Clinical, immunological, and microbiological analysis of the association between periodontitis and COVID-19: a case-control study.

PURPOSE: Periodontitis and coronavirus disease (COVID-19) share risk factors and activate similar immunopathological pathways, intensifying systemic inflammation. This study investigated the clinical, immunological and microbiological parameters in individuals with COVID-19 and controls, exploring whether periodontitis-driven inflammation contributes to worsening COVID-19 endpoints. METHODS: Case (positive RT-PCR for SARS-CoV-2) and control (negative RT-PCR) individuals underwent clinical and periodontal assessments. Salivary levels of TNF-α, IL-6, IL-1ß, IL-10, OPG, RANKL, neutrophil extracellular traps, and subgingival biofilm were analyzed at two timepoints. Data on COVID-19-related outcomes and comorbidity information were evaluated from medical records. RESULTS: Ninety-nine cases of COVID-19 and 182 controls were included for analysis. Periodontitis was associated with more hospitalization (p = 0.009), more days in the intensive care unit (ICU) (p = 0.042), admission to the semi-ICU (p = 0.047), and greater need for oxygen therapy (p = 0.042). After adjustment for confounders, periodontitis resulted in a 1.13-fold increase in the chance of hospitalization. Salivary IL-6 levels (p = 0.010) were increased in individuals with COVID-19 and periodontitis. Periodontitis was associated with increased RANKL and IL-1ß after COVID-19. No significant changes were observed in the bacterial loads of the periodontopathogens Porphyromona gingivalis, Aggregatibacter actinomycetemcomitans, Tanerella forsythia, and Treponema denticola. CONCLUSIONS: Periodontitis was associated with worse COVID-19 outcomes, suggesting the relevance of periodontal care to reduce the burden of overall inflammation. Understanding the crosstalk between SARS-CoV-2 infection and chronic conditions such as periodontitis that can influence disease outcome is important to potentially prevent complications of COVID-19.

Use of a Paclitaxel Drug-Eluting Stent for the Treatment of Hemodialysis Access Outflow Stenosis.

PURPOSE: To evaluate the outcomes and durability of drug-eluting stents (DESs) for the treatment of hemodialysis access outflow stenosis. MATERIAL AND METHODS: A single-center retrospective analysis was conducted of all patients with hemodialysis vascular access outflow stenosis treated with a paclitaxel-coated DES (Eluvia; Boston Scientific, Marlborough, Massachusetts) between January 2020 and July 2022. A total of 34 DESs were implanted to treat outflow stenosis in 32 patients. Primary target lesion patency after stent deployment was the main outcome. Comparison between the time interval free from target lesion reintervention (TLR) after previous plain balloon angioplasty (PBA) and that after stent deployment for the same target lesion was considered a secondary outcome. RESULTS: The primary patency at 6, 12, and 18 months was 63.1%, 47.6%, and 41.7%, respectively. The secondary patency rate was 100% at 18 months. The median time interval free from TLR increased from 4.1 to 11.9 months (P < .001). No adverse events were observed during the median follow-up period of 387 days. CONCLUSIONS: The patency rates after use of DES for hemodialysis access outflow stenosis were comparable with results for drug-coated balloons and stent grafts, addressing recoil and minimizing the risk of jailing by a covered stent.

The Endogenous Retinoic Acid Receptor Pathway Is Exploited by Mycobacterium tuberculosis during Infection, Both In Vitro and In Vivo.

