[This corrects the article DOI: 10.3389/fnhum.2026.1845376.].

Conditioned immune responses demonstrate that learned sensory cues can modulate peripheral immunity without re-exposure to the original immunological trigger. In 2026, this research area reaches the centennial of early Pavlovian immune-reflex experiments that already reported conditioned leukocyte shifts and enhancement-like resistance to infection. Although modern psychoneuroimmunology has been shaped largely by conditioned immunosuppression, conditioned immune enhancement remains comparatively less explored despite its relevance to anticipatory host defense, immune surveillance, tumor biology, and neuroimmune regulation. This mini review focuses on the efferent, or recall, pathways of conditioned immune enhancement and separates them from afferent acquisition signals and central cue-immune-state representations. Classical odor-conditioning paradigms using camphor and the viral mimic polyinosinic:polycytidylic acid identified interferon-β as an acquisition-related signal, whereas recall studies implicated β-endorphin, μ-opioid receptor, glutamatergic/NMDA, monoaminergic, catecholaminergic, cholinergic, serotonergic, ACTH-related, interferon-α-related, and endocrine mechanisms. Conditioned enhancement has been shown for natural killer cell activity, cytotoxic T-lymphocyte responses, neutrophil activity, antibody responses, and tumor-model readouts. We further integrate recent circuit-level studies of insular immune-state retrieval, brain-to-spleen humoral control, vagal cytokine coding, and descending sympathetic inflammatory pathways, together with transcriptomic data from a gene-agnostic multi-tissue pilot study assessing post-recall gene-expression dynamics. Together, these findings argue against a simple hypothalamic-pituitary-adrenal axis model and instead support a temporally organized, multi-channel efferent architecture. Dissecting and understanding this emerging architecture may provide the mechanistic basis for translating the efferent arm of conditioned immune enhancement into future therapeutic concepts with clinical impact.

Background: Behaviorally conditioned immune functions are suggested to be regulated by bidirectional interactions between CNS and peripheral immune system via the hypothalamic-pituitary-adrenal (HPA) axis, sympathetic nervous system (SNS), and the parasympathetic nervous system (PNS). Since the current knowledge about biochemical pathways triggering conditioned immune enhancement is limited, the aim of this pilot study was gaining more insights into that. Methods: Rats were conditioned with camphor smell and poly I:C injection, mimicking a viral infection. Following stimulus re-exposure, animals were sacrificed at different time points, and neural tissues along the HPA axis was analyzed with a rat genome array together with plasma protein using Luminex analysis. Results: In the hypothalamus, we observed a strong upregulation of genes related to Wnt/β-catenin signaling (Otx2, Spp1, Fzd6, Zic1), monoaminergic transporter Slc18a2 and opioid-inhibitory G-protein Gpr88 as well as downregulation of dopaminergic receptors, vasoactive intestinal peptide Vip, and pro-melanin-concentrating hormone Pmch. In the pituitary, we recognized mostly upregulation of steroid synthesis in combination with GABAergic, cholinergic and opioid related neurotransmission, in adrenal glands, altered genes showed a pattern of activated metabolism plus upregulation of adrenoceptors Adrb3 and Adra1a. Data obtained from spleen showed a strong upregulation of immunomodulatory genes, chemo-/cytokines and glutamatergic/cholinergic neurotransmission related genes, as also confirmed by increased chemokine and ACTH levels in plasma. Conclusions: Our data indicate that in addition to the classic HPA axis, there could be additional pathways as e.g. the cholinergic anti-inflammatory pathway (CAIP), connecting brain and immune system, modulating and finetuning communication between brain and immune system.

