Identification of autophagy receptors for the Crohn's disease-associated adherent-invasive Escherichia coli.

Introduction: Crohn's disease (CD) is a chronic inflammatory bowel disease, of which the etiology involves genetic, environmental and microbial factors. Adherent-invasive Escherichia coli (AIEC) and polymorphisms in autophagy-related genes have been implicated in CD etiology. Autophagy is a key process for the maintenance of cellular homeostasis, which allows the degradation of damaged cytoplasmic components and pathogens via lysosome. We have shown that a functional autophagy is necessary for AIEC clearance. Here, we aimed at identifying the autophagy receptor(s) responsible to target AIEC to autophagy for degradation. Methods: The levels of autophagy receptors p62, NDP52, NBR1, TAX1BP1 and Optineurin were knocked down in human intestinal epithelial cells T84 using siRNAs. The NDP52 knock-out (KO) and p62 KO HeLa cells, as well as NDP52 KO HeLa cells expressing the wild-type NDP52 or the mutated NDP52Val248Ala protein were used. Results and discussion: We showed that, among the tested autophagy receptors (p62, NDP52, NBR1, TAX1BP1 and Optineurin), diminished expression of p62 or NDP52 increased the number of the clinical AIEC LF82 strain inside epithelial cells. This was associated with increased pro-inflammatory cytokine production. Moreover, p62 or NDP52 directly colocalized with AIEC LF82 and LC3, an autophagy marker. As the NDP52Val248Ala polymorphism has been associated with increased CD susceptibility, we investigated its impact on AIEC control. However, in HeLa cell and under our experimental condition, no effect of this polymorphism neither on AIEC LF82 intracellular number nor on pro-inflammatory cytokine production was observed. Together, our results suggest that p62 and NDP52 act as autophagy receptors for AIEC recognition, controlling AIEC intracellular replication and inflammation.

Novel Variant and Known Mutation in 23S rRNA Gene of Mycoplasma pneumoniae, Northern Vietnam, 2023.

During a 2023 outbreak of Mycoplasma pneumoniae-associated community-acquired pneumonia among children in northern Vietnam, we analyzed M. pneumoniae isolated from nasopharyngeal samples. In almost half (6 of 13) of samples tested, we found known A2063G mutations (macrolide resistance) and a novel C2353T variant on the 23S rRNA gene.

Oral administration of a 2-aminopyrimidine robenidine analogue (NCL195) significantly reduces Staphylococcus aureus infection and reduces Escherichia coli infection in combination with sub-inhibitory colistin concentrations in a bioluminescent mouse model.

We have previously reported promising in vivo activity of the first-generation 2-aminopyramidine robenidine analogue NCL195 against Gram-positive bacteria (GPB) when administered via the systemic route. In this study, we examined the efficacy of oral treatment with NCL195 (± low-dose colistin) in comparison to oral moxifloxacin in bioluminescent Staphylococcus aureus and Escherichia coli peritonitis-sepsis models. Four oral doses of 50 mg/kg NCL195, commencing immediately post-infection, were administered at 4 h intervals in the S. aureus peritonitis-sepsis model. We used a combination of four oral doses of 50 mg/kg NCL195 and four intraperitoneal doses of colistin at 0.125 mg/kg, 0.25 mg/kg, or 0.5 mg/kg in the E. coli peritonitis-sepsis model. Subsequently, the dose rates of four intraperitoneal doses of colistin were increased to 0.5 mg/kg, 1 mg/kg, or 2 mg/kg at 4 h intervals to treat a colistin-resistant E. coli infection. In the S. aureus infection model, oral treatment of mice with NCL195 resulted in significantly reduced S. aureus infection loads (P < 0.01) and longer survival times (P < 0.001) than vehicle-only treated mice. In the E. coli infection model, co-administration of NCL195 and graded doses of colistin resulted in a dose-dependent significant reduction in colistin-susceptible (P < 0.01) or colistin-resistant (P < 0.05) E. coli loads compared to treatment with colistin alone at similar concentrations. Our results confirm that NCL195 is a potential candidate for further preclinical development as a specific treatment for multidrug-resistant infections, either as a stand-alone antibiotic for GPB or in combination with sub-inhibitory concentrations of colistin for Gram-negative bacteria.