Retinoic acid (RA) is a fundamental vitamin A metabolite involved in regulating immune responses through the nuclear RA receptor (RAR) and retinoid X receptor. While performing experiments using THP-1 cells as a model for Mycobacterium tuberculosis infection, we observed that serum-supplemented cultures displayed high levels of baseline RAR activation in the presence of live, but not heat-killed, bacteria, suggesting that M. tuberculosis robustly induces the endogenous RAR pathway. Using in vitro and in vivo models, we have further explored the role of endogenous RAR activity in M. tuberculosis infection through pharmacological inhibition of RARs. We found that M. tuberculosis induces classical RA response element genes such as CD38 and DHRS3 in both THP-1 cells and human primary CD14+ monocytes via a RAR-dependent pathway. M. tuberculosis-stimulated RAR activation was observed with conditioned media and required nonproteinaceous factor(s) present in FBS. Importantly, RAR blockade by (4-[(E)-2-[5,5-dimethyl-8-(2-phenylethynyl)-6H-naphthalen-2-yl]ethenyl]benzoic acid), a specific pan-RAR inverse agonist, in a low-dose murine model of tuberculosis significantly reduced SIGLEC-F+CD64+CD11c+high alveolar macrophages in the lungs, which correlated with 2× reduction in tissue mycobacterial burden. These results suggest that the endogenous RAR activation axis contributes to M. tuberculosis infection both in vitro and in vivo and reveal an opportunity for further investigation of new antituberculosis therapies.

Institutional Experience With Venous Aneurysms - Insights On The Natural History And Outcomes Of Surgical Treatment.

INTRODUCTION: Venous aneurysms are rare, so their natural history is not fully understood. Indications for treatment are often determined by the location and size of the aneurysm; however, considering the scarcity of data, there are no specific recommendations. Surgery is the mainstay for venous aneurysm treatment, but some authors reported successful endovascular treatment. We intend to describe our experience with this type of rare disorder. METHODS: A post hoc observational study of a prospectively maintained registry including consecutive patients admitted with the diagnosis of a venous aneurysm at different locations between January 2007 and September 2021. Demographic data, anatomic location, and medical history, including trauma or venous surgery, were analyzed. All vascular reconstructions and outcomes have been evaluated. RESULTS: We identified 30 venous aneurysms in 24 patients. Fifteen patients were male (63%). The most common anatomical location was the popliteal vein (n=19; 63%). Four patients had multiple venous aneurysms, and three patients had synchronous arterial aneurysms. Twelve (63%) of the popliteal vein aneurysms identified were surgically treated, most commonly by tangential aneurysmectomy and lateral venorrhaphy. The average diameter at the time of surgery was 22,8±3,6 mm. After discharge, all patients were anticoagulated for 6 to 12 months, in most cases with rivaroxaban. With a median follow-up time of 32 months (12 - 168 months), primary patency was 92%. Aneurysm recurrence was only observed in one case (1/12; 8%) with non-occlusive thrombosis of the aneurysm 14 years after surgery. One patient had a 21 mm gemelar vein aneurysm, having been proposed for surgery, with thrombosis before the intervention. Two patients had common femoral vein aneurysms treated with partial aneurysmectomy and lateral venorrhaphy without thromboembolic events during follow-up. Two patients presented with portal system aneurysms, one associated with portal hypertension. No treatment was performed, and an increase in aneurysm size was observed during follow-up. Another patient presented with acute deep vein thrombosis on chronically thrombosed bilateral iliac vein aneurysms. Three patients had aneurysms of the superficial venous system associated with previous trauma, which were treated with simple ligation and excision. CONCLUSION: Venous aneurysms are rare and most commonly located in the popliteal vein, which seems to be associated with chronic venous disease. Treating these aneurysms, even without symptoms, can be important to avoid thromboembolic complications. However, close long-term follow-up with duplex ultrasound should be considered to detect late recurrence. Aneurysms from other locations are even rarer, and treatment decisions should be individualized, weighing the risks and benefits of the intervention.

Antecubital perforating vein stent-grafting for radiocephalic arteriovenous fistula recovery: A case report.

