There remains to this day a great gap in understanding as to the role of B cells and their products-antibodies and cytokines-in mediating the protective response to Francisella tularensis, a Gram-negative coccobacillus belonging to the group of facultative intracellular bacterial pathogens. We previously have demonstrated that Francisella interacts directly with peritoneal B-1a cells. Here, we demonstrate that, as early as 12 h postinfection, germ-free mice infected with Francisella tularensis produce infection-induced antibody clones reacting with Francisella tularensis proteins having orthologs or analogs in eukaryotic cells. Production of some individual clones was limited in time and was influenced by virulence of the Francisella strain used. The phylogenetically stabilized defense mechanism can utilize these early infection-induced antibodies both to recognize components of the invading pathogens and to eliminate molecular residues of infection-damaged self cells.

Department of Immunology and Gnotobiology Institute of Microbiology of the Academy of Sciences of the Czech Republic Videnska 1083 142 20 Prague 4 Czech Republic

Department of Molecular Pathology and Biology Faculty of Military Health Sciences University of Defence Trebesska 1575 500 01 Hradec Kralove Czech Republic

Department of Toxicology and Military Pharmacy Faculty of Military Health Sciences University of Defence Trebesska 1575 500 01 Hradec Kralove Czech Republic

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Jia Q, Horwitz MA. Live attenuated tularemia vaccines for protection against respiratory challenge with virulent F. tularensis subsp. tularensis. Front. Cell. Infect. Microbiol. 2018;8:154. doi: 10.3389/fcimb.2018.00154. PubMed DOI PMC

Anthony LS, Ghadirian E, Nestel FP, Kongshavn PA. The requirement for gamma interferon in resistance of mice to experimental tularemia. Microb. Pathog. 1989;7:421–428. doi: 10.1016/0882-4010(89)90022-3. PubMed DOI

Fortier AH, Polsinelli T, Green SJ, Nacy CA. Activation of macrophages for destruction of Francisella tularensis: Identification of cytokines, effector cells, and effector molecules. Infect. Immun. 1992;60:817–825. doi: 10.1128/IAI.60.3.817-825.1992. PubMed DOI PMC

Leiby DA, Fortier AH, Crawford RM, Schreiber RD, Nacy CA. In vivo modulation of the murine immune response to Francisella tularensis LVS by administration of anticytokine antibodies. Infect. Immun. 1992;60:84–89. doi: 10.1128/IAI.60.1.84-89.1992. PubMed DOI PMC

Elkins KL, Rhinehart-Jones TR, Culkin SJ, Yee D, Winegar RK. Minimal requirements for murine resistance to infection with Francisella tularensis LVS. Infect. Immun. 1996;64:3288–3293. doi: 10.1128/IAI.64.8.3288-3293.1996. PubMed DOI PMC

Macela, A. Interaction of Francisella tularensis wirh the cells of mononuclear phagocytic system in the course of early stages of infection. Thesis, (Faculty of Science, Charles University, 1980).

Kovarova H, Marcela A, Stulik J. Macrophage activating factors produced in the course of murine tularemia: Effect on multiplication of microbes. Arch. Immunol. Ther. Exp. (Warsz.) 1992;40:183–190. PubMed

Hernychova L, et al. Early consequences of macrophage-Francisella tularensis interaction under the influence of different genetic background in mice. Immunol. Lett. 1997;57:75–81. doi: 10.1016/S0165-2478(97)00063-1. PubMed DOI

Hrstka R, Stulík J, Vojtesek B. The role of MAPK signal pathways during Francisella tularensis LVS infection-induced apoptosis in murine macrophages. Microbes Infect. Inst. Pasteur. 2005;7:619–625. doi: 10.1016/j.micinf.2004.12.020. PubMed DOI

Hrstka R, et al. Francisella tularensis strain LVS resides in MHC II-positive autophagic vacuoles in macrophages. Folia Microbiol. (Praha) 2007;52:631–636. doi: 10.1007/BF02932193. PubMed DOI

Steiner DJ, Furuya Y, Jordan MB, Metzger DW. Protective role for macrophages in respiratory Francisella tularensis infection. Infect. Immun. 2017;85:00064–117. doi: 10.1128/IAI.00064-17. PubMed DOI PMC

