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Nfkbid Is Required for Immunity and Antibody Responses to Toxoplasma Gondii

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Nfkbid Is Required for Immunity and Antibody Responses to Toxoplasma Gondii bioRxiv preprint doi: https://doi.org/10.1101/2020.06.26.174151; this version posted June 26, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Nfkbid is required for immunity and antibody responses to Toxoplasma gondii 2 3 Scott P Souza1, Samantha D Splitt1, Julia A Alvarez1, Safuwra Wizzard1, Jessica N Wilson1, 4 Zheng Luo2, Nicole Baumgarth2, Kirk DC Jensen1# 5 6 1School of Natural Sciences, University of California, Merced 7 2Center for Immunology & Infectious Diseases, and Department of Pathology, Microbiology and 8 Immunology, University of California, Davis 9 10 # Correspondence: Kirk D.C. Jensen, [email protected] 11 12 ABSTRACT 13 No fully protective vaccine has yet been developed for any human parasite. We previously 14 reported that South American strains of Toxoplasma gondii are adept at immune evasion and 15 cause lethal secondary infections in chronically infected mice. Here we report that unlike 16 susceptible C57BL/6J mice, A/J mice were highly resistant to secondary infection. Mapping 17 immunity loci that segregated within a recombinant inbred panel of mice we identified Nfkbid, a 18 nuclear regulator of NF-κB that is required for B-1 cell development. Nfkbid-null mice (bumble) 19 were susceptible to secondary, but not primary infections and failed to generate parasite- 20 specific IgM and lacked robust parasite-specific IgG. In resistant mice, B-1 cells bore evidence 21 for Nfkbid-dependent responses, including Ighg expression, and were partially responsible for 22 the immunity defect in bumble mice. We propose a model where adaptive immunity to T. gondii 23 must be ‘layered’ with B-1 responses to promote protection to virulent challenge. 24 25 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.06.26.174151; this version posted June 26, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 26 INTRODUCTION 27 The goal of vaccination is to induce immunological memory that can protect from natural 28 infection challenge. Depending on the pathogen, effective memory would need to protect also 29 against a wide variety of pathogen-specific strains encountered in nature. Such protection is 30 termed heterologous immunity, and is effective against pathogen strains that differ in virulence, 31 immune evasion or polymorphic antigens. Parasites represent a special challenge to vaccine 32 development. Indeed, an entirely protective vaccine has yet to be achieved for any human 33 parasite 1. The apicomplexan parasite Toxoplasmas gondii, provides an excellent system to 34 explore requirements for heterologous immunity to a parasitic pathogen. T. gondii is a globally 35 spread intracellular protozoan parasite of warm-blooded animals that exhibits great genetic 36 diversity 2. T. gondii strains differ dramatically in primary infection virulence in laboratory mice 3 37 and in severity of human toxoplasmosis 4-7. Such infections can be overcome by immunological 38 memory responses elicited by vaccination or natural infection. In particular, memory CD8 T cells 39 and induction of IFNγ are primarily responsible for protection against lethal secondary infections 40 with the widely studied type I RH strain, which has a lethal dose of one parasite in naïve mice 8- 41 13. CD4 T cells are required to help the formation of effector CD8 T cell 14, 15 and B cell 42 responses 16, but the ability to adoptively transfer vaccine-elicited cellular immunity to naïve 43 recipients against the type I RH challenge is unique to memory CD8 T cells 10, 11. 44 The role of B cells in T. gondii infections is less understood. Previous studies showed 45 that B cell deficient mice (muMT) are extremely susceptible to primary 17, chronic 18 and 46 secondary infections 19, despite unimpaired levels of IFNγ. Passive transfer of antibodies from 47 immunized animals into vaccinated muMT mice significantly prolongs their survival after 48 challenge 16, 19. IgM seems particularly suited for blocking cellular invasion by T. gondii 20, while 49 IgG can perform both neutralization 21 and opsonization functions 22-24. Antibody responses 50 against T. gondii are dependent on CD4 T cells 16, 25, and are regulated by cytokines that 51 modulate T follicular helper cell and germinal center B cell formation in secondary lymphoid 2 bioRxiv preprint doi: https://doi.org/10.1101/2020.06.26.174151; this version posted June 26, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 52 organs 26, 27, suggesting conventional “B-2” B cell responses provide antibody-mediated 53 immunity to T. gondii. 