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Correlation between cyclophosphamide-induced viral susceptibility and depletion of Junin virus-induced suppressor
O E Campetella1, N V Galassi, H A Barrios
1Departamento de Microbiología, Facultad de Medicina, Universidad de Buenos Aires, Argentina.
Abstract:
In contrast to lymphocytic choriomeningitis virus, another arenavirus, Junin virus (JV), the etiologic agent of Argentine hemorrhagic fever, when inoculated into suckling mice, induces lethal meningoencephalitis characterized by a delayed-type hypersensitivity (DTH)-like immune response. However, the adult BALB/c mouse is resistant to infection and no DTH reaction can be seen. This different viral sensitivity may be related to the development of an antigen non-specific DTH-suppressor cell pathway at work in the adult mouse. When the resistant mice are treated with cyclophosphamide (Cy) (50 mg/kg each dose) given at days -1,+1,+4 (zero: infection day), animals become susceptible and develop DTH reaction in brain that leads to death. We analyze the influence of the timing of Cy administration on the suppressor system developing after infection. It was found that Cy depletes the previously described JV-induced suppressor populations (Tsv) but a new suppressor cell (Tsv*) is disclosed bearing the Thy 1+ Ly1+2- phenotype which is unable to depress DTH in Cy-treated animals. With only two doses of Cy corresponding to days -1 and +1, the target of Tsv* cells is depleted but the third dose is still required to achieve full depletion of Tsv cells which are able to employ the Cy-resistant antigen-specific suppressor cells as targets. Since the Cy treatment is able to deplete the Tsv population together with the target of Tsv* cells, animals became unable to regulate lethal DTH reaction. Thus, a cellular explanation for an empirically established Cy schedule able to abrogate the adult mouse resistance to JV is proposed.
Insights
Junin virus (JV) causes lethal meningoencephalitis in young mice but not adults. Cyclophosphamide (Cy) treatment in adult mice abrogates resistance by depleting specific suppressor cells, revealing a new targetable suppressor cell population.
Area of Science:
- Immunology
- Virology
- Neuroscience
Background:
- Junin virus (JV), the cause of Argentine hemorrhagic fever, induces lethal meningoencephalitis in suckling mice via a delayed-type hypersensitivity (DTH) response.
- Adult BALB/c mice are resistant to JV infection and do not develop a DTH reaction, suggesting an active suppressor cell pathway.
- Previous studies showed cyclophosphamide (Cy) treatment renders adult mice susceptible to JV infection.
Purpose of the Study:
- To investigate the influence of cyclophosphamide (Cy) administration timing on the suppressor system following Junin virus (JV) infection.
- To identify the specific suppressor cell populations affected by Cy treatment and their role in regulating the immune response to JV.
Main Methods:
- Adult BALB/c mice were infected with Junin virus (JV) and treated with cyclophosphamide (Cy) at various time points relative to infection.
- Flow cytometry and phenotypic analysis were used to characterize suppressor cell populations (Tsv and Tsv*) in Cy-treated and untreated infected mice.
- The ability of these suppressor cells to inhibit DTH responses was assessed in vivo.
Main Results:
- Cyclophosphamide (Cy) treatment depleted previously identified JV-induced suppressor cells (Tsv).
- A novel suppressor cell population (Tsv*) with a Thy 1+ Ly1+2- phenotype was identified, which is unaffected by Cy treatment alone.
- Specific Cy dosing schedules were found to deplete both Tsv cells and the targets of Tsv* cells, leading to an inability to regulate lethal DTH responses and abrogation of adult mouse resistance to JV.
Conclusions:
- The resistance of adult mice to Junin virus (JV) is mediated by an antigen non-specific DTH-suppressor cell pathway.
- Cyclophosphamide (Cy) treatment abrogates this resistance by depleting specific suppressor cell populations (Tsv and Tsv* targets) in a time-dependent manner.
- This study provides a cellular explanation for the empirically determined Cy treatment schedule that overcomes adult mouse resistance to JV infection.