Steiner DJ, Furuya Y, Metzger DW. Detrimental influence of alveolar macrophages on protective humoral immunity during Francisella tularensis SchuS4 pulmonary infection. Infect. Immun. 2018;86:00787–817. doi: 10.1128/IAI.00787-17. PubMed DOI PMC

Sjöstedt A, Conlan JW, North RJ. Neutrophils are critical for host defense against primary infection with the facultative intracellular bacterium Francisella tularensis in mice and participate in defense against reinfection. Infect. Immun. 1994;62:2779–2783. doi: 10.1128/IAI.62.7.2779-2783.1994. PubMed DOI PMC

Bosio CM, Elkins KL. Susceptibility to secondary Francisella tularensis live vaccine strain infection in B-cell-deficient mice is associated with neutrophilia but not with defects in specific T-cell-mediated immunity. Infect. Immun. 2001;69:194–203. doi: 10.1128/IAI.69.1.194-203.2001. PubMed DOI PMC

KuoLee R, Harris G, Conlan JW, Chen W. Role of neutrophils and NADPH phagocyte oxidase in host defense against respiratory infection with virulent Francisella tularensis in mice. Microbes Infect. 2011;13:447–456. doi: 10.1016/j.micinf.2011.01.010. PubMed DOI

Malik M, et al. Matrix metalloproteinase 9 activity enhances host susceptibility to pulmonary infection with type A and B strains of Francisella tularensis. J. Immunol. Baltim. Md. 2007;1950(178):1013–1020. PubMed

Bosio CM, Dow SW. Francisella tularensis induces aberrant activation of pulmonary dendritic cells. J. Immunol. Baltim. Md. 2005;1950(175):6792–6801. PubMed

Fabrik I, Härtlova A, Rehulka P, Stulik J. Serving the new masters—dendritic cells as hosts for stealth intracellular bacteria. Cell. Microbiol. 2013;15:1473–1483. doi: 10.1111/cmi.12160. PubMed DOI

Fabrik I, et al. The early dendritic cell signaling induced by virulent Francisella tularensis strain occurs in phases and involves the activation of extracellular signal-regulated kinases (ERKs) and p38 In the later stage. Mol. Cell. Proteom. MCP. 2018;17:81–94. doi: 10.1074/mcp.RA117.000160. PubMed DOI PMC

Claflin JL, Larson CL. Infection-immunity in tularemia: Specificity of cellular immunity. Infect. Immun. 1972;5:311–318. doi: 10.1128/IAI.5.3.311-318.1972. PubMed DOI PMC

Kostiala AA, McGregor DD, Logie PS. Tularaemia in the rat. I. The cellular basis on host resistance to infection. Immunology. 1975;28:855–869. PubMed PMC

Tärnvik A, Löfgren S. Stimulation of human lymphocytes by a vaccine strain of Francisella tularensis. Infect. Immun. 1975;12:951–957. doi: 10.1128/IAI.12.5.951-957.1975. PubMed DOI PMC

Koskela P, Herva E. Cell-mediated immunity against Francisella tularensis after natural infection. Scand. J. Infect. Dis. 1980;12:281–287. doi: 10.3109/inf.1980.12.issue-4.08. PubMed DOI

Sjöstedt A, Sandström G, Tärnvik A, Jaurin B. Molecular cloning and expression of a T-cell stimulating membrane protein of Francisella tularensis. Microb. Pathog. 1989;6:403–414. doi: 10.1016/0882-4010(89)90082-X. PubMed DOI

Surcel HM, Ilonen J, Poikonen K, Herva E. Francisella tularensis-specific T-cell clones are human leukocyte antigen class II restricted, secrete interleukin-2 and gamma interferon, and induce immunoglobulin production. Infect. Immun. 1989;57:2906–2908. doi: 10.1128/IAI.57.9.2906-2908.1989. PubMed DOI PMC

Surcel HM, Tapaninaho S, Herva E. Cytotoxic CD4+ T cells specific for Francisella tularensis. Clin. Exp. Immunol. 1991;83:112–115. doi: 10.1111/j.1365-2249.1991.tb05598.x. PubMed DOI PMC