Background Behaviorally conditioned immune functions are suggested to be regulated by bidirectional interactions between CNS and peripheral immune system via the hypothalamic-pituitary-adrenal (HPA) axis, sympathetic nervous system (SNS), and the parasympathetic nervous system (PNS). Since the current knowledge about biochemical pathways triggering conditioned immune enhancement is limited, the aim of this pilot study was gaining more insights into that. Methods Rats were conditioned with camphor smell and poly I:C injection, mimicking a viral infection. Following stimulus re-exposure, animals were sacrificed at different time points, and neural tissues along the HPA axis was analyzed with a rat genome array together with plasma protein using Luminex analysis. Results In the hypothalamus, we observed a strong upregulation of genes related to Wnt/β-catenin signaling (Otx2, Spp1, Fzd6, Zic1), monoaminergic transporter Slc18a2 and opioid-inhibitory G-protein Gpr88 as well as downregulation of dopaminergic receptors, vasoactive intestinal peptide Vip, and pro-melanin-concentrating hormone Pmch. In the pituitary, we recognized mostly upregulation of steroid synthesis in combination with GABAergic, cholinergic and opioid related neurotransmission, in adrenal glands, altered genes showed a pattern of activated metabolism plus upregulation of adrenoceptors Adrb3 and Adra1a. Data obtained from spleen showed a strong upregulation of immunomodulatory genes, chemo-/cytokines and glutamatergic/cholinergic neurotransmission related genes, as also confirmed by increased chemokine and ACTH levels in plasma. Conclusions Our data indicate that in addition to the classic HPA axis, there could be additional pathways as e.g. the cholinergic anti-inflammatory pathway (CAIP), connecting brain and immune system, modulating and finetuning communication between brain and immune system.

Introduction:In case of newly emerging pathogens, convalescent plasma (CP) is often the only early available treatment option. It has been shown that different IgG subclasses contribute differently to CP neutralizing activity. As CP donors often have a risk profile like first-time donors, especially with respect to window-period viral transmission, pathogen reduction (PR) could mitigate that risk. The aim of our study, especially in the light of potential future pandemics, was to evaluate the impact of commercially available PR technologies on total IgG and IgG subclasses quantity and distribution in CP using COVID-19 CP (CCP) as surrogate for CP in a side-by-side comparison approach.Methods:36 apheresis CCP donations were allocated to three study groups and a side-by-side assessment of the potential impact of amotosalen (AS)/UVA treatment compared to a riboflavin (RB)/UVB treatment, AS against methylene blue (MB) treatment, and RB against MB treatment on the quantity of IgG and IgG subclasses with a nephelometric analyzer was performed.Results:IgG subclass distributions were not significantly changed post PR treatment with all three technologies. There was also no significant difference in the median loss of concentration for IgG1 and IgG2 between the three technologies. We recognized a non-significant trend of a higher IgG4 median loss post RB treatment compared to post AS and MB treatment, respectively.Conclusion:Although the three commercially available PR systems do not significantly alter the distribution of IgG subclasses, we detected a non-significant trend of higher IgG4 loss after RB treatment. The potential impact of that finding needs further investigation.

OBJECTIVES:The detection of SARS-CoV-2 RNA in blood and platelet concentrates from asymptomatic donors, and the detection of viral particles on the surface and inside platelets during in vitro experiments, raised concerns over the potential risk for transfusion-transmitted-infection (TTI). The objective of this study was to assess the efficacy of the amotosalen/UVA pathogen reduction technology for SARS-CoV-2 in human platelet concentrates to mitigate such potential risk.MATERIAL AND METHODS:Five apheresis platelet units in 100% plasma were spiked with a clinical SARS-CoV-2 isolate followed by treatment with amotosalen/UVA (INTERCEPT Blood System), pre- and posttreatment samples were collected as well as untreated positive and negative controls. The infectious viral titer was assessed by plaque assay and the genomic titer by quantitative RT-PCR. To exclude the presence of infectious particles post-pathogen reduction treatment below the limit of detection, three consecutive rounds of passaging on permissive cell lines were conducted.RESULTS:SARS-CoV-2 in platelet concentrates was inactivated with amotosalen/UVA below the limit of detection with a mean log reduction of>3.31±0.23. During three consecutive rounds of passaging, no viral replication was detected. Pathogen reduction treatment also inhibited nucleic acid detection with a log reduction of>4.46±0.51 PFU equivalents.CONCLUSION:SARS-CoV-2 was efficiently inactivated in platelet concentrates by amotosalen/UVA treatment. These results are in line with previous inactivation data for SARS-CoV-2 in plasma as well as MERS-CoV and SARS-CoV-1 in platelets and plasma, demonstrating efficient inactivation of human coronaviruses.