Stent-grafts have been increasingly used in hemodialysis arteriovenous accesses, particularly in recurrent stenosis or in cases of vein rupture after percutaneous transluminal angioplasty (PTA). Although they limit neointimal hyperplasia, stenosis development at stent edges remains a concern. Despite their advantages, they are seldom used on the forearm veins due to fracture risk associated with elbow motion and the potential to limit cannulation sites. This report presents a novel application of stent-grafts in salvaging a radio-cephalic arteriovenous fistula in an 84-year-old male to treat a single outflow path at the elbow through a stenosed antecubital perforating vein, after failed PTA. The vascular access remained patent 18 months after the procedure, with no need for additional treatments at this target lesion, even though a PTA was required for juxta-anastomotic stenosis. This report highlights a possible further use of covered stents in arteriovenous vascular accesses.

Recombinant Bacillus Calmette-Guérin Expressing SARS-CoV-2 Chimeric Protein Protects K18-hACE2 Mice against Viral Challenge.

COVID-19 has accounted for more than 6 million deaths worldwide. Bacillus Calmette-Guérin (BCG), the existing tuberculosis vaccine, is known to induce heterologous effects over other infections due to trained immunity and has been proposed to be a potential strategy against SARS-CoV-2 infection. In this report, we constructed a recombinant BCG (rBCG) expressing domains of the SARS-CoV-2 nucleocapsid and spike proteins (termed rBCG-ChD6), recognized as major candidates for vaccine development. We investigated whether rBCG-ChD6 immunization followed by a boost with the recombinant nucleocapsid and spike chimera (rChimera), together with alum, provided protection against SARS-CoV-2 infection in K18-hACE2 mice. A single dose of rBCG-ChD6 boosted with rChimera associated with alum elicited the highest anti-Chimera total IgG and IgG2c Ab titers with neutralizing activity against SARS-CoV-2 Wuhan strain when compared with control groups. Importantly, following SARS-CoV-2 challenge, this vaccination regimen induced IFN-γ and IL-6 production in spleen cells and reduced viral load in the lungs. In addition, no viable virus was detected in mice immunized with rBCG-ChD6 boosted with rChimera, which was associated with decreased lung pathology when compared with BCG WT-rChimera/alum or rChimera/alum control groups. Overall, our study demonstrates the potential of a prime-boost immunization system based on an rBCG expressing a chimeric protein derived from SARS-CoV-2 to protect mice against viral challenge.

Outflow Rescue of Elbow-Blockade Forearm Arteriovenous Fistulas: Outcomes of Open Surgical Techniques.

BACKGROUND: Venous scarring at the elbow is a common problem that can cause early and late forearm arteriovenous fistula (AVF) dysfunction in hemodialysis patients. However, any effort to prolong the long-term patency of distal vascular accesses could benefit the patient's survival, maximizing the use of restricted venous patrimony. This study aims to report a single-center experience in the recovery of distal autologous AVF with venous outflow obstruction at the elbow using different surgical techniques. METHODS: Retrospective observational study of all patients treated at a single vascular access center from January 2011 to March 2022, with dysfunctional forearm AVFs presenting with outflow stenosis or occlusions at the elbow treated by open surgery, using 3 different surgical techniques. Demographics and clinically relevant data were collected. Evaluated endpoints included primary, assisted primary, and secondary patency rates at 1 and 2 years. RESULTS: Twenty-three patients with elbow-blocked outflow forearm AVFs have been treated with a mean age of 64 ± 15 years. The majority (96%) had a radiocephalic fistula. The median time from vascular access creation to intervention was 34.5 months (12-216 months). A total of 24 procedures have been performed using 3 different surgical techniques for bypassing the obstructed venous outflow at the elbow. Technical success was achieved in 96% of the surgically treated patients. Primary and secondary patency rates at 1 year were 67.4% and 89.4%, respectively, and 52.9% and 82.0% at 2 years, with a median follow-up of 19 months (6-92 months). CONCLUSIONS: AVFs outflow stenosis or occlusions at the elbow not amenable to endovascular therapy could lead to vascular access abandonment. Our study demonstrates multiple surgical solutions to avoid this adverse outcome. Elbow venous outflow surgical reconstruction seems effective for distal vascular access preservation. Close surveillance is essential for timely endovascular treatment of newly developed stenosis at the venous drainage.

