Two polygenic mouse models of major depressive disorders identify TMEM161B as a potential biomarker of disease in humans.

Treatments are only partially effective in major depressive disorders (MDD) but no biomarker exists to predict symptom improvement in patients. Animal models are essential tools in the development of antidepressant medications, but while recent genetic studies have demonstrated the polygenic contribution to MDD, current models are limited to either mimic the effect of a single gene or environmental factor. We developed in the past a model of depressive-like behaviors in mice (H/Rouen), using selective breeding based on behavioral reaction after an acute mild stress in the tail suspension test. Here, we propose a new mouse model of depression (H-TST) generated from a more complex genetic background and based on the same selection process. We first demonstrated that H/Rouen and H-TST mice had similar phenotypes and were more sensitive to glutamate-related antidepressant medications than selective serotonin reuptake inhibitors. We then conducted an exome sequencing on the two mouse models and showed that they had damaging variants in 174 identical genes, which have also been associated with MDD in humans. Among these genes, we showed a higher expression level of Tmem161b in brain and blood of our two mouse models. Changes in TMEM161B expression level was also observed in blood of MDD patients when compared with controls, and after 8-week treatment with duloxetine, mainly in good responders to treatment. Altogether, our results introduce H/Rouen and H-TST as the two first polygenic animal models of MDD and demonstrate their ability to identify biomarkers of the disease and to develop rapid and effective antidepressant medications.

Precision microbial intervention improves social behavior but not autism severity: A pilot double-blind randomized placebo-controlled trial.

Autism spectrum disorder (ASD) is characterized by the presence of restricted/repetitive behaviors and social communication deficits. Because effective treatments for ASD remain elusive, novel therapeutic strategies are necessary. Preclinical studies show that L. reuteri selectively reversed social deficits in several models for ASD. Here, in a double-blind, randomized, placebo-controlled trial, we tested the effect of L. reuteri (a product containing a combination of strains ATCC-PTA-6475 and DSM-17938) in children with ASD. The treatment does not alter overall autism severity, restricted/repetitive behaviors, the microbiome composition, or the immune profile. However, L. reuteri combination yields significant improvements in social functioning that generalized across different measures. Interestingly, ATCC-PTA-6475, but not the parental strain of DSM-17938, reverses the social deficits in a preclinical mouse model for ASD. Collectively, our findings show that L. reuteri enhances social behavior in children with ASD, thereby warranting larger trials in which strain-specific effects should also be investigated.

Extrapolating the Coffee and Caffeine (1,3,7-Trimethylxanthine) Effects on Exercise and Metabolism-A Concise Review.

The consumption of coffee and caffeine (1,3,7-trimethylxanthine) is part of many cultures worldwide. Their properties include serving as a neurostimulant aid, enhancing energy substrate levels, and improving general exercise performance. Both present therapeutic effects that can also be used to control chronic and metabolic diseases due to four mechanisms: adenosine receptor antagonism, increased catecholamine concentrations, a phosphodiesterase inhibitor, and a stimulator of calcium-release channels. Despite the individual genetic variabilities, distinct mechanisms have been demonstrated to improve physical performance, thermogenesis, lipolysis, insulin sensitivity, and hormonal modulation. Thus, coffee consumption and caffeine supplementation may enhance physical and mental performance and may improve metabolic variables, reducing oxidative stress, inflammation, and insulin resistance. Current data reveal vital aspects of coffee and caffeine consumption in specific populations, although further studies are needed to define clinical interventions with caffeine in obesity and chronic conditions.

Compartmentalized Regulation of Pulmonary and Systemic Inflammation in Critical COVID-19 Patients.