Assessment of the impact of pooling five single‐donor plasma (SDP) units to obtain six pathogen‐reduced therapeutic plasma (PTP) units on standardisation and the retention of labile coagulation factors.

INTERCEPT Blood System utilise l'amotosalen et les UVA (IA) pour atténuer les agents pathogènes et les leucocytes dans le plasma et les plaquettes. Résumer les données obtenues quant à l'efficacité du système pour inactiver un large échantillonnage de virus, bactéries et parasites dans les concentrés plaquettaires (CP) en solution additive (PAS). Les CP-PAS ont été inoculés avec des titres élevés d'agents pathogènes et les échantillons prélevés avant et après le traitement IA ont été évalués pour leur niveau d'infectivité en culture cellulaire ou à l'aide de modèles animaux. Les facteurs de réduction (FRL exprimés en log10) ont été calculés comme la différence entre titres infectieux avant et après traitement IA. Un FRL ≥ 4,0 a été revendiqué pour 13 virus, 19 bactéries et 4 parasites dans les CP-PAS [> 4,3–> 7]. Des données d'inactivation ont été obtenues pour 25 virus enveloppés, 6 virus non-enveloppés, 22 bactéries et 4 parasites. L'inactivation de virus émergents incluant les flavivirus et les coronavirus (Tableau 1) a été démontrée. Les parasites présentent une sensibilité élevée au traitement IA avec des FRL > 6,0 pour P. falciparum, > 5,0 pour T. cruzi et > 5,3 pour B. microti. Les bactéries évaluées, dont 8 gram négatif, 11 gram positif et 2 spirochètes, présentaient toutes (sauf la forme sporulée de Bacillus cereus) une sensibilité élevée (FRL > 4,5) voire très élevée pour ≥ 70 % d'entre elles (FRL > 6,0). Le traitement IA est efficace pour réduire les niveaux d'infectiosité d'un large spectre d'agents pathogènes dans les PC avec une majorité de FRL ≥ 4,0.

INTERCEPT Blood System utilise l'amotosalen et les UVA (IA) pour atténuer les agents pathogènes et les leucocytes dans le plasma et les plaquettes. Résumer les données obtenues quant à l'efficacité du système pour inactiver un large échantillonnage de virus, bactéries et parasites dans les plasmas frais congelés (PFC). Les PFC ont été inoculés avec des titres élevés d'agents pathogènes et des échantillons prélevés avant et après le traitement IA ont été évalués pour leur niveau d'infectivité en culture cellulaire ou à l'aide de modèles animaux. Les facteurs de réduction (FRL exprimés en log10) ont été calculés comme la différence entre titres infectieux avant et après traitement IA. Un FRL ≥ 4,0 a été revendiqué pour 15 virus, 6 bactéries et 3 parasites dans les PFC [> 4,2–> 10,6]. Des données d'inactivation ont été obtenues pour 16 virus enveloppés et 3 virus non-enveloppés. L'inactivation de virus émergents incluant les flavivirus et les coronavirus (Tableau 1) a été démontrée. Les parasites présentent une sensibilité élevée au traitement IA avec des FRL > 6,9 pour P. falciparum, > 5,0 pour T. cruzi et > 5,3 pour B. microti. Les bactéries évaluées, dont 3 gram négatif, 1 gram positif et 2 spirochètes présentaient toutes une sensibilité élevée (FRL > 4,2) voire très élevée pour ≥ 80 % d'entre elles (FRL > 5,9). Le traitement IA est efficace pour réduire les niveaux d'infectiosité d'un large spectre d'agents pathogènes dans les PFC avec une majorité de FRL ≥ 4,0.

