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TNF receptor 1, IL-1 receptor, and iNOS genetic knockout mice are not protected from anthrax infection
John Kalns1, Julie Scruggs, Nancy Millenbaugh
1Davis Hyperbaric Laboratory, 2602 West Gate Road, Brooks Air Force Base, TX 78235-5252, USA. john.kalns@brooks.af.mil
Abstract:
Anthrax produces at least two toxins that cause an intense systemic inflammatory response, edema, shock, and eventually death. The relative contributions of various elements of the immune response to mortality and course of disease progression are poorly understood. We hypothesized that knockout mice missing components of the immune system will have an altered response to infection. Parent strain mice and knockouts were challenged with LD95 of anthrax spores (5 x 10(6)) administered subcutaneously. Our results show that all genetic knockouts succumbed to anthrax infection at the same frequency as the parent. TNF antibody delayed death but TNF receptor 1 knockout had no effect. IL-1 receptor or iNOS knockouts died sooner. Anthrax was more abundant in the injection site of TNF-alpha and iNOS knockouts compared to parent suggesting that attenuated cellular response increases rate of disease progression. With the exception of edema and necrosis at the injection site pathological changes in internal organs were not observed.
Insights
Investigating the immune response to anthrax, this study found that while most immune system knockouts had similar survival rates, some, like IL-1 receptor and iNOS knockouts, died sooner, indicating a complex role in disease progression.
Area of Science:
- Immunology
- Microbiology
- Pathology
Background:
- Bacillus anthracis toxins induce severe systemic inflammation, shock, and death.
- The specific roles of immune system components in anthrax mortality and disease progression remain unclear.
Purpose of the Study:
- To investigate the impact of specific immune system components on the host response to anthrax infection.
- To determine if genetic deficiencies in the immune system alter susceptibility or disease course in a murine model.
Main Methods:
- Parent strain mice and knockout mice lacking specific immune factors were subcutaneously challenged with a lethal dose (LD95) of anthrax spores.
- Survival rates, bacterial burden at the injection site, and pathological changes were assessed.
Main Results:
- All genetic knockouts exhibited similar mortality frequencies compared to parent strain mice.
- Tumor necrosis factor (TNF) antibody administration delayed death, but TNF receptor 1 knockout mice showed no difference in survival.
- Interleukin-1 receptor (IL-1R) and inducible nitric oxide synthase (iNOS) knockout mice succumbed to infection more rapidly.
- Increased anthrax burden at the injection site was observed in TNF-alpha and iNOS knockouts, suggesting impaired cellular response.
Conclusions:
- While overall mortality was not significantly altered by most immune gene knockouts, specific pathways like IL-1R and iNOS play a critical role in controlling early infection.
- An attenuated cellular immune response, as seen in iNOS knockouts, may accelerate anthrax disease progression.
- Pathological changes were primarily localized to the injection site, with minimal systemic organ damage observed.