Critical COVID-19 has been associated with altered patterns of cytokines. Distinct inflammatory processes in systemic and pulmonary sites have been reported, but studies comparing these two sites are still scarce. We aimed to evaluate the profile of pulmonary and systemic cytokines and chemokines in critically ill COVID-19 patients. Levels of cytokines and chemokines were measured in plasma samples and minibronchoalveolar lavage of critical COVID-19 patients within 48 h and 5-8 days after intubation. Distinct inflammatory processes were observed in the lungs and blood, which were regulated separately. Survivor patients showed higher lung cytokine levels including IFN-γ, IL-2, IL-4, G-CSF, and CCL4, while nonsurvivors displayed higher levels in the blood, which included IL-6, CXCL8, CXCL10, CCL2, and CCL4. Furthermore, our findings indicate that high TNF and CXCL8 levels in the mini-BAL were associated with better lung oxygen exchange capacity, whereas high levels of IFN-γ in plasma were associated with worse lung function, as measured using the PaO2/FiO2 ratio. These results suggest that a robust and localized inflammatory response in the lungs is protective and associated with survival, whereas a systemic inflammatory response is detrimental and associated with mortality in critical COVID-19.

Immunoglobulin A as a Key Immunological Molecular Signature of Post-COVID-19 Conditions.

COVID-19 has infected humans worldwide, causing millions of deaths or prolonged symptoms in survivors. The transient or persistent symptoms after SARS-CoV-2 infection have been defined as post-COVID-19 conditions (PCC). We conducted a study of 151 Brazilian PCC patients to analyze symptoms and immunoglobulin profiles, taking into account sex, vaccination, hospitalization, and age. Fatigue and myalgia were the most common symptoms, and lack of vaccination, hospitalization, and neuropsychiatric and metabolic comorbidities were relevant to the development of PCC. Analysis of serological immunoglobulins showed that IgA was higher in PCC patients, especially in the adult and elderly groups. Also, non-hospitalized and hospitalized PCC patients produced high and similar levels of IgA. Our results indicated that the detection of IgA antibodies against SARS-CoV-2 during the course of the disease could be associated with the development of PCC and may be an immunological signature to predict prolonged symptoms in COVID-19 patients.

Acute coronavirus infection triggers a TNF-dependent osteoporotic phenotype in mice.

AIMS: Millions of people died during the COVID-19 pandemic, but the vast majority of infected individuals survived. Now, some consequences of the disease, known as long COVID, are been revealed. Although the respiratory system is the target of Sars-CoV-2, COVID-19 can influence other parts of the body, including bone. The aim of this work was to investigate the impact of acute coronavirus infection in bone metabolism. MAIN METHODS: We evaluated RANKL/OPG levels in serum samples of patients with and without acute COVID-19. In vitro, the effects of coronavirus in osteoclasts and osteoblasts were investigated. In vivo, we evaluated the bone phenotype in a BSL2 mouse model of SARS-like disease induced by murine coronavirus (MHV-3). KEY FINDINGS: Patients with acute COVID-19 presented decreased OPG and increased RANKL/OPG ratio in the serum versus healthy individuals. In vitro, MHV-3 infected macrophages and osteoclasts, increasing their differentiation and TNF release. Oppositely, osteoblasts were not infected. In vivo, MHV-3 lung infection triggered bone resorption in the femur of mice, increasing the number of osteoclasts at 3dpi and decreasing at 5dpi. Indeed, apoptotic-caspase-3+ cells have been detected in the femur after infection as well as viral RNA. RANKL/OPG ratio and TNF levels also increased in the femur after infection. Accordingly, the bone phenotype of TNFRp55-/- mice infected with MHV-3 showed no signs of bone resorption or increase in the number of osteoclasts. SIGNIFICANCE: Coronavirus induces an osteoporotic phenotype in mice dependent on TNF and on macrophage/osteoclast infection.

Mucosal immunization with lactiplantibacillus plantarum-displaying recombinant SARS-CoV-2 epitopes on the surface induces humoral and mucosal immune responses in mice.

