title: Interleukin-6 is essential for primary resistance to Francisella tularensis live vaccine strain infection.
abstract: We employed Francisella tularensis live vaccine strain (LVS) to study mechanisms of protective immunity against intracellular pathogens and, specifically, to understand protective correlates. One potential molecular correlate identified previously was interleukin-6 (IL-6), a cytokine with pleotropic roles in immunity, including influences on T and B cell functions. Given its role as an immune modulator and the correlation with successful anti-LVS vaccination, we examined the role IL-6 plays in the host response to LVS. IL-6-deficient (IL-6 knockout [KO]) mice infected with LVS intradermally or intranasally or anti-IL-6-treated mice, showed greatly reduced 50% lethal doses compared to wild-type (WT) mice. Increased susceptibility was not due to altered splenic immune cell populations during infection or decreased serum antibody production, as IL-6 KO mice had similar compositions of each compared to WT mice. Although LVS-infected IL-6 KO mice produced much less serum amyloid A and haptoglobin (two acute-phase proteins) than WT mice, there were no other obvious pathophysiological differences between LVS-infected WT and IL-6 KO mice. IL-6 KO or WT mice that survived primary LVS infection also survived a high-dose LVS secondary challenge. Using an in vitro overlay assay that measured T cell activation, cytokine production, and abilities of primed splenocytes to control intracellular LVS growth, we found that IL-6 KO total splenocytes or purified T cells were slightly defective in controlling intracellular LVS growth but were equivalent in cytokine production. Taken together, IL-6 is an integral part of a successful immune response to primary LVS infection, but its exact role in precipitating adaptive immunity remains elusive.
authors.affiliation: Laboratory of Mycobacterial Diseases and Cellular Immunology, Division of Bacterial, Parasitic and Allergenic Products, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Rockville, MD, USA.
authors.forename: Sherry L
authors.initials: SL
authors.lastname: Kurtz
authors.forename: Oded
authors.initials: O
authors.lastname: Foreman
authors.forename: Catharine M
authors.initials: CM
authors.lastname: Bosio
authors.forename: Miriam R
authors.initials: MR
authors.lastname: Anver
authors.forename: Karen L
authors.initials: KL
authors.lastname: Elkins
mesh_terms: D000818:Animals; D001428:Bacterial Vaccines / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D005604:Francisella tularensis / Q000276:immunology* / Q000378:metabolism; D006242:Haptoglobins / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000685:Serum Amyloid A Protein / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014406:Tularemia / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology / Q000517:prevention & control; D014613:Vaccines, Attenuated / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology
chemical_list: D001428:Bacterial Vaccines; D006242:Haptoglobins; D015850:Interleukin-6; D000685:Serum Amyloid A Protein; D014613:Vaccines, Attenuated; C577686:interleukin-6, mouse