Exploiting the neonatal crystallizable fragment receptor to treat kidney disease.

The neonatal Fc receptor (FcRn) was initially discovered as the receptor that allowed passive immunity in newborns by transporting maternal IgG through the placenta and enterocytes. Since its initial discovery, FcRn has been found to exist throughout all stages of life and in many different cell types. Beyond passive immunity, FcRn is necessary for intrinsic albumin and IgG recycling and is important for antigen processing and presentation. Given its multiple important roles, FcRn has been utilized in many disease treatments including a new class of agents that were developed to inhibit FcRn for treatment of a variety of autoimmune diseases. Certain cell populations within the kidney also express high levels of this receptor. Specifically, podocytes, proximal tubule epithelial cells, and vascular endothelial cells have been found to utilize FcRn. In this review, we summarize what is known about FcRn and its function within the kidney. We also discuss how FcRn has been used for therapeutic benefit, including how newer FcRn inhibiting agents are being used to treat autoimmune diseases. Lastly, we will discuss what renal diseases may respond to FcRn inhibitors and how further work studying FcRn within the kidney may lead to therapies for kidney diseases.

Interactions of the Immune System with Human Kidney Organoids.

Kidney organoids are an innovative tool in transplantation research. The aim of the present study was to investigate whether kidney organoids are susceptible for allo-immune attack and whether they can be used as a model to study allo-immunity in kidney transplantation. Human induced pluripotent stem cell-derived kidney organoids were co-cultured with human peripheral blood mononuclear cells (PBMC), which resulted in invasion of allogeneic T-cells around nephron structures and macrophages in the stromal cell compartment of the organoids. This process was associated with the induction of fibrosis. Subcutaneous implantation of kidney organoids in immune-deficient mice followed by adoptive transfer of human PBMC led to the invasion of diverse T-cell subsets. Single cell transcriptomic analysis revealed that stromal cells in the organoids upregulated expression of immune response genes upon immune cell invasion. Moreover, immune regulatory PD-L1 protein was elevated in epithelial cells while genes related to nephron differentiation and function were downregulated. This study characterized the interaction between immune cells and kidney organoids, which will advance the use of kidney organoids for transplantation research.

Accelerated involution of germinal center in palatine tonsils in IgA nephropathy.

BACKGROUND: Altered immunological responses in the palatine tonsils may be involved in the pathogenesis of IgA nephropathy (IgAN). The germinal center serves as the site for antigen-specific humoral immune responses in the palatine tonsils. Germinal center involution is frequently observed in the palatine tonsils of IgAN (IgAN tonsils). However, the pathogenic significance of these characteristic changes remains unclear. This study aimed to investigate the morphological changes in secondary lymphoid follicles in IgAN tonsils and to evaluate the correlation between the morphometric results and the clinicopathological severity of IgAN. METHODS: The tonsils of age-matched patients with recurrent tonsillitis (RT tonsils) were used as controls. The correlation between the degree of lymphoid follicular involution and histopathological severities in clinical or kidney biopsy was evaluated. RESULTS: In total, 87 patients with IgAN were included (48% male, median age 35 years, median estimated glomerular filtration rate: 74 mL/min/1.73 m2). Compared to RT tonsils, IgAN tonsils showed smaller median sizes of lymphoid follicles and germinal centers (P < 0.001). The relative areas of lymphoid follicles (%LFA) and germinal centers (%GCA) in the total tonsillar tissue were smaller in the IgAN tonsils than in the RT tonsils (P < 0.001). In contrast, the median proportion of mantle zones in the total tonsillar tissue was comparable between the groups. A lower %LFA was associated with a longer period from the onset of urinary abnormalities to biopsy diagnosis and higher urinary protein excretion (P = 0.01). %LFA showed significant negative correlations with frequencies of glomeruli with both global and segmental sclerosis. CONCLUSIONS: The present study confirmed accelerated germinal center involution in the tonsils of patients with IgAN. This characteristic change in the IgAN tonsil correlates with heavy proteinuria and advanced chronic histopathological changes in the kidneys, thereby suggesting the involvement of repeated tonsillar immunoreactions during IgAN progression.

Leptospira-specific immunoglobulin Y (IgY) is protective in infected hamsters.

