Abstract
Immune correlates of protection against intracellular bacterial pathogens are largely thought to be cell-mediated, although a reasonable amount of data supports a role for antibody-mediated protection. To define a role for antibody-mediated immunity against an intracellular pathogen, Rhodococcus equi, that causes granulomatous pneumonia in horse foals, we devised and tested an experimental system relying solely on antibody-mediated protection against this host-specific etiologic agent. Immunity was induced by vaccinating pregnant mares 6 and 3 weeks prior to predicted parturition with a conjugate vaccine targeting the highly conserved microbial surface polysaccharide, poly-N-acetyl glucosamine (PNAG). We ascertained antibody was transferred to foals via colostrum, the only means for foals to acquire maternal antibody. Horses lack transplacental antibody transfer. Next, a randomized, controlled, blinded challenge was conducted by inoculating at ~4 weeks of age ~106 cfu of R. equi via intrabronchial challenge. Eleven of 12 (91%) foals born to immune mares did not develop clinical R. equi pneumonia, whereas 6 of 7 (86%) foals born to unvaccinated controls developed pneumonia (P = 0.0017). In a confirmatory passive immunization study, infusion of PNAG-hyperimmune plasma protected 100% of 5 foals against R. equi pneumonia whereas all 4 recipients of normal horse plasma developed clinical disease (P = 0.0079). Antibodies to PNAG mediated killing of extracellular and intracellular R. equi and other intracellular pathogens. Killing of intracellular organisms depended on antibody recognition of surface expression of PNAG on infected cells, along with complement deposition and PMN-assisted lysis of infected macrophages. Peripheral blood mononuclear cells from immune and protected foals released higher levels of interferon-γ in response to PNAG compared to controls, indicating vaccination also induced an antibody-dependent cellular release of this critical immune cytokine. Overall, antibody-mediated opsonic killing and interferon-γ release in response to PNAG may protect against diseases caused by intracellular bacterial pathogens.
Highlights
Correlates of cellular and humoral immunity to major intracellular, non-viral pathogens capable of informing vaccine development are incompletely understood
To address this problem against an important, and representative, equine intracellular pathogen, we chose to test a vaccine candidate for the ability to protect horse foals challenged at 4 weeks of age with Rhodococcus equi
Antibody in the pregnant mares was transferred to their foals and, after the foals were challenged, 91% of those born to vaccinated mares were protected against R. equi pneumonia
Summary
Correlates of cellular and humoral immunity to major intracellular, non-viral pathogens capable of informing vaccine development are incompletely understood. It is unknown which ones can form the basis of a highly effective vaccine to prevent diseases such as tuberculosis (TB). Rhodococcus equi is a Gram-positive, facultative intracellular pathogen carrying an essential virulence plasmid that primarily infects alveolar macrophages of horse foals following inhalation. R. equi replicates within a modified phagocytic vacuole, with survival dependent on the virulence plasmid preventing phagosome-lysosome fusion, resulting in a granulomatous pneumonia that is pathologically similar to that caused by Mycobacterium tuberculosis infection in humans [5]. There is no approved vaccine for R. equi in any animal species
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