Impact of the new membrane-targeting lipoglycopeptide antibiotic MCC5145 on the treatment of bacteremic pneumococcal pneumonia in mice.

Bacteremic Streptococcus pneumoniae pneumonia is one of the most severe forms of invasive pneumococcal disease (IPD) and with particularly high case-fatality rates among the elderly and individuals with comorbidities, exacerbated by rising antibiotic resistance and time to initiation of therapy. Here, we examined the efficacy of the preclinical "vancapticin" glycopeptide MCC5145 against fulminant infection by S. pneumoniae serotype 2 strain D39 in a bioluminescent, neutropenic mouse model of bacteremic pneumonia. MCC5145 is a semisynthetic vancomycin derivative chemically modified at the C-terminus with a membrane-targeting motif designed to preferentially bind the anionic bacterial surface. We show that similar to vancomycin, subcutaneous administration of MCC5145 to mice 1 day after intranasal infection with a bioluminescent derivative of S. pneumoniae D39 elicited time and concentration-dependent reduction in total flux in the lungs and blood. Together, our finding supports the further development of MCC5145 as a potential new treatment option for pneumonia and/or bacteremic pneumonia in clinical settings, particularly for immunocompromised individuals. IMPORTANCE S. pneumoniae (the pneumococcus) causes severe community acquired lung and blood infection, especially among the elderly and people with underlying medical conditions and/or weakened immune systems. The rising incidence of antibiotic resistance and delays between diagnosis of infection and commencement of effective therapy make treatment difficult and result in high mortality rates. In this work, we show that a new derivative (MCC5145) of an existing antibiotic (vancomycin) rapidly eradicated lethal pneumococcal challenge from the lungs and blood of mice with a suppressed immune system. Our findings support that MCC5145 is a promising option for the treatment of lung and blood infections caused by the pneumococcus at point-of-care settings, particularly for the elderly and individuals with a weakened immune system.

Effective aqueous chromate treatment using triethanolamine anacardate coated magnetic nanoparticles.

Low-cost adsorbents derived from agricultural by-products incorporated magnetic nanoparticles (NPs) are promising for wastewater treatment. They are always preferred due to their great performance and easy separation. This study reports cobalt superparamagnetic (CoFe2O4) nanoparticles (NPs) incorporated with triethanolamine (TEA) based surfactants from cashew nut shell liquid, namely TEA-CoFe2O4, for the removal of chromium (VI) ions from aqueous solutions. To have detailed characteristics of the morphology and structural properties, scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR) and vibrating sample magnetometry (VSM) were employed. The fabricated TEA-CoFe2O4 particles exhibit soft and superparamagnetic properties, which make the nanoparticles easily recycled by using a magnet. Chromate adsorption on the TEA-CoFe2O4 nanomaterials reached an optimal efficiency of 84.3% at pH = 3 with the initial adsorbent dose of 10 g/L and chromium (VI) concentration of 40 mg/L. The TEA-CoFe2O4 nanoparticles can maintain the effective adsorption of chromium (VI) ion (by 29% of efficiency loss) and retain the magnetic separation using a magnet up to three cycles of the regeneration, which promise a high potential of this low-cost adsorbent for long-term treatment of heavy metal ions from polluted waters.

Corrigendum: Tipping the balance between erythroid cell differentiation and induction of anemia in response to the inflammatory pathology associated with chronic trypanosome infections.

[This corrects the article DOI: 10.3389/fimmu.2022.1051647.].

Protein Characteristics and Bioactivity of Fish Protein Hydrolysates from Tra Catfish (Pangasius hypophthalmus) Side Stream Isolates.

