TNF-α producing antigen (Ag)-specific CD8 T cells induce upper genital tract (UGT) pathology following primary C. muridarum infection; therefore, we hypothesized that a vaccine regimen must subvert Ag-specific CD8 T cell response following immunization, and/or challenge to attenuate Chlamydia-induced UGT pathology. We evaluated three immunization regimens: live-chlamydial elementary body intranasal (EB-i.n.), live-EB i.m. (EB-i. m.), and irrelevant antigen bovine serum albumin i.n. (BSA-i.n.) that induced near-total (90%), partial (50%), and no (0% ) protection, respectively against oviduct pathology following i.vag. C. muridarum challenge in C57BL6/J animals. Live-EB-specific IFN-γ, TNF-α, and IL-17 response from purified splenic CD8 T cells was evaluated on days 7, 14, and 21 after immunization. There was no detectable reduction of Ag-specific CD8 T cell response following immunization with protective vaccine regimens. We evaluated splenic live-EB-specific CD8 T cell responses on days 3, 6, 9, and 12 following i.vag. chlamydial challenge. All groups of challenged animals displayed comparable induction of Ag-specific CD8 T cell cytokine responses on day 6 after challenge. As early as day 9 after challenge, Ag-specific IFN-γ and TNF-α production from CD8 T cells was significantly reduced in EB-i.n.-, compared to the EB-i.m.- or BSA-i.n.-immunized animals. On day 12, both EB-i.n.- and EB-i.m.-immunized animals displayed minimal Ag-specific TNF-α production, compared to enhanced TNF-α production from CD8 T cells in BSA-i.n. immunized animals. These results suggest that TNF-α producing CD8 T cell response could serve as a predictive biomarker of anti-chlamydia vaccine efficacy against reproductive pathology.
We have demonstrated previously that CD4 T cells are protective whereas CD8 T cells cause reproductive pathology following genital chlamydial infection. In this study, we explored the interactions of these cell types in context of vaccine-mediated protection. We evaluated three immunization regimens: live-chlamydial elementary body intranasal (EB-i.n.), live-EB i.m. (EB-i.m.), and irrelevant antigen bovine serum albumin i.n. (BSA-i.n.) that induced near-total (90%), partial (50%), and no (0%) protection, respectively against oviduct pathology following i.vag. C. muridarum challenge in C57BL6/J animals. We found no differences in Chlamydia-specific IFN-g, TNF-α, or IL-17 response from purified splenic CD8 T cells on days 7, 14, and 21 after immunization. We further evaluated Chlamydia-specific splenic CD8 T cell responses on days 3, 6, 9, and 12 following i.vag. chlamydial challenge. All groups of challenged animals displayed comparable induction of Ag-specific CD8 T cell cytokine responses on day 6 after challenge. As early as day 9 after challenge, Ag-specific IFN-g and TNF-α production from CD8 T cells was significantly reduced in EB-i.n.-immunized mice, and on day 12, both EB-i.n.- and EB-i.m.-immunized animals displayed minimal Ag-specific TNF-a production, compared to enhanced TNF-a production from CD8 T cells in BSA-i.n. immunized animals. Furthermore, adoptive transfer of Chlamydia-specific CD4 T cells at the time of genital infection induced significant reduction in Chlamydia-specific splenic CD8 T cell response on day 12 after challenge. In summary, these results suggest that Ag-specific CD4 T cells subvert a pathogenic Chlamydia-specific CD8 T cell response to protect against reproductive pathology.
Burkholderia cepacia complex is a group of closely related opportunistic Gram-negative species that can be found in soil and water. Burkholderia cepacia complex is commonly associated with pulmonary infections in patients with cystic fibrosis, hospital-borne outbreaks related to contaminated medicines and devices, and, rarely, prosthetic valve endocarditis. The treatment of Burkholderia cepacia remains challenging because of the organism’s intrinsic resistance to several antibiotics, and often requires combination therapy. Through this clinical vignette, we review an interesting case of culture-negative Burkholderia prosthetic valve endocarditis identified through metagenomic next-generation sequencing (mNGS) and the challenges associated with the diagnosis and selection of an appropriate treatment.
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