Frontiers in immunology · 2026
Systems biology approach unveils the cellular and molecular mechanisms of formalin-inactivated whole cell vaccine-induced protective immunity against Coxiella burnetii infection in mice.
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Kumaresan Venkatesh, Wang Duolin, Zhang Yan, Xu Dong, Zhang Guoquan
Аннотация
BACKGROUND: The formalin-inactivated Coxiella burnetii virulent phase I vaccine (PIV) has been shown to be more protective than the avirulent phase II vaccine (PIIV) against virulent C. burnetii challenge in animal models. However, the cellular and molecular mechanisms underlying the differential ability of PIV and PIIV to induce protective immunity remain unclear.
METHODS: PIV and PIIV were generated from axenic (ACCM-D) cultures and administered to mice using single or multiple immunization regimens. Protective efficacy was evaluated following challenge with virulent C. burnetii. Humoral immune responses were assessed by measuring phase I-specific IgM and IgG antibodies. Bulk RNA sequencing and flow cytometry were used to compare immune responses in PIV- and PIIV-vaccinated mice. The role of neutrophils in vaccine-mediated protection was examined through neutrophil depletion prior to challenge.
RESULTS: Regardless of single or multiple immunizations, PIV and PIIV generated from axenic (ACCM-D) cultures retained their differential protective efficacies, with PIV providing robust protection but PIIV did not. PIV elicited earlier phase I-specific IgM responses and sustained higher IgG responses compared to PIIV, indicating differences in immunogenicity. Cellular and transcriptomic analyses revealed that PIV induced a prolonged neutrophil response in the spleen, accompanied by upregulation of genes involved in neutrophil degranulation, metal sequestration, and TLR-dependent innate immune pathways. In contrast, the neutrophil response induced by PIIV was transient and did not persist into later stages of vaccination. Depletion of neutrophils in PIV-vaccinated mice prior to challenge significantly reduced the protective efficacy of PIV.
CONCLUSION: These findings demonstrate that PIV-induced protection against C. burnetii infection is partially dependent on sustained neutrophil activation. This study provides novel evidence that modulation of neutrophil-mediated effector functions plays a critical role in PIV-mediated protective immunity.
METHODS: PIV and PIIV were generated from axenic (ACCM-D) cultures and administered to mice using single or multiple immunization regimens. Protective efficacy was evaluated following challenge with virulent C. burnetii. Humoral immune responses were assessed by measuring phase I-specific IgM and IgG antibodies. Bulk RNA sequencing and flow cytometry were used to compare immune responses in PIV- and PIIV-vaccinated mice. The role of neutrophils in vaccine-mediated protection was examined through neutrophil depletion prior to challenge.
RESULTS: Regardless of single or multiple immunizations, PIV and PIIV generated from axenic (ACCM-D) cultures retained their differential protective efficacies, with PIV providing robust protection but PIIV did not. PIV elicited earlier phase I-specific IgM responses and sustained higher IgG responses compared to PIIV, indicating differences in immunogenicity. Cellular and transcriptomic analyses revealed that PIV induced a prolonged neutrophil response in the spleen, accompanied by upregulation of genes involved in neutrophil degranulation, metal sequestration, and TLR-dependent innate immune pathways. In contrast, the neutrophil response induced by PIIV was transient and did not persist into later stages of vaccination. Depletion of neutrophils in PIV-vaccinated mice prior to challenge significantly reduced the protective efficacy of PIV.
CONCLUSION: These findings demonstrate that PIV-induced protection against C. burnetii infection is partially dependent on sustained neutrophil activation. This study provides novel evidence that modulation of neutrophil-mediated effector functions plays a critical role in PIV-mediated protective immunity.