Enzymatic hydrolysis is a novel method to recover highly potent bioactive fish protein hydrolysates (FPHs) from fish processing side-streams. The common way of producing FPHs directly from fish side-streams may be inappropriate due to the excess of lipids and pro-oxidants, especially in lipid-rich streams, as obtained from Tra catfish. This study aimed to optimise the hydrolysis conditions for a commercial enzyme (Alcalase® 2.4 L) (enzyme concentrate, temperature, and time) in FPH production from the fish protein isolate obtained from Tra catfish dark muscle (DM-FPI) using the pH-shift method. The degree of hydrolysis (DH), protein recovery (PR), and antioxidant properties, including DPPH radical scavenging activity (DPPH-RSA) and total reducing power capacity (TRPC), were measured to evaluate the effects of the hydrolysis conditions on the FPHs. Optimal hydrolysis was obtained at an enzyme/substrate protein ratio of 3% (v/w) and a hydrolysis temperature of 50 °C for 3 h. The FPHs obtained from different substrates, including DM-FPI, abdominal cut-off (ACO) FPI, and head and backbone blend (HBB) FPI, had similar DHs under these optimum conditions, ranging from 22.5% to 24.0%. However, the FPH obtained from abdominal cut-off isolate (ACO-FPH) showed the highest PR of 81.5 ± 4.3% and the highest antioxidant properties, with a DPPH-RSA of 86.1 ± 1.6% and a TRPC of 6.4 ± 0.4 equivalent mg vitamin C/g protein. The resulting FPHs present a natural source of antioxidants with great potential for food applications, especially the ACO-FPH. In addition, all FPHs had excellent amino acid profiles, indicating strong potential for their use as supplements. Tra catfish protein-rich side-streams can thus be processed into high-value bioactive FPHs using Alcalase for human consumption.

Tipping the balance between erythroid cell differentiation and induction of anemia in response to the inflammatory pathology associated with chronic trypanosome infections.

Infection caused by extracellular single-celled trypanosomes triggers a lethal chronic wasting disease in livestock and game animals. Through screening of 10 Trypanosoma evansi field isolates, exhibiting different levels of virulence in mice, the current study identifies an experimental disease model in which infection can last well over 100 days, mimicking the major features of chronic animal trypanosomosis. In this model, despite the well-controlled parasitemia, infection is hallmarked by severe trypanosomosis-associated pathology. An in-depth scRNA-seq analysis of the latter revealed the complexity of the spleen macrophage activation status, highlighting the crucial role of tissue resident macrophages (TRMs) in regulating splenic extramedullary erythropoiesis. These new data show that in the field of experimental trypanosomosis, macrophage activation profiles have so far been oversimplified into a bi-polar paradigm (M1 vs M2). Interestingly, TRMs exert a double-sided effect on erythroid cells. On one hand, these cells express an erythrophagocytosis associated signature. On another hand, TRMs show high levels of Vcam1 expression, known to support their interaction with hematopoietic stem and progenitor cells (HSPCs). During chronic infection, the latter exhibit upregulated expression of Klf1, E2f8, and Gfi1b genes, involved in erythroid differentiation and extramedullary erythropoiesis. This process gives rise to differentiation of stem cells to BFU-e/CFU-e, Pro E, and Baso E subpopulations. However, infection truncates progressing differentiation at the orthochromatic erythrocytes level, as demonstrated by scRNAseq and flow cytometry. As such, these cells are unable to pass to the reticulocyte stage, resulting in reduced number of mature circulating RBCs and the occurrence of chronic anemia. The physiological consequence of these events is the prolonged poor delivery of oxygen to various tissues, triggering lactic acid acidosis and the catabolic breakdown of muscle tissue, reminiscent of the wasting syndrome that is characteristic for the lethal stage of animal trypanosomosis.

Apply MIKE 11 model to study impacts of climate change on water resources and develop adaptation plan in the Mekong Delta, Vietnam: a case of Can Tho city.