Yee D, Rhinehart-Jones TR, Elkins KL. Loss of either CD4+ or CD8+ T cells does not affect the magnitude of protective immunity to an intracellular pathogen, Francisella tularensis strain LVS. J. Immunol. Baltim. Md. 1996;1950(157):5042–5048. PubMed

Poquet Y, et al. Expansion of Vgamma9 Vdelta2 T cells is triggered by Francisella tularensis-derived phosphoantigens in tularemia but not after tularemia vaccination. Infect. Immun. 1998;66:2107–2114. doi: 10.1128/IAI.66.5.2107-2114.1998. PubMed DOI PMC

Henry T, et al. Type I IFN signaling constrains IL-17A/F secretion by gammadelta T cells during bacterial infections. J. Immunol. Baltim. Md. 2010;1950(184):3755–3767. PubMed PMC

Crane DD, Scott DP, Bosio CM. Generation of a convalescent model of virulent Francisella tularensis infection for assessment of host requirements for survival of tularemia. PLoS ONE. 2012;7:33349. doi: 10.1371/journal.pone.0033349. PubMed DOI PMC

Cowley SC, et al. CD4-CD8- T cells control intracellular bacterial infections both in vitro and in vivo. J. Exp. Med. 2005;202:309–319. doi: 10.1084/jem.20050569. PubMed DOI PMC

Tärnvik A, Holm SE. Stimulation of subpopulations of human lymphocytes by a vaccine strain of Francisella tularensis. Infect. Immun. 1978;20:698–704. doi: 10.1128/IAI.20.3.698-704.1978. PubMed DOI PMC

Culkin SJ, Rhinehart-Jones T, Elkins KL. A novel role for B cells in early protective immunity to an intracellular pathogen, Francisella tularensis strain LVS. J. Immunol. Baltim. Md. 1997;1950(158):3277–3284. PubMed

Elkins KL, Bosio CM, Rhinehart-Jones TR. Importance of B cells, but not specific antibodies, in primary and secondary protective immunity to the intracellular bacterium Francisella tularensis live vaccine strain. Infect. Immun. 1999;67:6002–6007. doi: 10.1128/IAI.67.11.6002-6007.1999. PubMed DOI PMC

Chou AY, Kennett NJ, Melillo AA, Elkins KL. Murine survival of infection with Francisella novicida and protection against secondary challenge is critically dependent on B lymphocytes. Microbes Infect. 2017;19:91–100. doi: 10.1016/j.micinf.2016.12.001. PubMed DOI

Krocova Z, et al. Interaction of B cells with intracellular pathogen Francisella tularensis. Microb. Pathog. 2008;45:79–85. doi: 10.1016/j.micpath.2008.01.010. PubMed DOI

Plzakova L, Krocova Z, Kubelkova K, Macela A. Entry of Francisella tularensis into murine B cells: The role of B cell receptors and complement receptors. PLoS ONE. 2015;10:0132571. doi: 10.1371/journal.pone.0132571. PubMed DOI PMC

Plzakova L, et al. B cell subsets are activated and produce cytokines during early phases of Francisella tularensis LVS infection. Microb. Pathog. 2014;75:49–58. doi: 10.1016/j.micpath.2014.08.009. PubMed DOI

Drabick JJ, Narayanan RB, Williams JC, Leduc JW, Nacy CA. Passive protection of mice against lethal Francisella tularensis (live tularemia vaccine strain) infection by the sera of human recipients of the live tularemia vaccine. Am. J. Med. Sci. 1994;308:83–87. doi: 10.1097/00000441-199408000-00003. PubMed DOI

Stenmark S, Lindgren H, Tärnvik A, Sjöstedt A. Specific antibodies contribute to the host protection against strains of Francisella tularensis subspecies holarctica. Microb. Pathog. 2003;35:73–80. doi: 10.1016/S0882-4010(03)00095-0. PubMed DOI

Kirimanjeswara GS, Golden JM, Bakshi CS, Metzger DW. Prophylactic and therapeutic use of antibodies for protection against respiratory infection with Francisella tularensis. J. Immunol. Baltim. Md. 2007;1950(179):532–539. PubMed

