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A mouse model for investigating the molecular pathogenesis of adenovirus pneumonia
H S Ginsberg1, L L Moldawer, P B Sehgal
1Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032.
Abstract:
Intranasal inoculation of type 5 adenovirus (Ad5) produced pneumonia in mice even though the virus did not replicate. To induce the pneumonia, however, a large viral infectious dose was required--i.e., 10(10) plaque-forming units. Four strains of inbred mouse were studied (C57BL/6N, C57BL/10ScN, CBA/N, and C3H/N): all showed similar inflammatory responses, although the greatest infiltration occurred in the C57BL/6N mice. The pathological response to Ad5 infection resembled that previously described in cotton rats: it consisted of overlapping early and late phases, and the infiltration contained primarily lymphocytes and monocytes/macrophages with a scattering of polymorphonuclear leukocytes. The prominent early phase and the presence of polymorphonuclear leukocytes suggested that induction of cytokines may play an important role in the pathogenesis of this pneumonia. Assays showed the appearance of tumor necrosis factor alpha (TNF-alpha), interleukin 1 (IL-1), and IL-6 in the infected mouse lungs concomitant with the developing early-phase infiltration. Only IL-6 was found in the peripheral blood. IL-6 reached maximum titers 6-24 hr after infection, whereas maximum levels of TNF-alpha and IL-1 were attained 2-3 days after infection. Specific RNAs for each of these cytokines were demonstrated in the infected lungs. To test the hypothesis that a cytotoxic T-cell response was responsible for the second phase, which primarily consisted of a perivascular and peribronchial infiltration of lymphocytes, Ad5 was used to infect C57BL/10ScN Nu/Nu and parent mice. The nude mice showed a normal early-phase response, but essentially no peribronchial and only minimal perivascular infiltrations occurred.
Insights
Adenovirus type 5 (Ad5) causes pneumonia in mice via inflammatory cytokines like TNF-alpha, IL-1, and IL-6, even without viral replication. T-cell responses contribute to later stages of lung inflammation.
Area of Science:
- Immunology
- Virology
- Pathology
Background:
- Adenovirus type 5 (Ad5) infection can lead to pneumonia in mice.
- The pathogenesis of Ad5-induced pneumonia involves inflammatory responses rather than viral replication.
- Understanding the immune mechanisms behind Ad5 pneumonia is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the pathological and immunological mechanisms of Ad5-induced pneumonia in mice.
- To identify the key inflammatory mediators and cellular responses involved in Ad5 pneumonia.
- To determine the role of T-cell responses in the late phase of Ad5 pneumonia.
Main Methods:
- Intranasal inoculation of Ad5 in four strains of inbred mice.
- Pathological examination of lung tissue for inflammatory cell infiltration.
- Measurement of cytokine levels (TNF-alpha, IL-1, IL-6) in lung and blood.
- Analysis of cytokine gene expression in infected lungs.
- Infection of nude mice (Nu/Nu) and parent mice to assess T-cell involvement.
Main Results:
- Ad5 induced pneumonia in mice at high doses (10^10 PFU) without significant viral replication.
- All mouse strains showed inflammatory responses, with C57BL/6N exhibiting the greatest infiltration.
- Pathology involved overlapping early and late phases with lymphocytes, monocytes/macrophages, and polymorphonuclear leukocytes.
- Cytokines TNF-alpha, IL-1, and IL-6 were detected in infected lungs, with IL-6 also found in peripheral blood.
- Nude mice had a normal early response but impaired late-phase infiltration, suggesting a T-cell role.
Conclusions:
- Ad5-induced pneumonia in mice is primarily driven by inflammatory cytokines and cellular infiltration, not viral replication.
- Cytokines TNF-alpha, IL-1, and IL-6 play significant roles in the early stages of Ad5 pneumonia.
- T-cell-mediated immunity is critical for the development of the late-phase inflammatory response in Ad5 pneumonia.