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Neonatal Listeria monocytogenes infection is refractory to interferon
R Bortolussi1, S Burbridge, P Durnford
1Department of Pediatrics, Dalhousie University, Halifax, Canada.
Abstract:
Despite aggressive treatment, early onset neonatal Listeria monocytogenes infection continues to have high morbidity and mortality. We recently showed that pretreatment of newborn L. monocytogenes-infected rats with interferon (IFN)-alpha/beta or recombinant rat IFN-gamma dramatically improves survival. However, in the present experiment, when newborn rats were treated with IFN-alpha/beta or recombinant rat IFN-gamma after intraperitoneal injection with Listeria there was no benefit. Because most deaths occurred at or before 3 d in this animal model, we reasoned that the effect of interferon may be evident if animals survived longer. To accomplish this and test this hypothesis, ampicillin (20 mg/kg/d) was given 48 h after bacterial challenge. When ampicillin-treated Listeria-infected rats were randomized to receive PBS, IFN-alpha/beta, or recombinant rat IFN-gamma, mortality rates were 79, 76, and 69%, respectively (p greater than 0.05 versus PBS). Animals treated in a similar fashion after a lower bacterial inoculum (25% lethal dose) were killed 5 d after bacterial challenge. Bacterial concentrations in the spleen were higher for IFN-treated animals than controls. We conclude that no direct benefit of IFN is found if it is given after bacterial infection has been established.
Insights
Administering interferon (IFN) after Listeria monocytogenes infection does not improve survival in newborn rats. Delayed treatment with IFN showed no benefit, even with antibiotic support, indicating established infections are refractory to IFN therapy.
Area of Science:
- Immunology
- Neonatal infections
- Bacterial pathogenesis
Background:
- Neonatal Listeria monocytogenes infection presents significant morbidity and mortality despite treatment.
- Previous studies demonstrated survival benefits of interferon (IFN)-alpha/beta and IFN-gamma pretreatment in infected rats.
- The efficacy of post-infection IFN administration remains largely unexplored.
Purpose of the Study:
- To evaluate the therapeutic effect of interferon (IFN)-alpha/beta and recombinant rat IFN-gamma when administered after the establishment of Listeria monocytogenes infection in newborn rats.
- To determine if prolonged survival, facilitated by antibiotic co-administration, reveals a therapeutic window for IFNs.
- To assess the impact of delayed IFN treatment on bacterial load in infected tissues.
Main Methods:
- Newborn rats were infected with Listeria monocytogenes.
- Interferon (IFN)-alpha/beta or recombinant rat IFN-gamma was administered after infection, with or without ampicillin co-treatment initiated 48 hours post-challenge.
- Mortality rates and bacterial concentrations in spleen tissue were assessed.
Main Results:
- IFN treatment administered after infection, even with delayed ampicillin, did not significantly reduce mortality rates compared to placebo.
- In a separate experiment with a lower inoculum, IFN-treated animals exhibited higher splenic bacterial concentrations than controls.
- These findings indicate a lack of therapeutic benefit when IFNs are given after the infection is established.
Conclusions:
- Interferon therapy provides no direct survival benefit when administered after Listeria monocytogenes infection has become established in a neonatal rat model.
- The timing of IFN administration is critical, with post-infection treatment being ineffective.
- Established bacterial infections appear refractory to the direct effects of interferon treatment.