Leptospirosis, a globally significant zoonotic disease caused by pathogenic Leptospira, continues to threaten the health and public safety of both humans and animals. Current clinical treatment of leptospirosis mainly relies on antibiotics but their efficacy in severe cases is controversial. Passive immunization has a protective effect in the treatment of infectious diseases. In addition, chicken egg yolk antibody (IgY) has gained increasing attention as a safe passive immunization agent. This study aimed to investigate whether hens produce specific IgY after immunization with inactivated Leptospira and the protective effect of specific IgY against leptospirosis. First, it was demonstrated that specific IgY could be extracted from the eggs of hens vaccinated with inactivated Leptospira and that specific IgY can specifically recognize and bind homotypic Leptospira with a high titre, as shown by MAT and ELISA. Next, we tested the therapeutic effects of IgY in early and late leptospirosis using a hamster model. The results showed that early specific IgY treatment increased the survival rate of hamsters to 100%, alleviated pathological damage to the liver, kidney, and lung, reduced leptospiral burden, and restored haematological indices as well as functional indicators of the liver and kidney. The therapeutic effect of early specific IgY was comparable to that of doxycycline. Late IgY treatment also enhanced the survival rate of hamsters and improved the symptoms of leptospirosis similar to early IgY treatment. However, the therapeutic effect of late IgY treatment was better when combined with doxycycline. Furthermore, no Leptospira colonization was observed in the kidneys, livers, or lungs of the surviving hamsters treated with specific IgY. Mechanistically, IgY was found to inhibit the growth and adhesion to cells of Leptospira. In conclusion, passive immunotherapy with specific IgY can be considered an effective treatment for leptospirosis, and may replace antibiotics regarding its therapeutic effects.

Methyl-supplemented nutrition delays the development of autoimmune disease in pristane-induced murine lupus.

The aetiology and progression of systemic lupus erythematosus (SLE) resulted from a complex sequence of events generated both from genetic and epigenetic processes. In the current research, the effect of methyl-supplemented nutrition on the development of SLE was studied in the pristane-induced mouse model of the disease. The results clearly demonstrated decreased anti-dsDNA antibody and proteinuria levels, modulation of cytokines and protected renal structures in the group of treated mice. An additional increase in the DNA methylation of mouse B lymphocytes was also observed. The beneficial effect of the diet is due to the methyl-containing micronutrients with possible anti-inflammatory and immunomodulating effects on cell proliferation and gene expression. Since these components are responsible for maintaining the physiological methylation level of DNA, the results point to the central role of methylation processes in environmentally triggered lupus. As nutrition represents one of the major epigenetic factors, these micronutrients may be considered novel agents with significant therapeutic outcomes.

Cognate antigen-independent differentiation of resident memory T cells in chronic kidney disease.

Resident memory T cells (TRMs), which are memory T cells that are retained locally within tissues, have recently been described as antigen-specific frontline defenders against pathogens in barrier and nonbarrier epithelial tissues. They have also been noted for perpetuating chronic inflammation. The conditions responsible for TRM differentiation are still poorly understood, and their contributions, if any, to sterile models of chronic kidney disease (CKD) remain a mystery. In this study, we subjected male C57BL/6J mice and OT-1 transgenic mice to five consecutive days of 2 mg/kg aristolochic acid (AA) injections intraperitoneally to induce CKD or saline injections as a control. We evaluated their kidney immune profiles at 2 wk, 6 wk, and 6 mo after treatment. We identified a substantial population of TRMs in the kidneys of mice with AA-induced CKD. Flow cytometry of injured kidneys showed T cells bearing TRM surface markers and single-cell (sc) RNA sequencing revealed these cells as expressing well-known TRM transcription factors and receptors responsible for TRM differentiation and maintenance. Although kidney TRMs expressed Cd44, a marker of antigen experience and T cell activation, their derivation was independent of cognate antigen-T cell receptor interactions, as the kidneys of transgenic OT-1 mice still harbored considerable proportions of TRMs after injury. Our results suggest a nonantigen-specific or antigen-independent mechanism capable of generating TRMs in the kidney and highlight the need to better understand TRMs and their involvement in CKD.NEW & NOTEWORTHY Resident memory T cells (TRMs) differentiate and are retained within the kidneys of mice with aristolochic acid (AA)-induced chronic kidney disease (CKD). Here, we characterized this kidney TRM population and demonstrated TRM derivation in the kidneys of OT-1 transgenic mice with AA-induced CKD. A better understanding of TRMs and the processes by which they can differentiate independent of antigen may help our understanding of the interactions between the immune system and kidneys.

Angiotensin II and post-streptococcal glomerulonephritis.

BACKGROUND: Post-streptococcal glomerulonephritis (PSGN) is a consequence of the infection by group A beta-hemolytic streptococcus. During this infection, various immunological processes generated by streptococcal antigens are triggered, such as the induction of antibodies and immune complexes. This activation of the immune system involves both innate and acquired immunity. The immunological events that occur at the renal level lead to kidney damage with chronic renal failure as well as resolution of the pathological process (in most cases). Angiotensin II (Ang II) is a molecule with vasopressor and pro-inflammatory capacities, being an important factor in various inflammatory processes. During PSGN some events are defined that make Ang II conceivable as a molecule involved in the inflammatory processes during the disease. CONCLUSION: This review is focused on defining which reported events would be related to the presence of this hormone in PSGN.