Klimpel GR, et al. Levofloxacin rescues mice from lethal intra-nasal infections with virulent Francisella tularensis and induces immunity and production of protective antibody. Vaccine. 2008;26:6874–6882. doi: 10.1016/j.vaccine.2008.09.077. PubMed DOI PMC

Sebastian S, et al. Cellular and humoral immunity are synergistic in protection against types A and B Francisella tularensis. Vaccine. 2009;27:597–605. doi: 10.1016/j.vaccine.2008.10.079. PubMed DOI PMC

Mara-Koosham G, Hutt JA, Lyons CR, Wu TH. Antibodies contribute to effective vaccination against respiratory infection by type A Francisella tularensis strains. Infect. Immun. 2011;79:1770–1778. doi: 10.1128/IAI.00605-10. PubMed DOI PMC

Kubelkova K, et al. Specific antibodies protect gamma-irradiated mice against Francisella tularensis infection. Microb. Pathog. 2012;53:259–268. doi: 10.1016/j.micpath.2012.07.006. PubMed DOI

Krocova Z, Plzakova L, Benuchova M, Macela A, Kubelkova K. Early cellular responses of germ-free and specific-pathogen-free mice to Francisella tularensis infection. Microb. Pathog. 2018;123:314–322. doi: 10.1016/j.micpath.2018.07.036. PubMed DOI

Lamousé-Smith E, Tzeng A, Starnbach M. The intestinal flora is required to support antibody responses to systemic immunization in infant and germ free mice. PLoS ONE. 2011;6:27662. doi: 10.1371/journal.pone.0027662. PubMed DOI PMC

Kubelkova K, et al. Gnotobiotic mouse model’s contribution to understanding host-pathogen interactions. Cell. Mol. Life Sci. CMLS. 2016;73:3961–3969. doi: 10.1007/s00018-016-2341-8. PubMed DOI PMC

Zarrella TM, et al. Host-adaptation of Francisella tularensis alters the bacterium’s surface-carbohydrates to hinder effectors of innate and adaptive immunity. PLoS ONE. 2011;6:22. doi: 10.1371/journal.pone.0022335. PubMed DOI PMC

Wallqvist A, et al. Using host-pathogen protein interactions to identify and characterize Francisella tularensis virulence factors. BMC Genom. 2015;16:1106. doi: 10.1186/s12864-015-2351-1. PubMed DOI PMC

Holland K, et al. Differential growth of francisella tularensis, which alters expression of virulence factors, dominant antigens, and surface-carbohydrate synthases, governs the apparent virulence of Ft SchuS4 to immunized animals. Front. Microbiol. 2017;8:1158. doi: 10.3389/fmicb.2017.01158. PubMed DOI PMC

Köppen K, et al. Screen for fitness and virulence factors of Francisella sp. strain W12–1067 using amoebae. Int. J. Med. Microbiol. 2019;309:151341. doi: 10.1016/j.ijmm.2019.151341. PubMed DOI

Spidlova P, Stojkova P, Sjöstedt A, Stulik J. Control of Francisella tularensis virulence at gene level: Network of transcription factors. Microorganisms. 2020;8:1622. doi: 10.3390/microorganisms8101622. PubMed DOI PMC

Syrjälä H, Herva E, Ilonen J, Saukkonen K, Salminen A. A whole-blood lymphocyte stimulation test for the diagnosis of human tularemia. J. Infect. Dis. 1984;150:912–915. doi: 10.1093/infdis/150.6.912. PubMed DOI

Karttunen R, Surcel HM, Andersson G, Ekre HP, Herva E. Francisella tularensis-induced in vitro gamma interferon, tumor necrosis factor alpha, and interleukin 2 responses appear within 2 weeks of tularemia vaccination in human beings. J. Clin. Microbiol. 1991;29:753–756. doi: 10.1128/JCM.29.4.753-756.1991. PubMed DOI PMC

Anthony LS, Skamene E, Kongshavn PA. Influence of genetic background on host resistance to experimental murine tularemia. Infect. Immun. 1988;56:2089–2093. doi: 10.1128/IAI.56.8.2089-2093.1988. PubMed DOI PMC

Macela A, et al. The immune response against Francisella tularensis live vaccine strain in Lps(n) and Lps(d) mice. FEMS Immunol. Med. Microbiol. 1996;13:235–238. doi: 10.1111/j.1574-695X.1996.tb00243.x. PubMed DOI