Kidney autotransplantation as a key solution for a BEVAR type IIIb endoleak.

OBJECTIVES: Target vessel endoleaks are one of the most common causes of revision procedures after a fenestrated or branched endovascular aneurysm repair. Usually, a redo stenting is an effective therapy, however, not always feasible. We present a case of a hybrid treatment for a type IIIb endoleak using the renal autotransplantation technique. METHODS: A 60-year-old man with a thoracoabdominal aortic aneurysm has been treated with a custom-made branched endoprosthesis. Occlusion of the bridging stent to the right renal artery with total infarction of the right kidney was identified one week later and conservatively managed. After four years, a type IIIb endoleak was identified. Endovascular treatment was attempted unsuccessfully. So, the endoleak was corrected using a hybrid strategy with the kidney autotransplantation technique. RESULTS: A left kidney autotransplantation followed by an aortic stent-graft relining with a tubular graft has been done uneventfully, in a phased manner. Postoperative computed tomography angiography confirmed the patency of vascular reconstructions with no endoleaks. No adverse events occurred during one year of follow-up. CONCLUSION: Our case highlights kidney autotransplantation as a viable solution for a hybrid treatment of target vessel endoleaks and shows that this technique can assist complex endovascular aortic reconstructions.

Neuraminidase is a host-directed approach to regulate neutrophil responses in sepsis and COVID-19.

BACKGROUND AND PURPOSE: Neutrophil overstimulation plays a crucial role in tissue damage during severe infections. Because pathogen-derived neuraminidase (NEU) stimulates neutrophils, we investigated whether host NEU can be targeted to regulate the neutrophil dysregulation observed in severe infections. EXPERIMENTAL APPROACH: The effects of NEU inhibitors on lipopolysaccharide (LPS)-stimulated neutrophils from healthy donors or COVID-19 patients were determined by evaluating the shedding of surface sialic acids, cell activation, and reactive oxygen species (ROS) production. Re-analysis of single-cell RNA sequencing of respiratory tract samples from COVID-19 patients also was carried out. The effects of oseltamivir on sepsis and betacoronavirus-induced acute lung injury were evaluated in murine models. KEY RESULTS: Oseltamivir and zanamivir constrained host NEU activity, surface sialic acid release, cell activation, and ROS production by LPS-activated human neutrophils. Mechanistically, LPS increased the interaction of NEU1 with matrix metalloproteinase 9 (MMP-9). Inhibition of MMP-9 prevented LPS-induced NEU activity and neutrophil response. In vivo, treatment with oseltamivir fine-tuned neutrophil migration and improved infection control as well as host survival in peritonitis and pneumonia sepsis. NEU1 also is highly expressed in neutrophils from COVID-19 patients, and treatment of whole-blood samples from these patients with either oseltamivir or zanamivir reduced neutrophil overactivation. Oseltamivir treatment of intranasally infected mice with the mouse hepatitis coronavirus 3 (MHV-3) decreased lung neutrophil infiltration, viral load, and tissue damage. CONCLUSION AND IMPLICATIONS: These findings suggest that interplay of NEU1-MMP-9 induces neutrophil overactivation. In vivo, NEU may serve as a host-directed target to dampen neutrophil dysfunction during severe infections.

Fatores associados à percepção do risco biológico e aos acidentes com material biológico em Agentes Comunitários de Saúde / Factors associated with the perception of biological risk and accidents with biological material in community health workers / Factores asociados a la percepción del riesgo biológico y de los accidentes con material biológico en los agentes comunitarios de salud