54 In addition, “B-1” cells are innate-like lymphocytes that are known for producing self- and 55 pathogen-reactive “natural” IgM. B-1 cells are the predominant B cell compartment within the 56 body cavities, including the peritoneal and plural spaces and contribute to antigen-specific 57 responses to many pathogens (reviewed in 28). In mouse models of secondary bacterial 58 infections, including Borrelia hermsii 29, Streptococcus pneumoniae 30 and non-typhoid 59 Salmonella 31, vaccination induces protective memory B-1 cells to T cell-independent bacterial 60 antigens. This memory is often restricted to the B-1(b), or CD5- subset of B-1 cells 32, but not in 61 all models 33. In the T. gondii model, one study suggested that primed CD5+ B-1(a) cells can 62 rescue B-cell-deficient mice during primary infection with a low virulence strain 17. Memory B 63 cells are also appreciated to secrete pathogen-specific IgM 34, and generate somatically 64 mutated IgM to combat blood stage secondary infection with Plasmodium 35. Whether IgM 65 responses to T. gondii are B-2 or B-1 derived is unknown. Moreover, the role of B-1 cells in 66 promoting immunity to T. gondii during a secondary infection has yet to be determined. 67 Particularly troubling for vaccine development for T. gondii is the lack of sterilizing 68 immunity achieved following infection 36, 37. Unlike the highly passaged lab type I RH strain, for 69 which most immunological memory studies have been performed, the less passaged type I GT1 70 strain and atypical strains, many of which are endemic to South America, cause lethal 71 secondary infections in C57BL/6J mice and co-infect (i.e. ‘superinfect’) the brains of challenged 72 survivors 37. During secondary infection, memory CD8 T cells become exhausted but checkpoint 73 blockade fails to reverse disease outcome 38. The data suggest that yet unknown mechanisms 74 are needed to provide heterologous immunity to highly virulent strains of T. gondii. Therefore, 75 we set out to address whether additional requirements are necessary for heterologous immunity 76 to T. gondii. Through use of forward and reverse genetics, we discovered a previously 77 unidentified, essential role for Nfkbid in immunity and antibody responses to T. gondii, and 3 bioRxiv preprint doi: https://doi.org/10.1101/2020.06.26.174151; this version posted June 26, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 78 present evidence that B-1 cells may assist effective immunity to secondary infection with a 79 highly virulent parasite strain. 80 81 RESULTS 82 Non-MHC loci control resistance to secondary infection with Toxoplasma gondii 83 When mice are given a natural infection with a low virulent type III CEP strain and 84 allowed to progress to chronic infection for 35-42 days, the immunological memory that 85 develops is known to protect against secondary infections with the commonly studied lab strain, 86 type I RH. In contrast, “atypical” strains such as those isolated from South America (VAND, 87 GUYDOS, GUYMAT, TgCATBr5) or France (MAS, GPHT, FOU) and the clonal type I GT1 88 strain led to morbidity and mortality in C57BL/6J mice at varying frequencies, depending on the 89 strain type and their virulence factors 37. To explore whether host genetics influenced the ability 90 to survive secondary infection, a similar experiment was performed with A/J mice. In contrast to 91 C57BL/6 mice, A/J mice were resistant to secondary infection with all virulent atypical T. gondii 92 strains analyzed (Fig 1A) and cleared parasite burden as early as day 4 post challenge (Fig 1B). 93 These results suggest that at least one or more genetic loci controls resistance to secondary 94 infection with T. gondii strains. 95 A/J mice are known to be resistant to primary infections with the intermediate virulent 96 type II strain 39, 40, and prevent cyst formation due to polymorphisms in their MHC class I H-2 97 molecule, Ld 41, 42. To determine the extent to which the H-2a locus may contribute to A/J mice’s 98 resistance to secondary infection we compared infections in C57BL/10 (B10) and C57BL/10.A 99 (B10.A) mouse strains, the latter carrying the MHC H-2 locus of A/J (H-2a) in place of that of 100 C57BL/6 (H-2b). Compared to mice with the H-2b haplotype, mice expressing H-2a had less 101 cysts and weighed more during chronic infection with type III strains (P<0.04; Fig S1).
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