infective doses/ml) as those from mice who received high passage levels (10 5.95−6.45 50% tissue culture infective doses/ml); however, death occurred only in animals given high-passage virus. Passage 3 (P3) and passage 9 (P9) viruses were selected as representative of low-passage and high-passage viruses, respectively. Although minimal differences were detected in infectivity for rhesus monkey kidney tissue cultures and mice, P9 virus was at least 10,000 times more lethal for mice (mean lethal dose = 10 4.2 ). Infection with P3 virus was accompanied by minimal bronchitis and bronchiolitis only, whereas P9-infected animals exhibited marked bronchitis, bronchiolitis, and pneumonia. Striking thymic cortical atrophy was also demonstrable in the P9-infected animals and, although virus was more commonly recovered from thymuses from these animals, immunofluorescent studies revealed only a few cells containing influenza virus antigens. To further explore the participation of thymus-derived lymphocytes in influenza, athymic nude mice and furred immunocompetent littermates were given 500 50% mouse infectious doses of P9 virus. Nude mice exhibited an increased survival time and, in contrast to the extensive lung pathology seen in furred littermates, manifested minimal cellular infiltration and no tissue destruction in lungs. Brains from nude mice exhibited encephalomalacia with lymphocytic perivascular cuffing, which was not seen in furred animals. Virus was recovered from brains of 6 of 13 nude mice and 1 of 10 furred animals. The contrasting models suggest that thymus-dependent cells play a significant role in the inflammatory response to influenza virus infection and should prove useful for probing host-virus interactions which characterize influenza virus virulence.

Hyperactive immune cells (T cells) may be responsible for acute lung injury in influenza virus infections: A need for early immune-modulators for severe cases

“…The viral titers in the lungs and the hemagglutinin antibody titers did not differ in the two groups [14]. Wyde et al observed that athymic nude (T cell deficient) mice exhibited increased survival times and had less cell infiltration with no destruction of the lungs, compared with immune-competent control mice which suffered severe lung destruction [15]. The thymuses of the control mice were markedly reduced in size at the time of death, suggesting the depletion of cortical lymphocytes [10,15].…”

“…However, it is likely that the innate immune response plays a crucial role in influenza virus elimination from the host [5,17]. It has been reported that nude mice which have no T cells [15,25] and 'Rag2' knockout mice which lack an acquired immune system [26] showed a similar clinical course compared to wild type animals when infected with influenza viruses. In cotton rat models, virus specific T cells and antibodies appear after virus clearance in the airways and lung inflammatory response peaks after virus is cleared [5,27].…”

“…Wyde et al observed that athymic nude (T cell deficient) mice exhibited increased survival times and had less cell infiltration with no destruction of the lungs, compared with immune-competent control mice which suffered severe lung destruction [15]. The thymuses of the control mice were markedly reduced in size at the time of death, suggesting the depletion of cortical lymphocytes [10,15]. Eichelberger reported that viral clearance in the airways of cotton rats appeared before the establishment of adaptive immunity (antibodies and antigen-specific T cells) in the host and that the expression of genes which may be associated with the innate immune response was upregulated until day 10 after infection [5,27].…”

“…However, it is still unclear whether antiviral drugs protect against rapidly progressive pneumonia or extrapulmonary diseases, because there have been no controlled clinical studies [55]. Since the initial viral load of an inoculation is associated with the clinical phenotype (tracheitis model and fatal pneumonia model) [4,5,15] and the time of appearance of lung lesions in experimental animals [32], early antiviral treatment is beneficial in reducing the initial immune response. Our results of corticosteroid treatment on influenza virus infections were obtained from a small series of patients.…”

“…Some experimental and clinical studies have also suggested that the pathogenesis of lung injury in influenza infections is associated with excessive host response including the cell-mediated immune reaction [7,[14][15][16][17]. It is postulated that infected hosts with progressive pneumonia may have an inadequate innate immune response to the initial viral insult.…”