Objetivos: identificar fatores associados à acidentes com material biológico e à percepção do risco biológico entre Agentes Comunitários de Saúde (ACS). Métodos: estudo transversal analítico realizado com ACS, mediante aplicação de questionário e consulta de registros no cartão de vacinas. Regressão múltipla de Poisson com variância robusta foi realizada para analisar os fatores associados aos acidentes com material biológico e à percepção do risco biológico. Resultados: dos 207 participantes, 50,24% (IC 95% = 43,4 - 56,9) apresentou autorrelato de acidentes com material biológico, tendo como fatores associados possuir formação de nível superior [RP ajustada = 2,2 (IC 95% = 1,0 - 4,7)], ter outro vínculo empregatício [RP ajustada = 1,5 (IC 95% = 1,0 - 2,3)] e conhecimento quanto às vacinas necessárias ao ACS [RP ajustada = 0,7 (0,5 - 0,9)]. Constatou-se que 74,39% dos ACS tinham percepção de algum risco biológico, mesmo de forma limitada. Entre as variáveis investigadas, na análise ajustada, nenhuma mostrou associação com a percepção de risco biológico pelos ACS. Conclusão: a prevalência de acidentes com material biológico em ACS é elevada, sendo fatores associados possuir formação de nível superior, ter outro vínculo empregatício e apresentar conhecimento quanto as vacinas necessárias para a atividade laboral. Há limitada percepção de risco pela maioria dos ACS. Não foram encontrados fatores associados à esta variável.

Objectives: to identify factors associated with accidents involving biological material and the perception of biological risk among community health workers (CHWs). Methods: an analytical cross-sectional study was carried out with CHWs using a questionnaire and consultation of vaccination card records. Poisson multiple regression with robust variance was conducted to analyze the factors associated with accidents involving biological material and perception of biological risk. Results: of the 207 participants, 50.24% (95% CI = 43.4 - 56.9) self-reported accidents with biological material, and the associated factors were having a university degree [adjusted PR = 2.2 (95% CI = 1.0 - 4.7)], having another job [adjusted PR = 1.5 (95% CI = 1.0 - 2.3)] and knowledge of the vaccines needed by CHWs [adjusted PR = 0.7 (0.5 - 0.9)]. It was found that 74.39% of CHWs were aware of some biological risk, even to a limited extent. Among the variables investigated, in the adjusted analysis, none showed an association with the perception of biological risk by CHWs. Conclusion: the prevalence of accidents involving biological material among CHWs is high, and the associated factors are having a university degree, having another job, and having knowledge of the vaccines required for the job. Most CHWs have a limited perception of the risk. No factors were associated with this variable.

Objetivos: identificar los factores asociados a los accidentes con material biológico y la percepción del riesgo biológico entre agentes comunitarios de salud (ACS). Métodos: estudio transversal analítico realizado con los ACS mediante cuestionario y consulta de los registros de las cartillas de vacunación. Se realizó una regresión múltiple de Poisson con varianza robusta para analizar los factores asociados a los accidentes con material biológico y la percepción del riesgo biológico. Resultados: de los 207 participantes, el 50,24% (IC 95% = 43,4 - 56,9) declararon haber sufrido accidentes con material biológico, y los factores asociados fueron tener un título universitario [PR ajustado = 2,2 (IC 95% = 1,0 - 4,7)], tener otro trabajo [PR ajustado = 1,5 (IC 95% = 1,0 - 2,3)] y conocer las vacunas que necesitan los ACS [PR ajustado = 0,7 (0,5 - 0,9)]. Se observó que el 74,39% de los ACS conocían algún riesgo biológico, aunque fuera de forma limitada. De las variables investigadas en el análisis ajustado, ninguna mostró una asociación con la percepción del riesgo biológico por parte de los ACS. Conclusión: la prevalencia de accidentes con material biológico entre los ACS es alta, y los factores asociados son tener un título universitario, tener otro trabajo y tener conocimientos sobre las vacunas necesarias para el trabajo. La mayoría de los ACS tienen una percepción limitada del riesgo. No se encontraron factores asociados a esta variable.

Hybrid Approach of a Complex Aneurysm of the Subclavian-Axillary-Brachial Axis: A Case Report.