BACKGROUND: The use of probiotic lactic acid bacteria as a mucosal vaccine vector is considered a promising alternative compared to the use of other microorganisms because of its "Generally Regarded as Safe" status, its potential adjuvant properties, and its tolerogenicity to the host. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease (COVID-19), is highly transmissible and pathogenic. This study aimed to determine the potential of Lactiplantibacillus plantarum expressing SARS-CoV-2 epitopes as a mucosal vaccine against SARS-CoV-2. RESULTS: In this study, the possible antigenic determinants of the spike (S1-1, S1-2, S1-3, and S1-4), membrane (ME1 and ME2), and envelope (E) proteins of SARS-CoV-2 were predicted, and recombinant L. plantarum strains surface-displaying these epitopes were constructed. Subsequently, the immune responses induced by these recombinant strains were compared in vitro and in vivo. Most surface-displayed epitopes induced pro-inflammatory cytokines [tumor necrosis factor alpha (TNF-α and interleukin (IL)-6] and anti-inflammatory cytokines (IL-10) in lipopolysaccharide-induced RAW 264.7, with the highest anti-inflammatory to pro-inflammatory cytokine ratio in the S1-1 and S1-2 groups, followed by that in the S1-3 group. When orally administered of recombinant L. plantarum expressing SARS-CoV-2 epitopes in mice, all epitopes most increased the expression of IL-4, along with induced levels of TNF-α, interferon-gamma, and IL-10, specifically in spike protein groups. Thus, the surface expression of epitopes from the spike S1 protein in L. plantarum showed potential immunoregulatory effects, suggesting its ability to potentially circumvent hyperinflammatory states relevant to monocyte/macrophage cell activation. At 35 days post immunization (dpi), serum IgG levels showed a marked increase in the S1-1, S1-2, and S1-3 groups. Fecal IgA levels increased significantly from 21 dpi in all the antigen groups, but the boosting effect after 35 dpi was explicitly observed in the S1-1, S1-2, and S1-3 groups. Thus, the oral administration of SARS-CoV-2 antigens into mice induced significant humoral and mucosal immune responses. CONCLUSION: This study suggests that L. plantarum is a potential vector that can effectively deliver SARS-CoV-2 epitopes to intestinal mucosal sites and could serve as a novel approach for SARS-CoV-2 mucosal vaccine development.

Reduction in the number of neutrophils in the broncho-alveolar aspirate is associated with worse prognosis in elderly patients with severe COVID-19.

The blood levels of neutrophils are associated with the severity of COVID -19. However, their role in the pulmonary environment during COVID -19 severity is not clear. Here, we found a decrease in the neutrophil count in BAL (bronchoalveolar lavage) in non-survivors and in older patients (> 60 years). In addition, we have shown that older patients have higher serum concentration of CXCL8 and increased IL-10 expression by neutrophils.

Effects of Consuming Fermented Fish (Surströmming) on the Fecal Microflora in Healthy Individuals.

Surströmming, a Swedish fermented fish, loved by some and avoided by others, occurs in many reports on improved or cured gastrointestinal problems even by a single meal. We tested the hypothesis that the microbes of the fermented food might have a potency to modify the gut microbiome. Two groups of voluntary participants (11 male, 8 female; aged 20-80 years) were exposed to a single meal containing the fish. A 7-day dietary intervention was carried out comprising the fish as the main source of protein in a single adult. The microbiome was characterized using 16S rRNA and metagenomic sequencing. Individual community-level changes in the microbiome were compared, as well as the presence of bacteria associated with the fermented fish. We focused on Shannon alpha and UniFrac beta diversity. We did not detect any global changes in the gut microbiome in response to Surströmming, nor were we able to recover and identify any members of Halanaerobium, which were associated with and abundant in the ingested fish, in the stool samples of the participants. Our results suggest that Surströmming consumption does not alter the microbiome of healthy individuals. However, beneficial effects on a diseased gut, impaired gut microbiome, or other effects in disease remain to be studied.

Cardio-Metabolic Health and HRT in Menopause: Novel Insights in Mitochondrial Biogenesis and RAAS.