Can Tho city in the Mekong Delta is in the top ten areas affected by climate change. Therefore, assessing climate change impacts, social and economic activities require proposed solutions to respond to climate change. This study aims to (i) apply the MIKE 11 model (Hydrodynamic module and Advection-Dispersion module) to simulate the impacts of climate change scenarios on water resources in Can Tho city; (ii) calculate water balance in Can Tho city; and (iii) suggest climate change adaptation plan for sustainable social-economic activities of the city. The results show that when the rainfall changes due to climate change, the flow rate tends to decrease at high tide and increase at low tide. When the sea level rises due to climate change, the flow rate tends to increase at high tide and decrease at low tide. For 2030, the flow will decrease up to 15.6% and 14.3% at the low tide period for RCP 2.6 and RCP 8.5 compared to the present, respectively. The flow will increase up to 63.5% and 58.9% at the high tide period for RCP 2.6 and RCP 8.5 compared to the present, respectively. The water demand evaluation shows that the water resource reserve in Can Tho city meets water demands in current and future scenarios under climate change. While rainwater and groundwater can provide enough water in the rainy season, the city has to use surface water during the dry season due to a lack of rainwater. Of these, agriculture contributes the most water demands (85%). Eight adaptation measures to climate change for Can Tho city are developed from 2021 to 2050.

Protein Recovery of Tra Catfish (Pangasius hypophthalmus) Protein-Rich Side Streams by the pH-Shift Method.

Increasing protein demand has led to growing attention being given to the full utilization of proteins from side streams in industrial fish processing. In this study, proteins were recovered from three protein-rich side streams during Tra catfish (Pangasius hypophthalamus) processing (dark muscle; head-backbone; and abdominal cut-offs) by an optimized pH-shift process. Physicochemical characteristics of the resulting fish protein isolates (FPIs) were compared to industrial surimi from the same raw material batch. The pH had a significant influence on protein extraction, while extraction time and the ratio of the extraction solution to raw material had little effect on the protein and dry matter recoveries. Optimal protein extraction conditions were obtained at pH 12, a solvent to raw material ratio of 8, and an extraction duration of 150 min. The resulting FPI contained <10% of the fat and <15% of the ash of the raw material, while the FPI protein recovery was 83.0−88.9%, including a good amino acid profile. All FPIs had significantly higher protein content and lower lipid content than the surimi, indicating the high efficiency of using the pH-shift method to recover proteins from industrial Tra catfish side streams. The FPI made from abdominal cut-offs had high whiteness, increasing its potential for the development of a high-value product.

Measurement properties of the life history of aggression in adolescents: Data from Morocco, Serbia, Sweden, Vietnam, and the USA.

The Life History of Aggression (LHA) is a frequently used scale for assessing trait aggression, but its psychometric properties have not been evaluated among adolescents. The aim of this study was to evaluate the psychometric properties of the LHA among high school students from Morocco, Serbia, Sweden, Vietnam, and the United States of America (USA). The total sample included 4867 adolescents, aged 15-19 years, from Morocco (n = 508), Serbia (n = 1067), Sweden (n = 1570), Vietnam (n = 1401), and the USA (n = 321). A two-factor, nine-item model containing an aggression factor (5 items) and a consequences/antisocial behavior factor (4 items) was created. The two-factor model had an acceptable-to-good model fit for the data for the total sample and all five countries, including gender. Cronbach's alpha (α) was satisfactory across countries. Still, the construct was noninvariant across countries and genders. The LHA with nine items in two subscales showed sound construct validity and internal consistency and can be used for group-level or within-group assessments of trait aggression in adolescents by either gender or country. However, it should not be used for cross-gender or cross-country comparisons due to a lack of measurement invariance.

Targeting the endo-lysosomal autophagy pathway to treat inflammatory bowel diseases.