BACKGROUND: Upper extremity arterial aneurysms are a rare, potentially limb-threatening disorder. Due to its rarity, the best treatment modality and outcomes are not entirely established; however, there is a consensus that open surgery is the first-line treatment. We present a complex case of an arterial aneurysm of the subclavian-axillary-brachial axis adequately treated using a hybrid surgical and endovascular treatment. CASE PRESENTATION: A 59-year-old man presented to the emergency department with acute ischemia of the right upper limb. An extensive thrombosed aneurysm of the subclavian-axillary-brachial axis was identified. The treatment was carried out in two stages. In the first phase, urgent limb revascularization was performed using the great saphenous vein to perform a subclavian-brachial artery bypass. Later, the aneurysm was excluded using a vascular plug and multiple coils. Successful treatment was achieved with no morbidity for the patient. CONCLUSIONS: Although the gold standard for treating upper limb aneurysms is open surgery, endovascular techniques can be a significant adjunct, reducing treatment morbidity and even mortality.

Neuraminidase inhibitors rewire neutrophil function in vivo in murine sepsis and ex vivo in COVID-19.

Neutrophil overstimulation plays a crucial role in tissue damage during severe infections. Neuraminidase (NEU)-mediated cleavage of surface sialic acid has been demonstrated to regulate leukocyte responses. Here, we report that antiviral NEU inhibitors constrain host NEU activity, surface sialic acid release, ROS production, and NETs released by microbial-activated human neutrophils. In vivo, treatment with Oseltamivir results in infection control and host survival in peritonitis and pneumonia models of sepsis. Single-cell RNA sequencing re-analysis of publicly data sets of respiratory tract samples from critical COVID-19 patients revealed an overexpression of NEU1 in infiltrated neutrophils. Moreover, Oseltamivir or Zanamivir treatment of whole blood cells from severe COVID-19 patients reduces host NEU-mediated shedding of cell surface sialic acid and neutrophil overactivation. These findings suggest that neuraminidase inhibitors can serve as host-directed interventions to dampen neutrophil dysfunction in severe infections.

Influence of tendon injuries on the clinical outcome of ankle and hindfoot fractures.

BACKGROUND: Associations of tendon injuries with ankle and hindfoot fractures is a current concern and recent research has linked specific fractures with specific tendon injuries, despite its functional impact being unknown. The purpose of this study is to assess that impact. METHODS: Computed tomography scans of patients with ankle and hindfoot fractures were reviewed for tendon injuries. Patients were clinically evaluated with the Visual Analogue Scale (VAS) and the Manchester-Oxford Foot Questionnaire (MOXFQ), via a telephonic interview. RESULTS: Eighty-five patients were included in the study. The mean age was of 49.9 ± 16.5 (14-80) years and there were 43 females (50,6%). Mean follow-up was of 43,7 ± 15,1 (24,4-82,2) months. Tendon injuries were identified in 23 patients (27,1%) and the most common lesion was tendon entrapment. The tibialis posterior tendon (TP) was injured in 18 patients (21,2%) and comprised 58,1% of all tendon injuries. Tendon injuries were mostly associated with pilon fractures, which was the most common fracture type (44,7%). There was no clinical difference between patients with a tendon injury [VAS of 4,3 ± 2,6 (0-8) and MOXFQ score of 35,1 ± 22,4 (5-80)], and those without [VAS of 3,9 ± 2,5 (0-10) and MOXFQ of 34,3 ± 26,0 (0-95), respectively (p = 0,281 and 0,689)]. CONCLUSION: Tendon injuries were present in 27% of patients with ankle and hindfoot injuries. The most frequently injured tendon was the TP in association with pilon fractures, with entrapment being the most common lesion. These lesions, however, do not seem to reflect in a worse functional outcome at two years of follow-up.

Ruptured arteriovenous fistula pseudoaneurysm treatment by balloon-assisted direct percutaneous thrombin injection.