Complement Activation via the Lectin and Alternative Pathway in Patients With Severe COVID-19.

Complement plays an important role in the direct defense to pathogens, but can also activate immune cells and the release of pro-inflammatory cytokines. However, in critically ill patients with COVID-19 the immune system is inadequately activated leading to severe acute respiratory syndrome (SARS) and acute kidney injury, which is associated with higher mortality. Therefore, we characterized local complement deposition as a sign of activation in both lungs and kidneys from patients with severe COVID-19. Using immunohistochemistry we investigated deposition of complement factors C1q, MASP-2, factor D (CFD), C3c, C3d and C5b-9 as well as myeloperoxidase (MPO) positive neutrophils and SARS-CoV-2 virus particles in lungs and kidneys from 38 patients who died from COVID-19. In addition, tissue damage was analyzed using semi-quantitative scores followed by correlation with complement deposition. Autopsy material from non-COVID patients who died from cardiovascular causes, cerebral hemorrhage and pulmonary embolism served as control (n=8). Lung injury in samples from COVID-19 patients was significantly more pronounced compared to controls with formation of hyaline membranes, thrombi and edema. In addition, in the kidney tubular injury was higher in these patients and correlated with lung injury (r=0.361*). In autopsy samples SARS-CoV-2 spike protein was detected in 22% of the lungs of COVID-19 patients but was lacking in kidneys. Complement activation was significantly stronger in lung samples from patients with COVID-19 via the lectin and alternative pathway as indicated by deposition of MASP-2, CFD, C3d and C5b9. Deposits in the lung were predominantly detected along the alveolar septa, the hyaline membranes and in the alveolar lumina. In the kidney, complement was significantly more deposited in patients with COVID-19 in peritubular capillaries and tubular basement membranes. Renal COVID-19-induced complement activation occurred via the lectin pathway, while activation of the alternative pathway was similar in both groups. Furthermore, MPO-positive neutrophils were found in significantly higher numbers in lungs and kidneys of COVID-19 patients and correlated with local MASP-2 deposition. In conclusion, in patients who died from SARS-CoV-2 infection complement was activated in both lungs and kidneys indicating that complement might be involved in systemic worsening of the inflammatory response. Complement inhibition might thus be a promising treatment option to prevent deregulated activation and subsequent collateral tissue injury in COVID-19.

TIMP2 mediates endoplasmic reticulum stress contributing to sepsis-induced acute kidney injury.

Tissue inhibitor of metalloproteinase 2 (TIMP2) has been recognized as an important biomarker for predicting acute kidney injury (AKI) because of its involvement in the process of inflammation and apoptosis in septic AKI. Endoplasmic reticulum (ER) stress, a condition of disrupted ER homeostasis, is implicated in multiple pathophysiological processes, including kidney disease. Herein, we investigated the correlation between ER stress and septic AKI and further explored how TIMP2 regulated ER stress-mediated apoptosis. To assess the role of TIMP2 in sepsis-induced AKI, we used a cecal ligation and puncture (CLP) model in mice with tubule-specific deficiency of TIMP2 (Ksp-Cre/TIMP2flox/flox ) and their wild-type counterparts. Compared to the wild-type mice, TIMP2-deficient mice demonstrated lower serum creatinine levels and decreased ER stress-mediated apoptosis when subjected to CLP. Interestingly, in human kidney (HK-2) cells, overexpression of TIMP2 caused ER stress, whereas TIMP2 knockdown attenuated lipopolysaccharide-induced ER stress and apoptosis. TIMP2 interacted with the binding immunoglobulin protein, an ER chaperone, and facilitates its extracellular secretion, thereby triggering ER stress. This study identified that the deletion of TIMP2 in mouse tubules mitigated sepsis-induced AKI by inhibiting ER stress-mediated apoptosis, which might be a potential therapeutic strategy to alleviate renal injury.

The CD6/ALCAM pathway promotes lupus nephritis via T cell-mediated responses.