Inflammatory bowel disease (IBD) is a serious public health problem in Western society with a continuing increase in incidence worldwide. Safe, targeted medicines for IBD are not yet available. Autophagy, a vital process implicated in normal cell homeostasis, provides a potential point of entry for the treatment of IBDs, as several autophagy-related genes are associated with IBD risk. We conducted a series of experiments in three distinct mouse models of colitis to test the effectiveness of therapeutic P140, a phosphopeptide that corrects autophagy dysfunctions in other autoimmune and inflammatory diseases. Colitis was experimentally induced in mice by administering dextran sodium sulfate and 2,4,6 trinitrobenzene sulfonic acid. Transgenic mice lacking both il-10 and iRhom2 - involved in tumor necrosis factor α secretion - were also used. In the three models investigated, P140 treatment attenuated the clinical and histological severity of colitis. Post-treatment, altered expression of several macroautophagy and chaperone-mediated autophagy markers, and of pro-inflammatory mediators was corrected. Our results demonstrate that therapeutic intervention with an autophagy modulator improves colitis in animal models. These findings highlight the potential of therapeutic peptide P140 for use in the treatment of IBD.

Impact of a Novel Anticoccidial Analogue on Systemic Staphylococcus aureus Infection in a Bioluminescent Mouse Model.

In this study, we investigated the potential of an analogue of robenidine (NCL179) to expand its chemical diversity for the treatment of multidrug-resistant (MDR) bacterial infections. We show that NCL179 exhibits potent bactericidal activity, returning minimum inhibitory concentration/minimum bactericidal concentrations (MICs/MBCs) of 1-2 µg/mL against methicillin-resistant Staphylococcus aureus, MICs/MBCs of 1-2 µg/mL against methicillin-resistant S. pseudintermedius and MICs/MBCs of 2-4 µg/mL against vancomycin-resistant enterococci. NCL179 showed synergistic activity against clinical isolates and reference strains of Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa in the presence of sub-inhibitory concentrations of colistin, whereas NCL179 alone had no activity. Mice given oral NCL179 at 10 mg/kg and 50 mg/kg (4 × doses, 4 h apart) showed no adverse clinical effects and no observable histological effects in any of the organs examined. In a bioluminescent S. aureus sepsis challenge model, mice that received four oral doses of NCL179 at 50 mg/kg at 4 h intervals exhibited significantly reduced bacterial loads, longer survival times and higher overall survival rates than the vehicle-only treated mice. These results support NCL179 as a valid candidate for further development to treat MDR bacterial infections as a stand-alone antibiotic or in combination with existing antibiotic classes.

Inhibition of Oomycetes by the Mixture of Maleic Acid and Copper Sulfate.

Since the protective activity of the Bordeaux mixture against plant disease caused by oomycetes was discovered, copper compounds have been used for more than a century as an effective plant protection strategy. However, the application of excessive copper can cause adverse effects through long-term heavy metal accumulation in soils. Therefore, it is necessary to develop new strategies to reduce or replace copper in pesticides based on organic and low-input farming systems. Organic acids are eco-friendly. In this study, we tested the antifungal and anti-oomycete activity of maleic acid (MA) and copper sulfate (CS) against 13 plant pathogens. Treatment with a mixture of MA and CS showed strong anti-oomycetes activity against Phytophthora xcambivora, P. capsici, and P. cinnamomi. Moreover, the concentration of CS in the activated mixture of MA and CS was lower than that in the activated CS only, and the mixture showed synergy or partial synergy effects on the anti-oomycete activity. Application of a wettable powder formulation of MA and CS mixture (MCS 30WP; 26.67% MA and 3.33% CS) had excellent protective activity in pot experiments with control values of 73% Phytophthora blight on red pepper, 91% damping-off on cucumber, and 84% Pythium blight on creeping bentgrass, which are similar to those of the CS wettable powder formulation (6.67% CS) containing two times the CS content of MCS 30WP. These observations suggest that the synergistic effect of the MA and CS combination is a sustainable alternative for effective management of destructive oomycete diseases.

Single-cell transcriptome profiling and the use of AID deficient mice reveal that B cell activation combined with antibody class switch recombination and somatic hypermutation do not benefit the control of experimental trypanosomosis.

