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Rhesus macaques self-curing from a schistosome infection can display complete immunity to challenge

ABSTRACT: The rhesus macaque provides a unique model of acquired immunity against schistosomes, which afflict >200 million people worldwide. By monitoring bloodstream levels of parasite-gut derived antigen, we show that from week 10 onwards an established infection with Schistosoma mansoni was cleared in an exponential manner, eliciting resistance to reinfection. Secondary challenge at week 42 demonstrated that protection was strong in all animals and complete in some. Antibody profiles suggest that antigens mediating protection are the released products of developing schistosomula. In culture they are killed by addition of rhesus plasma, collected from week 8 post-infection onwards, and even more efficiently with post-challenge plasma. Furthermore, cultured schistosomula lose chromatin activating marks at the transcription start site of genes related to worm development as well as showing altered expression of genes related to lysosomes and lytic vacuoles involved with autophagy. Overall, our results indicate that enhanced antibody responses against the challenge migrating larvae mediate the naturally acquired protective immunity and will inform the route to an effective vaccine.

ORGANISM(S): Schistosoma mansoni

PROVIDER: GSE182594 | GEO | 2021/12/31

REPOSITORIES: GEO

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Project description:Using whole-blood transcriptional profiling, we investigated differences in the host response to vaccination and challenge in a rhesus macaque AIDS vaccine trial. Samples were collected from animals prior to and after vaccination with live irradiated vaccine cells secreting the modified endoplasmic reticulum chaperone gp96-Ig loaded with SIV peptides, either alone or in combination with a SIV-gp120 protein boost. Additional samples were collected following multiple low-dose rectal challenge with SIVmac251. Animals in the boosted group had a 73% reduced risk of infection. Surprisingly, few changes in gene expression were observed during the vaccination phase. Focusing on post-challenge comparisons, in particular for protected animals, we identified a host response signature of protection comprised of strong interferon signaling after the first challenge, which then largely abated after further challenges. We also identified a host response signature, comprised of early macrophage-mediated inflammatory responses, in animals with undetectable viral load five days after the first challenge, but which had unusually high viral titers after subsequent challenges. Statistical analysis showed that prime-boost vaccination significantly lowered the probability of infection in a time-consistent manner throughout several challenges. Given that humoral responses in the prime-boost group were highly significant pre-challenge correlates of protection, the strong innate signaling after the first challenge suggests that interferon signaling enhances vaccine-induced antibody responses and is an important contributor to protection from infection during repeated low-dose exposure to SIV. 36 Indian-origin outbred, young adult, male and female rhesus macaques divided into thre vaccination groups of 12 animals each. Groups were balanced for Mamu-A*01 (three in each group), Mamu-B*08 (one in each group), and for susceptible and resistant TRIM5α alleles. There were no Mamu-B*17+ animals. The prime group (PG) received Gp96 SIV Ig vaccine 292 cells that were transfected with plasmids encoding gp96-Ig, SIVmac251 rev-tat-nef, Gag and gp160 (35). They were injected intraperitoneally with 107 irradiated gp96SIVIg vaccine cells in HBSS, which secrete 10 μg of gp96SIVIg per 24 h. For the prime-boost group (PBG), 100 g of rSIVgp120 protein was added to the vaccine cells. The control group received 292-gp96 Ig cells not transfected with SIV antigens. After a 32-week vaccination phase, which consisted of priming in weeks 0, 6, and 25 and (for the PBG only) additional boosts in weeks 6 and 25, all animals were subject to up to seven weekly low-dose intrarectal challenges starting at 33-week with SIVmac251 at a dosage of 120 TCID50. Whenever an animal had detectable viral load (>50 copies/ml of plasma) at 5 days post challenge, it was considered viremic, further challenges were suspended, and only viral load screening continued on a weekly basis. Whole blood samples (preserved in PAXgene tubes) were collected 2 weeks prior to the first prime, 1 week after the first prime, 2 weeks before and 1 week after the third prime, 1 week before the first challenge, for newly infected animals five days into the corresponding study week and from viremic animals four days into the study week (also denoted as challenge 2 and challenge 3). Total RNA was isolated from Paxgene tubes using Paxgene Blood RNeasy Mini Kits (Qiagen) following the manufacturer’s protocol. RNA quality was assessed on an Agilent 2100 Bioanalyzer using the nanochip format, and only intact RNA was used for microarray analyses.

Project description:The radiation-attenuated (RA) cercarial vaccine is still the best model eliciting high protection levels, although the immune mechanisms have not yet been fully characterized. In order to identify genes and pathways underlying protection we investigated patterns of gene expression in PBMC and skin draining Lymph Nodes (LN) from mice using two exposure comparisons: vaccination with 500 attenuated cercariae versus infection with 500 normal cercariae; one versus three doses. Vaccinated mice were challenged with 120 normal parasites. Integration of PBMC and LN data from the infected group revealed early up-regulation of pathways associated with Th2 skewing and polarization of IgG antibody profiles. Additionally, hemostasis pathways were downregulated in infected mice, correlating with platelet reduction, potentially a mechanism to assist parasite migration through capillary beds. Conversely, up regulation of such mechanisms after vaccination may explain parasite blockade in the lungs. In contrast, a single exposure to attenuated parasites revealed early establishment of a Th1 bias (signaling of IL-1, IFN-γ; and Leishmania infection). Genes encoding chemokines and their receptors were more prominent in vaccinated mice, indicating an enhanced capacity for inflammation, potentially augmenting the inhibition of intravascular migration. Increasing the vaccinations from one to three did not dramatically elevate protection, but there was a clear shift towards antibody-mediated effectors. However, elements of the Th1 bias were still evident. Notable features after three vaccinations were markers of cytotoxicity (including IL-6 and NK cells) together with growth factors and their receptors (FGFR/VEGF/EGF) and the apoptosis pathway. Indeed, there is evidence for the development of anergy after three vaccinations, borne out by the limited responses detected in samples after challenge. We infer that persistence of a Th1 response puts a limit on expression of antibody-mediated mechanisms. This feature may explain the failure of multiple doses to drive protection towards sterile immunity. We suggest that the secretions of lung stage parasites would make a novel cohort of antigens for testing in protection experiments.

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Rhesus macaques self-curing from a schistosome infection can display complete immunity to challenge

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