Kovárová H, Hernychová L, Hajdúch M, Sírová M, Macela A. Influence of the bcg locus on natural resistance to primary infection with the facultative intracellular bacterium Francisella tularensis in mice. Infect. Immun. 2000;68:1480–1484. doi: 10.1128/IAI.68.3.1480-1484.2000. PubMed DOI PMC

López MC, Duckett NS, Baron SD, Metzger DW. Early activation of NK cells after lung infection with the intracellular bacterium Francisella tularensis LVS. Cell. Immunol. 2004;232:75–85. doi: 10.1016/j.cellimm.2005.02.001. PubMed DOI

Gosselin EJ, Gosselin DR, Lotz SA. Natural killer and CD8 T cells dominate the response by human peripheral blood mononuclear cells to inactivated Francisella tularensis live vaccine strain. Hum. Immunol. 2005;66:1039–1049. doi: 10.1016/j.humimm.2005.08.240. PubMed DOI

Rumyantsev S. Constitutional and non-specific immunity to infection. Revue scientifique et technique (International Office of Epizootics) 1998;17:26–42. PubMed

Elkins KL, MacIntyre AT, Rhinehart-Jones TR. Nonspecific early protective immunity in Francisella and Listeria infections can be dependent on lymphocytes. Infect. Immun. 1998;66:3467–3469. doi: 10.1128/IAI.66.7.3467-3469.1998. PubMed DOI PMC

Fuller CL, et al. Dominance of human innate immune responses in primary Francisella tularensis live vaccine strain vaccination. J. Allergy Clin. Immunol. 2006;117:1186–1188. doi: 10.1016/j.jaci.2006.01.044. PubMed DOI

Fuller CL, et al. Transcriptome analysis of human immune responses following live vaccine strain (LVS) Francisella tularensis vaccination. Mol. Immunol. 2007;44:3173–3184. doi: 10.1016/j.molimm.2007.01.037. PubMed DOI PMC

Seibert K, Pollard M, Nordin A. Some aspects of humoral immunity in germ-free and conventional SJL-J mice in relation to age and pathology. Cancer Res. 1974;34:1707–1719. PubMed

Ohwaki M, Yasutake N, Yasui H, Ogura R. A comparative study on the humoral immune responses in germ-free and conventional mice. Immunology. 1977;32:43–48. PubMed PMC

Taniguchi T, et al. Difference in antibody production to heterologius erythrocytes in conventional, specific-pathogen-free (SPF), Germfree and antigen-free mice. Microbiol. Immunol. 1978;22:793–802. doi: 10.1111/j.1348-0421.1978.tb00433.x. PubMed DOI

Maddur MS, et al. Natural antibodies: From first-line defense against pathogens to perpetual immune homeostasis. Clin. Rev. Allergy Immunol. 2020;58:213–228. doi: 10.1007/s12016-019-08746-9. PubMed DOI

Cohen IR, Cooke A. Natural autoantibodies might prevent autoimmune disease. Immunol. Today. 1986;7:363–364. doi: 10.1016/0167-5699(86)90026-5. PubMed DOI

Baumgarth N, Waffarn EE, Nguyen TTT. Natural and induced B-1 cell immunity to infections raises questions of nature versus nurture. Ann. N. Y. Acad. Sci. 2015;1362:188–199. doi: 10.1111/nyas.12804. PubMed DOI PMC

Bos NA, Meeuwsen CG, Wostmann BS, Pleasants JR, Benner R. The influence of exogenous antigenic stimulation on the specificity repertoire of background immunoglobulin-secreting cells of different isotypes. Cell. Immunol. 1988;112:371–380. doi: 10.1016/0008-8749(88)90306-1. PubMed DOI

Ochsenbein AF, et al. Control of early viral and bacterial distribution and disease by natural antibodies. Science. 1999;286:2156–2159. doi: 10.1126/science.286.5447.2156. PubMed DOI

Ochsenbein AF, Zinkernagel RM. Natural antibodies and complement link innate and acquired immunity. Immunol. Today. 2000;21:624–630. doi: 10.1016/S0167-5699(00)01754-0. PubMed DOI