Salivarian trypanosomes are extracellular protozoan parasites causing infections in a wide range of mammalian hosts, with Trypanosoma evansi having the widest geographic distribution, reaching territories far outside Africa and occasionally even Europe. Besides causing the animal diseases, T. evansi can cause atypical Human Trypanosomosis. The success of this parasite is attributed to its capacity to evade and disable the mammalian defense response. To unravel the latter, we applied here for the first time a scRNA-seq analysis on splenocytes from trypanosome infected mice, at two time points during infection, i.e. just after control of the first parasitemia peak (day 14) and a late chronic time point during infection (day 42). This analysis was combined with flow cytometry and ELISA, revealing that T. evansi induces prompt activation of splenic IgM+CD1d+ Marginal Zone and IgMIntIgD+ Follicular B cells, coinciding with an increase in plasma IgG2c Ab levels. Despite the absence of follicles, a rapid accumulation of Aicda+ GC-like B cells followed first parasitemia peak clearance, accompanied by the occurrence of Xbp1+ expressing CD138+ plasma B cells and Tbx21+ atypical CD11c+ memory B cells. Ablation of immature CD93+ bone marrow and Vpreb3+Ly6d+Ighm+ expressing transitional spleen B cells prevented mature peripheral B cell replenishment. Interestingly, AID-/- mice that lack the capacity to mount anti-parasite IgG responses, exhibited a superior defense level against T. evansi infections. Here, elevated natural IgMs were able to exert in vivo and in vitro trypanocidal activity. Hence, we conclude that in immune competent mice, trypanosomosis associated B cell activation and switched IgG production is rapidly induced by T. evansi, facilitating an escape from the detrimental natural IgM killing activity, and resulting in increased host susceptibility. This unique role of IgM and its anti-trypanosome activity are discussed in the context of the dilemma this causes for the future development of anti-trypanosome vaccines.

Changes in Adolescents' Psychosocial Functioning and Well-Being as a Consequence of Long-Term COVID-19 Restrictions.

This work studied self-reports from adolescents on how the COVID-19 pandemic has changed their behaviors, relationships, mood, and victimization. Data collection was conducted between September 2020 and February 2021 in five countries (Sweden, the USA, Serbia, Morocco, and Vietnam). In total, 5114 high school students (aged 15 to 19 years, 61.8% females) responded to our electronic survey. A substantial proportion of students reported decreased time being outside (41.7%), meeting friends in real life (59.4%), and school performance (30.7%), while reporting increased time to do things they did not have time for before (49.3%) and using social media to stay connected (44.9%). One third of the adolescents increased exercise and felt that they have more control over their life. Only a small proportion of adolescents reported substance use, norm-breaking behaviors, or victimization. The overall COVID-19 impact on adolescent life was gender-specific: we found a stronger negative impact on female students. The results indicated that the majority of adolescents could adapt to the dramatic changes in their environment. However, healthcare institutions, municipalities, schools, and social services could benefit from the findings of this study in their work to meet the needs of those young people who signaled worsened psychosocial functioning, increased stress, and victimization.

Repurposing of the Fasciolicide Triclabendazole to Treat Infections Caused by Staphylococcus spp. and Vancomycin-Resistant Enterococci.