We present the case of a male patient on hemodialysis with a ruptured pseudoaneurysm in a brachiocephalic arteriovenous fistula (AVF) and with edema and pain in the right arm attended to in the emergency department. An ultrasonographic scan identified a ruptured pseudoaneurysm with hemorrhagic infiltration of the arm muscular tissues. We performed a percutaneous ultrasound-guided thrombin injection with an angioplasty balloon inflated in the lumen of the AVF achieving the pseudoaneurysm thrombosis. After 6 months of follow-up, the patient's arteriovenous access remains functional. Percutaneous ultrasound-guided thrombin injection assisted by an angioplasty balloon may be a good alternative to surgical intervention in the treatment of symptomatic growing pseudoaneurysms of the arteriovenous fistula with the benefit of preserving the vascular access.

COX-2 promotes mammary adipose tissue inflammation, local estrogen biosynthesis, and carcinogenesis in high-sugar/fat diet treated mice.

Obesity is a major risk factor for breast cancer, especially in post-menopausal women. In the breast tissue of obese women, cyclooxygenase-2 (COX-2)-dependent prostaglandin E2 (PGE2) production has been correlated with inflammation and local estrogen biosynthesis via aromatase. Using a mouse model of 7,12-dimethylbenz[a]anthracene/medroxyprogesterone-acetate (DMBA/MPA)-induced carcinogenesis, we demonstrated that an obesogenic diet promotes mammary tissue inflammation and local estrogen production, and accelerates mammary tumor formation in a COX-2-dependent manner. High-sugar/fat (HSF) diet augmented the levels of the pro-inflammatory mediators MCP-1, IL-6, COX-2, and PGE2 in mammary tissue, and this was accompanied by crown-like structures of breast (CLS-B) formation and aromatase/estrogen upregulation. Treatment with a COX-2 selective inhibitor, etoricoxib, decreased PGE2, IL-6, MCP-1, and CLS-B formation as well as reduced aromatase protein and estrogen levels in the mammary tissue of mice fed a HSF diet. Etoricoxib-treated mice showed increased latency and decreased incidence of mammary tumors, which resulted in prolonged animal survival when compared to HSF diet alone. Inhibition of tumor angiogenesis also seemed to account for the prolonged survival of COX-2 inhibitor-treated animals. In conclusion, obesogenic diet-induced COX-2 is sufficient to trigger inflammation, local estrogen biosynthesis, and mammary tumorigenesis.

IL-21 treatment recovers follicular helper T cells and neutralizing antibody production in respiratory syncytial virus infection.

Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infections in children under 1 year. RSV vaccines are currently unavailable, and children suffering from multiple reinfections by the same viral strain fail to develop protective responses. Although RSV-specific antibodies can be detected upon infection, these have limited neutralizing capacity. Follicular helper T (Tfh) cells are specialized in providing signals to B cells and help the production and affinity maturation of antibodies, mainly via interleukin (IL) 21 secretion. In this study, we evaluated whether RSV could inhibit Tfh responses. We observed that Tfh cells fail to upregulate IL-21 production upon RSV infection. In the lungs, RSV infection downregulated the expression of IL-21/interleukin-21 receptor (IL-21R) in Tfh cells and upregulated programmed death-ligand 1 (PD-L1) expression in dendritic cells (DCs) and B cells. PD-L1 blockade during infection recovered IL-21R expression in Tfh cells and increased the secretion of IL-21 in a DC-dependent manner. IL-21 treatment decreased RSV viral load and lung inflammation, inducing the formation of tertiary lymphoid organs in the lung. It also decreased regulatory follicular T cells, and increased Tfh cells, B cells, antibody avidity and neutralization capacity, leading to an overall improved anti-RSV humoral response in infected mice. Passive immunization with purified immunoglobulin G from IL-21-treated RSV-infected mice protected against RSV infection. Our results unveil a pathway by which RSV affects Tfh cells by increasing PD-L1 expression on antigen-presenting cells, highlighting the importance of an IL-21-PD-L1 axis for the generation of protective responses to RSV infection.