Recent evidence shows the cardiometabolic effects of estrogen administration in postmenopausal women. Women have a cardiometabolic advantage during their reproductive years, which is lost at menopause due to declining estradiol (E2). E2, also known as 17-beta-estradiol, has diverse effects in its target tissues, including the cardiovascular (CV) system, through genomic and non-genomic signaling. Metabolic changes characteristic of menopause include a worsening lipid profile, changes in body fat distribution, epicardial and pericardial fat deposition, increased susceptibility to weight gain, and increased blood pressure, resulting in an increased risk of accelerated cardiovascular disease (CVD) development. E2 mediates its cardioprotective actions by increasing mitochondrial biogenesis, angiogenesis, and vasodilation, decreasing reactive oxygen species (ROS) and oxidative stress, and modulating the renin-angiotensin-aldosterone system (RAAS). In this review, we assess whether it is prudent to develop an approach to managing postmenopausal women based on modifying the patient's CV risk that includes human-identical hormone replacement therapy (HRT), modulation of RAAS, and stimulating mitochondrial biogenesis. Further research is needed to assess the safety and benefit of HRT to reduce cardiometabolic risk.

Coenzyme Q10 for Diabetes and Cardiovascular Disease: Useful or Useless?

INTRODUCTION: Diabetes mellitus (T2DM) and cardiovascular diseases (CVDs) have become some of the most urgent and prevalent health problems in recent decades, side by side with the growing obesity crisis. The close relationship between T2DM and CVD has become clear: endothelial dysfunction caused by oxidative stress and inflammation resulting from hyperglycaemia are the key factors in the development of vascular complications of T2DM, leading to CVD. Coenzyme Q10 (CoQ10) is a great candidate for the treatment of these diseases, acting precisely at the intersection between T2DM and CVD that is oxidative stress, due to its strong antioxidant activity and fundamental physiological role in mitochondrial bioenergetics. CoQ10 is a biologically active liposoluble compound comprising a quinone group and a side chain of 10 isoprenoid units, which is synthesized endogenously in the body from tyrosine and mevalonic acid. The main biochemical action of CoQ10 is as a cofactor in the electron transport chain that synthesizes adenosine triphosphate (ATP). As most cellular functions depend on an adequate supply of ATP, CoQ10 is essential for the health of virtually all human tissues and organs. CoQ10 supplementation has been used as an intensifier of mitochondrial function and an antioxidant with the aim of palliating or reducing oxidative damage that can worsen the physiological outcome of a wide range of diseases including T2DM and CVDs. CONCLUSION: Although there is not enough evidence to conclude it is effective for different therapeutic indications, CoQ10 supplementation is probably safe and well-tolerated, with few drug interactions and minor side effects. Many valuable advances have been made in the use of CoQ10 in clinical practice for patients with T2DM and a high risk of CVD. However, further research is needed to assess the real safety and benefit to indicate CoQ10 supplementation in patients with T2DM.

Dysfunctional phenotype of systemic and pulmonary regulatory T cells associate with lethal COVID-19 cases.

Severe cases of COVID-19 present hyperinflammatory condition that can be fatal. Little is known about the role of regulatory responses in SARS-CoV-2 infection. In this study, we evaluated the phenotype of regulatory T cells in the blood (peripheral blood mononuclear cell) and the lungs (broncho-alveolar) of adult patients with severe COVID-19 under invasive mechanical ventilation. Our results show important dynamic variation on Treg cells phenotype during COVID-19 with changes in number and functional parameters from the day of intubation (Day 1 of intensive care unit admission) to Day 7. We observed that compared with surviving patients, non-survivors presented lower numbers of Treg cells in the blood. In addition, lung Tregs of non-survivors also displayed higher PD1 and lower FOXP3 expressions suggesting dysfunctional phenotype. Further signs of Treg dysregulation were observed in non-survivors such as limited production of IL-10 in the lungs and higher production of IL-17A in the blood and in the lungs, which were associated with increased PD1 expression. These findings were also associated with lower pulmonary levels of Treg-stimulating factors like TNF and IL-2. Tregs in the blood and lungs are profoundly dysfunctional in non-surviving COVID-19 patients.