Su J, et al. Genome-wide identification of Francisella tularensis virulence determinants. Infect. Immun. 2007;75:3089–3101. doi: 10.1128/IAI.01865-06. PubMed DOI PMC

Elkins KL, Leiby DA, Winegar RK, Nacy CA, Fortier AH. Rapid generation of specific protective immunity to Francisella tularensis. Infect. Immun. 1992;60:4571–4577. doi: 10.1128/IAI.60.11.4571-4577.1992. PubMed DOI PMC

Elkins KL, Rhinehart-Jones T, Nacy CA, Winegar RK, Fortier AH. T-cell-independent resistance to infection and generation of immunity to Francisella tularensis. Infect. Immun. 1993;61:823–829. doi: 10.1128/IAI.61.3.823-829.1993. PubMed DOI PMC

Baumgarth N, et al. Innate and acquired humoral immunities to influenza virus are mediated by distinct arms of the immune system. Proc. Natl. Acad. Sci. U.S.A. 1999;96:2250–2255. doi: 10.1073/pnas.96.5.2250. PubMed DOI PMC

Choi YS, Baumgarth N. Dual role for B-1a cells in immunity to influenza virus infection. J. Exp. Med. 2008;205:3053–3064. doi: 10.1084/jem.20080979. PubMed DOI PMC

Cole LE, et al. Antigen-specific B-1a antibodies induced by Francisella tularensis LPS provide long-term protection against F. tularensis LVS challenge. Proc. Natl. Acad. Sci. U.S.A. 2009;106:4343–4348. doi: 10.1073/pnas.0813411106. PubMed DOI PMC

Cole LE, et al. Role of TLR signaling in Francisella tularensis-LPS-induced, antibody-mediated protection against Francisella tularensis challenge. J. Leukoc. Biol. 2011;90:787–797. doi: 10.1189/jlb.0111014. PubMed DOI PMC

Yang Y, et al. Antigen-specific antibody responses in B-1a and their relationship to natural immunity. Proc. Natl. Acad. Sci. U. S. A. 2012;109:5382–5387. doi: 10.1073/pnas.1121631109. PubMed DOI PMC

Krocova Z, Macela A, Kubelkova K. Innate immune recognition. Implications for the interaction of Francisella tularensis with the host immune system. Front. Cell Infect. Microbiol. 2017 doi: 10.3389/fcimb.2017.00446. PubMed DOI PMC

Chamberlain R. Evaluation of live tularemia vaccine prepared in a chemically defined medium. Appl. Microbiol. 1965;13:232–235. doi: 10.1128/AM.13.2.232-235.1965. PubMed DOI PMC

Havlasova J, et al. Proteomic analysis of anti-Francisella tularensis LVS antibody response in murine model of tularemia. Proteomics. 2005;5:2090–2103. doi: 10.1002/pmic.200401123. PubMed DOI

The UniProt Consortium UniProt: A worldwide hub of protein knowledge. Nucleic Acids Res. 2019;47:506–515. doi: 10.1093/nar/gky1049. PubMed DOI PMC

Jaime Huerta-Cepas J, et al. eggNOG 5.0: A hierarchical, functionally and phylogenetically annotated orthology resource based on 5090 organisms and 2502 viruses. Nucl Acids Res. 2019;47:309–314. doi: 10.1093/nar/gky1085. PubMed DOI PMC

Yu NY, et al. PSORTb 3.0: Improved protein subcellular localization prediction with refined localization subcategories and predictive capabilities for all prokaryotes. Bioinformatics (Oxford, England) 2010;26:1608–1615. doi: 10.1093/bioinformatics/btq249. PubMed DOI PMC

Almagro Armenteros JJ, et al. SignalP 5.0 improves signal peptide predictions using deep neural networks. Nat. Biotechnol. 2019;37:420–423. doi: 10.1038/s41587-019-0036-z. PubMed DOI

Rahman O, et al. Methods for the bioinformatic identification of bacterial lipoproteins encoded in the genomes of Gram-positive bacteria. World J. Microbiol. Biotechnol. 2008;24:2377–2382. doi: 10.1007/s11274-008-9795-2. DOI

Francisella and Antibodies

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