Background: The INTERCEPT Blood System pathogen reduction (PR) technology using amotosalen and ultraviolet A light (UVA) was developed for the inactivation of pathogens and leukocytes in plasma and platelet components The technology has been used worldwide with kits sold to produce more than 6 9 million transfusable blood products Aims: To summarize the published data describing inactivation efficacy for viruses, bacteria, and parasites Methods: Twenty-five enveloped and 6 non-enveloped viruses, 22 bacterial strains and 4 parasites species, were evaluated for sensitivity to amotosalen/UVA treatment The data were obtained in studies in which high titers of pathogens were spiked into plasma or platelet concentrates (PC) resuspended in 35% plasma/ 65% platelet additive solution (PAS) or in 100% plasma Samples harvested pre- and post-PR treatment were assessed for infectivity using culture systems and, where appropriate, animal models Log10 reduction factors (LRF) were defined as the difference in infectious titers pre- and post-PR treatment Results: Inactivation data have been obtained for 25 enveloped viruses, 6 nonenveloped viruses, 22 bacterial strains, and 4 parasites including vector-borne disease agents that have emerged over the past two decades LRF of ≥ 4 0 have been claimed for 13 viruses, 19 bacterial strains, and 4 parasites in platelets in plasma/ PAS [\u003e4 3-\u003e7], 14 viruses, 8 bacterial strains, 3 parasites in platelets in 100% plasma [\u003e4 2 to \u003e 7 6], and 15 viruses, 6 bacterial strains, and 3 parasites [\u003e4 2- \u003e10 6] in plasma Inactivation of flaviviruses by amotosalen/UVA was demonstrated for West Nile, dengue virus, Zika (ZIKV) and yellow fever virus with LRFs \u003e 4 0 in PCs and plasma Inactivation of alphaviruses was demonstrated for chikungunya virus (CHIKV), with LRFs \u003e 6 4 in PC and ≥ 7 6 in plasma, and with LRF \u003e 5 1 for Ross River virus and \u003e 6 9 for Mayaro virus in PC With the recent emergence of the new coronavirus 2019-nCoV, it is important to note that LRFs ≥ 5 5 in plasma and \u003e 6 2 in PC were documented for the closely related SARS-CoV, and recent investigator-initiated studies have demonstrated LRFs ≥ 4 5 for MERS-CoV in PC and \u003e 4 7 in plasma Parasites with large global impact on immunocompromised transfusion recipients demonstrated high sensitivity to PR treatment with LRFs \u003e 6 0 in PC and ≥ 6 9 in plasma for P falciparum, \u003e5 0 in PC and plasma for T cruzi, and \u003e 5 3 in PC and plasma for B microti Beyond emerging viruses and parasites, bacteria were evaluated including 9 Gram-negative, 11 Gram-positive, and 2 spirochetes Out of 22 evaluated bacterial strains, 21 exhibited LRF \u003e 4 5, with LRFs \u003e 6 0 for 18 of them Routine-use hemovigilance data have shown that the system is efficacious to reduce septic transfusion reactions Summary/Conclusions: The amotosalen/UVA PRT is effective at reducing infectivity levels of a broad spectrum of pathogens in plasma and PC Industry guidelines consider INTERCEPT Blood System for platelets as an alternative to screening strategies for bacteria, ZIKV, cytomegalovirus, and parasites that cause malaria and babesia, or as an alternative to procedures such as gamma irradiation The data here presented are of interest to inform worldwide blood safety and emerging infectious diseases (EID) preparedness programs

