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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.
Insights
High-passage influenza virus (H3N2) adapted to mice caused severe lung damage and death, unlike low-passage virus. Thymus-dependent cells are crucial for the inflammatory response to influenza, influencing virulence.
Area of Science:
- Virology
- Immunology
- Pathology
Background:
- Influenza virus adaptation can alter virulence.
- The role of the thymus in influenza pathogenesis is not fully understood.
Purpose of the Study:
- To investigate the impact of influenza virus passage level on virulence in a mouse model.
- To explore the role of thymus-dependent lymphocytes in influenza-induced pathology and host response.
Main Methods:
- Serial passage of human influenza A (H3N2) virus in mice.
- Comparison of low-passage (P3) and high-passage (P9) virus infectivity, lethality, and pathology.
- Infection of athymic nude mice and immunocompetent littermates with high-passage virus.
Main Results:
- High-passage P9 virus was significantly more lethal and caused severe lung pathology (bronchitis, bronchiolitis, pneumonia) and thymic atrophy compared to low-passage P3 virus.
- Athymic nude mice showed increased survival and minimal lung pathology, but developed brain lesions (encephalomalacia) with lymphocytic infiltration.
- Virus was recovered from brains of nude mice, suggesting neuroinvasion.
Conclusions:
- Thymus-dependent cells play a significant role in the inflammatory response and lung pathology during influenza virus infection.
- The mouse model, particularly using athymic nude mice, is valuable for studying host-virus interactions and influenza virulence factors.