One approach to combat the increasing incidence of multidrug-resistant (MDR) bacterial pathogens involves repurposing existing compounds with known safety and development pathways as new antibacterial classes with potentially novel mechanisms of action. Here, triclabendazole (TCBZ), a drug originally developed to treat Fasciola hepatica (liver fluke) in sheep and cattle, and later in humans, was evaluated as an antibacterial alone or in combination with sub-inhibitory concentrations of polymyxin B (PMB) against clinical isolates and reference strains of key Gram-positive and Gram-negative bacteria. We show for the first time that in vitro, TCBZ selectively kills methicillin-sensitive and methicillin-resistant Staphylococcus aureus and Staphylococcus pseudintermedius at a minimum inhibitory concentration (MIC) range of 2-4 µg/mL, and vancomycin-resistant enterococci at a MIC range of 4-8 µg/mL. TCBZ also inhibited key Gram-negative bacteria in the presence of sub-inhibitory concentrations of PMB, returning MIC90 values of 1 µg/mL for Escherichia coli, 8 µg/mL for Klebsiella pneumoniae, 2 µg/mL for Acinetobacter baumannii and 4 µg/mL for Pseudomonasaeruginosa. Interestingly, TCBZ was found to be bacteriostatic against intracellular S. aureus but bactericidal against intracellular S. pseudintermedius. Additionally, TCBZ's favourable pharmacokinetic (PK) and pharmacodynamic (PD) profile was further explored by in vivo safety and efficacy studies using a bioluminescent mouse model of S. aureus sepsis. We show that repeated four-hourly oral treatment of mice with 50 mg/kg TCBZ after systemic S. aureus challenge resulted in a significant reduction in S. aureus populations in the blood to 18 h post-infection (compared to untreated mice) but did not clear the bacterial infection from the bloodstream, consistent with in vivo bacteriostatic activity. These results indicate that additional pharmaceutical development of TCBZ may enhance its PK/PD, allowing it to be an appropriate candidate for the treatment of serious MDR bacterial pathogens.

The History of Anti-Trypanosome Vaccine Development Shows That Highly Immunogenic and Exposed Pathogen-Derived Antigens Are Not Necessarily Good Target Candidates: Enolase and ISG75 as Examples.

Salivarian trypanosomes comprise a group of extracellular anthroponotic and zoonotic parasites. The only sustainable method for global control of these infection is through vaccination of livestock animals. Despite multiple reports describing promising laboratory results, no single field-applicable solution has been successful so far. Conventionally, vaccine research focusses mostly on exposed immunogenic antigens, or the structural molecular knowledge of surface exposed invariant immunogens. Unfortunately, extracellular parasites (or parasites with extracellular life stages) have devised efficient defense systems against host antibody attacks, so they can deal with the mammalian humoral immune response. In the case of trypanosomes, it appears that these mechanisms have been perfected, leading to vaccine failure in natural hosts. Here, we provide two examples of potential vaccine candidates that, despite being immunogenic and accessible to the immune system, failed to induce a functionally protective memory response. First, trypanosomal enolase was tested as a vaccine candidate, as it was recently characterized as a highly conserved enzyme that is readily recognized during infection by the host antibody response. Secondly, we re-addressed a vaccine approach towards the Invariant Surface Glycoprotein ISG75, and showed that despite being highly immunogenic, trypanosomes can avoid anti-ISG75 mediated parasitemia control.

African Trypanosomosis Obliterates DTPa Vaccine-Induced Functional Memory So That Post-Treatment Bordetella pertussis Challenge Fails to Trigger a Protective Recall Response.

Salivarian trypanosomes are extracellular parasites causing anthroponotic and zoonotic infections. Anti-parasite vaccination is considered the only sustainable method for global trypanosomosis control. Unfortunately, no single field applicable vaccine solution has been successful so far. The active destruction of the host's adaptive immune system by trypanosomes is believed to contribute to this problem. Here, we show that Trypanosome brucei brucei infection results in the lasting obliteration of immunological memory, including vaccine-induced memory against non-related pathogens. Using the well-established DTPa vaccine model in combination with a T. b. brucei infection and a diminazene diaceturate anti-parasite treatment scheme, our results demonstrate that while the latter ensured full recovery from the T. b. brucei infection, it failed to restore an efficacious anti-B. pertussis vaccine recall response. The DTPa vaccine failure coincided with a shift in the IgG1/IgG2a anti-B. pertussis antibody ratio in favor of IgG2a, and a striking impact on all of the spleen immune cell populations. Interestingly, an increased plasma IFNγ level in DTPa-vaccinated trypanosome-infected mice coincided with a temporary antibody-independent improvement in early-stage trypanosomosis control. In conclusion, our results are the first to show that trypanosome-inflicted immune damage is not restored by successful anti-parasite treatment.