Background/Case Studies: Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) was identified in January 2020 as the responsible agent for COVID-19 First recognized in late 2019, the COVID-19 epidemic developed into a pandemic with, as of July 23, 2020, more than 15 million cases and 600,000 deaths reported globally SARS-CoV-2 RNA was detected in blood samples and blood components from asymptomatic blood donors including frozen plasma units and platelet concentrates This suggests that SARS-CoV-2 may be a potential bloodborne pathogen and pathogen reduction offers potential to reduce the risk of transfusion transmission We investigated the efficacy of amotosalen/UVA light to inactivate SARS-CoV-2 in human plasma Study Design/Methods: Five pools of whole-blood derived human plasma units (630-650 mL each) were inoculated with a local clinical isolate (SARS-CoV-2/ human/SAU/85791C/2020) with a 1:100 dilution Spiked pools were used to evaluate the efficacy of amotosalen/ UVA treatment (INTERCEPT® Blood System, Cerus Corporation, Concord, U S A ) to inactivate SARS-CoV-2 in plasma Infectious and genomic viral titers were assessed by plaque assay and quantitative PCR (Altona Diagnostics, Hamburg, Germany), respectively, in spiked and treated samples in parallel with positive and negative controls Results/Findings: Treatment of spiked plasma (titer of the viral stock: 5 6±0 2 log10 pfu/mL) with amotosalen/ UVA light resulted in complete inactivation of infectious viral titer with mean log reduction of >3 3±0 2 log10 pfu/mL No viral replication or cytopathic effect (CPE) was observed in cells inoculated with inactivated samples even after 9 days of incubation and three successive passages Evaluation of genomic titer expressed in genome equivalent (GEq/mL) in inactivated samples showed equivalent reduction to the limit of detection of 7 10±0 2 log10 GEq/mL Conclusions: Complete and efficient inactivation of SARS-CoV-2 was observed with amotosalen/UVA light treatment of spiked human plasma units suggesting that treatment of plasma with this pathogen reduction technology could reduce the risk of transfusion-transmitted SARS-CoV-2 infection These findings are consistent with prior inactivation data with amotosalen/UVA for other human-pathogenic coronaviruses (SARS-CoV-1 and MERS-CoV) in platelets and plasma

BACKGROUNDThe INTERCEPT Blood System pathogen reduction technology (PRT), which uses amotosalen and ultraviolet A light treatment (amotosalen/UV‐PRT), inactivates pathogens in plasma and platelet components (PCs). This review summarizes data describing the inactivation efficacy of amotosalen/UVA‐PRT for a broad spectrum of viruses and parasites.METHODSTwenty‐five enveloped viruses, six nonenveloped viruses (NEVs), and four parasites species were evaluated for sensitivity to amotosalen/UVA‐PRT. Pathogens were spiked into plasma and PC at high titers. Samples were collected before and after PRT and assessed for infectivity with cell cultures or animal models. Log reduction factors (LRFs) were defined as the difference in infectious titers before and after amotosalen/UV‐PRT.RESULTSLRFs of ≥4.0 log were reported for 19 pathogens in plasma (range, ≥4.0 to ≥7.6), 28 pathogens in PC in platelet additive solution (PC‐PAS; ≥4.1‐≥7.8), and 14 pathogens in PC in 100% plasma (PC‐100%; (≥4.3‐>8.4). Twenty‐five enveloped viruses and two NEVs were sensitive to amotosalen/UV‐PRT; LRF ranged from >2.9 to ≥7.6 in plasma, 2.4 or greater to greater than 6.9 in PC‐PAS and >3.5 to >6.5 in PC‐100%. Infectious titers for four parasites were reduced by >4.0 log in all PC and plasma (≥4.9 to >8.4).CONCLUSIONAmotosalen/UVA‐PRT demonstrated effective infectious titer reduction for a broad spectrum of viruses and parasites. This confirms the capacity of this system to reduce the risk of viral and parasitic transfusion‐transmitted infections by plasma and PCs in various geographies.

BACKGROUND The INTERCEPT Blood System pathogen reduction technology (PRT), which uses amotosalen and ultraviolet A light treatment (amotosalen/UV-PRT), inactivates pathogens in plasma and platelet components (PCs). This review summarizes data describing the inactivation efficacy of amotosalen/UVA-PRT for a broad spectrum of viruses and parasites. METHODS Twenty-five enveloped viruses, six nonenveloped viruses (NEVs), and four parasites species were evaluated for sensitivity to amotosalen/UVA-PRT. Pathogens were spiked into plasma and PC at high titers. Samples were collected before and after PRT and assessed for infectivity with cell cultures or animal models. Log reduction factors (LRFs) were defined as the difference in infectious titers before and after amotosalen/UV-PRT. RESULTS LRFs of >= 4.0 log were reported for 19 pathogens in plasma (range, >= 4.0 to >= 7.6), 28 pathogens in PC in platelet additive solution (PC-PAS; >= 4.1->= 7.8), and 14 pathogens in PC in 100% plasma (PC-100%; (>= 4.3->8.4). Twenty-five enveloped viruses and two NEVs were sensitive to amotosalen/UV-PRT; LRF ranged from >2.9 to >= 7.6 in plasma, 2.4 or greater to greater than 6.9 in PC-PAS and >3.5 to >6.5 in PC-100%. Infectious titers for four parasites were reduced by >4.0 log in all PC and plasma (>= 4.9 to >8.4). CONCLUSION Amotosalen/UVA-PRT demonstrated effective infectious titer reduction for a broad spectrum of viruses and parasites. This confirms the capacity of this system to reduce the risk of viral and parasitic transfusion-transmitted infections by plasma and PCs in various geographies.