Effect of proton pump inhibitors in infants with esophageal atresia on the gut microbiome: a pilot cohort.

BACKGROUND: The effects of proton-pump inhibitors (PPIs) on the infant microbiome remain unclear. Swedish pilot cohort study to assess the longitudinal effect of long-term PPI on the infant gut microbiome, including ten newborn infants operated for esophageal atresia exposed to PPIs (mean 57 weeks), compared to healthy one-year-old controls. All children were born vaginally and were otherwise healthy. Within- and between sample diversity of the fecal microbiome was assessed using untargeted whole genome Shotgun metagenomics which sequences all the DNA in the sample and can capture genes rather than a taxonomic fingerprint. RESULTS: A longer duration of PPI-use was associated with considerable changes in evenness and high variation on diversity within samples compared to a shorter duration of use. The limited difference between baseline samples and controls suggests that this shift was most likely due to the drug exposure and not the underlying alterations on the microbiome. We found no associations with the number of antibiotic treatment episodes among the PPI-users. CONCLUSION: Prolonged PPI-use may alter the early infant gut microbiome composition, especially those with the most prolonged duration of use.

Long-Term Association between Intensive Medical Treatment and the Incidence of Cardiovascular Outcomes in Patients with Dyslipidemia: an Observational Study.

INTRODUCTION: The management of patients with dyslipidemia (DLP) requires intensive medical follow-up as an essential part of treatment and to reduce the risk of cardiovascular (CV) outcomes. The aim of this study was to evaluate whether adherence to medical treatment changed the prevalence of CV disease events in a retrospective 7-year follow-up analysis. METHODS: This retrospective study involved 92 patients divided into two groups according to their adherence: the REG group with 64 patients who had medical appointments from 2012 to 2018, and the DROP group, with 28 patients who had medical appointments in 2012 but did not complete regular appointments until 2018. Cox proportional hazard models were fitted to estimate hazard ratios associated with CV outcomes as primary endpoints. RESULTS: We observed a total of 32 cases of acute myocardial infarction (AMI) in the study population, 17 (338.41 pY) in the REG group and 15 (62.97 pY) in the DROP group. An increased hazard of AMIs was observed in the DROP group compared with the REG group by follow-up time (p < 0.001). We found that previous events of AMI and congestive heart failure (CHF) were associated with progression to treatment dropout (p < 0.05) and that two drugs were considered a risk factor for treatment dropout, diuretics and fibrates (p < 0.05). CONCLUSIONS: A reduced hazard of AMI was observed in patients who complete a greater number of medical appointments and receive multidisciplinary treatment on a regular basis.

Hacking Commensal Bacteria to Consolidate the Adaptive Mucosal Immune Response in the Gut-Lung Axis: Future Possibilities for SARS-CoV-2 Protection.

Infectious diseases caused by mucosal pathogens significantly increase mortality and morbidity. Thus, the possibility to target these pathogens at their primary entry points can consolidate protective immunity. Regarding SARS-CoV-2 infection, it has been observed that the upper respiratory mucosa is highly affected and that dysregulation of resident microbiota in the gut-lung axis plays a crucial role in determining symptom severity. Thus, understanding the possibility of eliciting various mucosal and adaptive immune responses allows us to effectively design bacterial mucosal vaccine vectors. Such design requires rationally selecting resident bacterial candidates as potential host carriers, evaluating effective carrier proteins for stimulating an immune response, and combining these two to improve antigenic display and immunogenicity. This review investigated mucosal vaccine vectors from 2015 to present, where a few have started to utilize Salmonella and lactic acid bacteria (LAB) to display SARS-CoV-2 Spike S proteins or fragments. Although current literature is still lacking for its studies beyond in vitro or in vivo efficiency, decades of research into these vectors show promising results. Here, we discuss the mucosal immune systems focusing on the gut-lung axis microbiome and offer new insight into the potential use of alpha streptococci in the upper respiratory tract as a vaccine carrier.

