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Minimal requirements for murine resistance to infection with Francisella tularensis LVS
K L Elkins1, T R Rhinehart-Jones, S J Culkin
1Laboratory of Enteric and Sexually Transmitted Diseases, Division of Bacterial Products, Center for Biologics Evaluation and Research, Rockville, Maryland 20852, USA.
Abstract:
Intraperitoneal or intravenous infection of mice with Francisella tularensis LVS is lethal, with an intraperitoneal 50% lethal dose (LD50) approaching a single bacterium. Intradermal (i.d.) LVS infection has a much higher LD50, about 10(6) bacteria in BALB/cByJ mice, and survival of i.d. infection leads to solid generation of immunity against lethal challenge. To define the minimal requirements for both initial and long-term survival of i.d. infection, we characterized the nature of i.d. LVS infection in lymphocyte-deficient BALB/cByJ.scid (scid) mice. scid mice infected i.d. with strain LVS survived for about 20 days and then died from overwhelming disseminated infection. However, scid mice treated with monoclonal antibodies to gamma interferon, tumor necrosis factor alpha, or neutrophils-granulocytes all died within 1 week of infection, indicating that these were essential for early control of infection. Studies using GKO (gamma interferon knockout) mice emphasized that gamma interferon is absolutely required for initial survival of i.d. LVS infection. scid mice could be reconstituted for long-term survival of i.d. LVS infection and clearance of bacteria by intravenous transfer of splenic lymphocytes or purified B220-/T+ lymphocytes but not nu/nu lymphocytes. T cells are therefore required for long-term clearance and survival of i.d. LVS infection; efforts to determine whether CD4+ T cells, CD8+ T cells, or both are involved are ongoing.
Insights
Francisella tularensis LVS intradermal infection requires gamma interferon and neutrophils for initial control. T cells are essential for long-term survival and bacterial clearance in mice.
Area of Science:
- Immunology
- Microbiology
- Infectious Diseases
Background:
- Francisella tularensis LVS infection is lethal via intraperitoneal or intravenous routes.
- Intradermal infection has a higher LD50 and confers immunity upon survival.
- Understanding initial and long-term survival requirements for intradermal infection is crucial.
Purpose of the Study:
- To define the minimal immune requirements for initial and long-term survival following intradermal Francisella tularensis LVS infection.
- To characterize the nature of intradermal LVS infection in lymphocyte-deficient mice.
Main Methods:
- Infection of BALB/cByJ.scid (severe combined immunodeficient) mice with F. tularensis LVS.
- Treatment of scid mice with monoclonal antibodies against gamma interferon, tumor necrosis factor alpha, or neutrophils-granulocytes.
- Studies using gamma interferon knockout (GKO) mice.
- Reconstitution of scid mice with splenic lymphocytes or purified B220-/T+ lymphocytes.
Main Results:
- scid mice survived intradermal LVS infection for approximately 20 days before succumbing to disseminated infection.
- Depletion of gamma interferon, tumor necrosis factor alpha, or neutrophils-granulocytes led to rapid death within 1 week.
- Gamma interferon is absolutely required for initial survival.
- Intravenous transfer of splenic lymphocytes or purified B220-/T+ lymphocytes restored long-term survival and bacterial clearance in scid mice.
Conclusions:
- Gamma interferon and neutrophils are essential for early control of intradermal F. tularensis LVS infection.
- T cells are required for long-term clearance and survival of intradermal LVS infection.
- Further investigation is needed to determine the specific roles of CD4+ and CD8+ T cells.