SUMMARYObjectiveThis study aimed to assess the efficacy of the INTERCEPT™ Blood System [amotosalen/ultraviolet A (UVA) light] to reduce the risk of Middle East respiratory syndrome‐Coronavirus (MERS‐CoV) transmission by human platelet concentrates.BackgroundSince 2012, more than 2425 MERS‐CoV human cases have been reported in 27 countries. The infection causes acute respiratory disease, which was responsible for 838 deaths in these countries, mainly in Saudi Arabia. Viral genomic RNA was detected in whole blood, serum and plasma of infected patients, raising concerns of the safety of blood supplies, especially in endemic areas.MethodsFour apheresis platelet units in 100% plasma were inoculated with a clinical MERS‐CoV isolate. Spiked units were then treated with amotosalen/UVA to inactivate MERS‐CoV. Infectious and genomic viral titres were quantified by plaque assay and quantitative real‐time reverse transcription polymerase chain reaction (RT‐qPCR). Inactivated samples were successively passaged thrice on Vero E6 cells to exclude the presence of residual replication‐competent viral particles in inactivated platelets.ResultsComplete inactivation of MERS‐CoV in spiked platelet units was achieved by treatment with Amotosalen/UVA light with a mean log reduction of 4·48 ± 0·3. Passaging of the inactivated samples in Vero E6 showed no viral replication even after nine days of incubation and three passages. Viral genomic RNA titration in inactivated samples showed titres comparable to those in pre‐treatment samples.ConclusionAmotosalen and UVA light treatment of MERS‐CoV‐spiked platelet concentrates efficiently and completely inactivated MERS‐CoV infectivity (>4 logs), suggesting that such treatment could minimise the risk of transfusion‐related MERS‐CoV transmission.

Objective: Early identification of causative microorganism(s) in patients with severe infection is crucial to optimize antimicrobial use and patient survival. However, current culture-based pathogen identification is slow and unreliable such that broad-spectrum antibiotics are often used to insure coverage of all potential organisms, carrying risks of overtreatment, toxicity, and selection of multidrug-resistant bacteria. We compared the results obtained using a novel, culture-independent polymerase chain reaction/electrospray ionization-mass spectrometry technology with those obtained by standard microbiological testing and evaluated the potential clinical implications of this technique. Design: Observational study. Setting: Nine ICUs in six European countries. Patients: Patients admitted between October 2013 and June 2014 with suspected or proven bloodstream infection, pneumonia, or sterile fluid and tissue infection were considered for inclusion. Interventions: None. Measurements and Main Results: We tested 616 bloodstream infection, 185 pneumonia, and 110 sterile fluid and tissue specimens from 529 patients. From the 616 bloodstream infection samples, polymerase chain reaction/electrospray ionization-mass spectrometry identified a pathogen in 228 cases (37%) and culture in just 68 (11%). Culture was positive and polymerase chain reaction/electrospray ionization-mass spectrometry negative in 13 cases, and both were negative in 384 cases, giving polymerase chain reaction/electrospray ionization-mass spectrometry a sensitivity of 81%, specificity of 69%, and negative predictive value of 97% at 6 hours from sample acquisition. The distribution of organisms was similar with both techniques. Similar observations were made for pneumonia and sterile fluid and tissue specimens. Independent clinical analysis of results suggested that polymerase chain reaction/electrospray ionization-mass spectrometry technology could potentially have resulted in altered treatment in up to 57% of patients. Conclusions: Polymerase chain reaction/electrospray ionization-mass spectrometry provides rapid pathogen identification in critically ill patients. The ability to rule out infection within 6 hours has potential clinical and economic benefits.