Treatment with Distinct Antibiotic Classes Causes Different Pulmonary Outcomes on Allergic Airway Inflammation Associated with Modulation of Symbiotic Microbiota.

Background: Asthma is a chronic pulmonary disease that affects about 300 million people worldwide. Previous studies have associated antimicrobial use with allergies, but the real impact of antibiotics on asthma is still elusive. We investigated the potential impact of amoxicillin (Amox), trimethoprim/sulfamethoxazole (TMP/SMX), and metronidazole (Metro) in a murine model of OVA-induced allergic airway inflammation. Methods: BALB/c mice received three cycles of 7 days of antibiotics in drinking water followed by 7 days washout and were sensitized i.p. with OVA/Alum at days 0 and 14. After the end of the last antibiotic washout, the mice were challenged with aerosolized OVA. Pulmonary parameters were evaluated, and serum, BAL, and feces were collected for analysis. Results: Amox- and TMP/SMX-treated animals displayed more severe allergic airway inflammation parameters with increased airway hyperresponsiveness, reduced lung alveolar volume, and increased levels in BAL of IL-4 and IL-6. In contrast, Metro-treated mice showed preserved FEV-50, decreased lung inflammation, and higher levels of butyrate and propionate in their feces. Metro treatment was associated with increased OVA-specific IgA in serum. BAL microbiota was abundant in allergic groups but not in nonallergic controls with the Amox-treated group displaying the increased frequency of Proteobacteria, while Metro and TMP/SMX showed increased levels of Firmicutes. In the gut, we observed the enrichment of Akkermansia muciniphila associated with reduced airway inflammation phenotype in the Metro group, even after the recovery period. Conclusion: Our data suggest that different antibiotic treatments may impact the course of experimental allergic airway inflammation in diverse ways by several mechanisms, including modulation of short-chain fat acids production by intestinal microbiota.

Myricitrin exhibits antidepressant-like effects and reduces IL-6 hippocampal levels in the chronic mild stress model.

The flavonoid myricitrin showed an antidepressant-like effect in the tail suspension test and increased hippocampal neurogenesis, as well as demonstrating anti-inflammatory effects. Interestingly, inflammation has been linked to depression, and anti-inflammatory drugs showed promising results as antidepressant-like drugs. Thus, the present study evaluated the effects of myricitrin in the chronic mild stress (CMS) model, a translational and valid animal model of depression, using the mini-experiment design to improve the reproducibility of the findings. The sucrose preference test (SPT), forced swim test (FST), and tail suspension test (TST) were the readouts of depressive-like phenotypes induced by CMS. Relative adrenal weight was employed as an index of the hypothalamus-pituitary-adrenal (HPA) axis activation. Interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha levels were measured in the hippocampus. Myricitrin (10 mg/kg, intraperitoneally, for 14 days) reversed depressive-like behaviors induced by CMS (increased immobility in the FST, the TST and anhedonia), as well as decreased adrenal hypertrophy and hippocampal levels of IL-6 in stressed mice. Similar results were observed by imipramine (20 mg/kg, intraperitoneally, for 14 days), a serotonin and norepinephrine reuptake inhibitor (positive control). A significant correlation was observed between immobility time in the TST, and hippocampal IL-6 levels. Hippocampal TNF-α levels were not affected by CMS or drug treatment. In conclusion, myricitrin exhibited an antidepressant-like profile in CMS, and this effect may be associated with its anti-inflammatory activity.

Helminth infection modulates number and function of adipose tissue Tregs in high fat diet-induced obesity.

BACKGROUND: Epidemiological and experimental studies have shown a protective effect of helminth infections in weight gain and against the development of metabolic dysfunctions in the host. However, the mechanisms Treg cells exert in the helminth-obesity interface has been poorly investigated. The present study aimed to verify the influence of Heligmosomoides polygyrus infection in early stages of high fat diet-induced obesity. PRINCIPAL FINDINGS: The presence of infection was able to prevent exacerbated weight gain in mice fed with high fat diet when compared to non-infected controls. In addition, infected animals displayed improved insulin sensitivity and decreased fat accumulation in the liver. Obesity-associated inflammation was reduced in the presence of infection, demonstrated by lower levels of leptin and resistin, lower infiltration of Th1 and Th17 cells in adipose tissue, higher expression of IL10 and adiponectin, increased infiltration of Th2 and eosinophils in adipose tissue of infected animals. Of note, the parasite infection was associated with increased Treg frequency in adipose tissue which showed higher expression of cell surface markers of function and activation, like LAP and CD134. The infection could also increase adipose Treg suppressor function in animals on high fat diet. CONCLUSION: These data suggest that H. polygyrus modulates adipose tissue Treg cells with implication for weight gain and metabolic syndrome.

Targeting the Annexin A1-FPR2/ALX pathway for host-directed therapy in dengue disease.

Host immune responses contribute to dengue's pathogenesis and severity, yet the possibility that failure in endogenous inflammation resolution pathways could characterise the disease has not been contemplated. The pro-resolving protein Annexin A1 (AnxA1) is known to counterbalance overexuberant inflammation and mast cell (MC) activation. We hypothesised that inadequate AnxA1 engagement underlies the cytokine storm and vascular pathologies associated with dengue disease. Levels of AnxA1 were examined in the plasma of dengue patients and infected mice. Immunocompetent, interferon (alpha and beta) receptor one knockout (KO), AnxA1 KO, and formyl peptide receptor 2 (FPR2) KO mice were infected with dengue virus (DENV) and treated with the AnxA1 mimetic peptide Ac2-26 for analysis. In addition, the effect of Ac2-26 on DENV-induced MC degranulation was assessed in vitro and in vivo. We observed that circulating levels of AnxA1 were reduced in dengue patients and DENV-infected mice. Whilst the absence of AnxA1 or its receptor FPR2 aggravated illness in infected mice, treatment with AnxA1 agonistic peptide attenuated disease manifestationsatteanuated the symptoms of the disease. Both clinical outcomes were attributed to modulation of DENV-mediated viral load-independent MC degranulation. We have thereby identified that altered levels of the pro-resolving mediator AnxA1 are of pathological relevance in DENV infection, suggesting FPR2/ALX agonists as a therapeutic target for dengue disease.

Peculiarities of Zika Immunity and Vaccine Development: Lessons from Dengue and the Contribution from Controlled Human Infection Model.

The Zika virus (ZIKV) was first isolated from a rhesus macaque in the Zika forest of Uganda in 1947. Isolated cases were reported until 2007, when the first major outbreaks of Zika infection were reported from the Island of Yap in Micronesia and from French Polynesia in 2013. In 2015, ZIKV started to circulate in Latin America, and in 2016, ZIKV was considered by WHO to be a Public Health Emergency of International Concern due to cases of Congenital Zika Syndrome (CZS), a ZIKV-associated complication never observed before. After a peak of cases in 2016, the infection incidence dropped dramatically but still causes concern because of the associated microcephaly cases, especially in regions where the dengue virus (DENV) is endemic and co-circulates with ZIKV. A vaccine could be an important tool to mitigate CZS in endemic countries. However, the immunological relationship between ZIKV and other flaviviruses, especially DENV, and the low numbers of ZIKV infections are potential challenges for developing and testing a vaccine against ZIKV. Here, we discuss ZIKV vaccine development with the perspective of the immunological concerns implicated by DENV-ZIKV cross-reactivity and the use of a controlled human infection model (CHIM) as a tool to accelerate vaccine development.