T cells are central to the pathogenesis of lupus nephritis (LN), a common complication of systemic lupus erythematosus (SLE). CD6 and its ligand, activated leukocyte cell adhesion molecule (ALCAM), are involved in T cell activation and trafficking. Previously, we showed that soluble ALCAM is increased in urine (uALCAM) of patients with LN, suggesting that this pathway contributes to disease. To investigate, uALCAM was examined in 1038 patients with SLE and LN from 5 ethnically diverse cohorts; CD6 and ALCAM expression was assessed in LN kidney cells; and disease contribution was tested via antibody blockade of CD6 in murine models of SLE and acute glomerulonephritis. Extended cohort analysis offered resounding validation of uALCAM as a biomarker that distinguishes active renal involvement in SLE, irrespective of ethnicity. ALCAM was expressed by renal structural cells whereas CD6 expression was exclusive to T cells, with elevated numbers of CD6+ and ALCAM+ cells in patients with LN. CD6 blockade in models of spontaneous lupus and immune-complex glomerulonephritis revealed significant decreases in immune cells, inflammatory markers, and disease measures. Our data demonstrate the contribution of the CD6/ALCAM pathway to LN and SLE, supporting its use as a disease biomarker and therapeutic target.

Macrophage Depletion Reduces Disease Pathology in Factor H-Dependent Immune Complex-Mediated Glomerulonephritis.

Complement factor H (FH) is a key regulator of the alternative pathway of complement, in man and mouse. Earlier, our studies revealed that the absence of FH causes the C57BL6 mouse to become susceptible to chronic serum sickness (CSS) along with an increase in the renal infiltration of macrophages compared to controls. To understand if the increased recruitment of macrophages (Mϕs) to the kidney was driving inflammation and propagating injury, we examined the effect of Mϕ depletion with clodronate in FH knockout mice with CSS. Eight-week-old FHKO mice were treated with apoferritin (4 mg/mouse) for 5 wks and with either vehicle (PBS) or clodronate (50 mg/kg ip, 3 times/wk for the last 3 weeks). The administration of clodronate decreased monocytes and Mϕs in the kidneys by >80%. Kidney function assessed by BUN and albumin remained closer to normal on depletion of Mϕs. Clodronate treatment prevented the alteration in cytokines, TNFα and IL-6, and increase in gene expression of connective tissue growth factor (CTGF), TGFß-1, matrix metalloproteinase-9 (MMP9), fibronectin, laminin, and collagen in FHKO mice with CSS (P < 0.05). Clodronate treatment led to relative protection from immune complex- (IC-) mediated disease pathology during CSS as assessed by the significantly reduced glomerular pathology (GN) and extracellular matrix. Our results suggest that complement activation is one of the mechanism that regulates the macrophage landscape and thereby fibrosis. The exact mechanism remains to be deciphered. In brief, our data shows that Mϕs play a critical role in FH-dependent ICGN and Mϕ depletion reduces disease progression.

Gut dysbiosis is associated with acceleration of lupus nephritis.

The gut microbiota (GM) exerts a strong influence over the host immune system and dysbiosis of this microbial community can affect the clinical phenotype in chronic inflammatory conditions. To explore the role of the GM in lupus nephritis, we colonized NZM2410 mice with Segmented Filamentous Bacteria (SFB). Gut colonization with SFB was associated with worsening glomerulonephritis, glomerular and tubular immune complex deposition and interstitial inflammation compared to NZM2410 mice free of SFB. With SFB colonization mice experienced an increase in small intestinal lamina propria Th17 cells and group 3 innate lymphoid cells (ILC3s). However, although serum IL-17A expression was elevated in these mice, Th17 cells and ILC3s were not detected in the inflammatory infiltrate in the kidney. In contrast, serum and kidney tissue expression of the macrophage chemoattractants MCP-1 and CXCL1 were significantly elevated in SFB colonized mice. Furthermore, kidney infiltrating F4/80+CD206+M2-like macrophages were significantly increased in these mice. Evidence of increased gut permeability or "leakiness" was also detected in SFB colonized mice. Finally, the intestinal microbiome of SFB colonized mice at 15 and 30 weeks of age exhibited dysbiosis when compared to uncolonized mice at the same time points. Both microbial relative abundance as well as biodiversity of colonized mice was found to be altered. Collectively, SFB gut colonization in the NZM2410 mouse exacerbates kidney disease, promotes kidney M2-like macrophage infiltration and overall intestinal microbiota dysbiosis.

Diet-Derived Advanced Glycation End Products (dAGEs) Induce Proinflammatory Cytokine Expression in Cardiac and Renal Tissues of Experimental Mice: Protective Effect of Curcumin.

The beneficial effect of curcumin (CU) on dietary AGEs (dAGEs) involves blocking the overexpression of proinflammatory cytokine genes in the heart and kidney tissues of experimental mice. The animals were divided into six groups (n = 6/group) and were fed a heat-exposed diet (dAGEs) with or without CU for 6 months. Their blood pressure (BP) was monitored by a computerized tail-cuff BP-monitoring system. The mRNA and protein expression levels of proinflammatory genes were analyzed by RT-PCR and western blot, respectively. A marked increase in BP (108 ± 12 mmHg vs 149 ± 15 mmHg) accompanied by a marked increase in the heart and kidney weight ratio was noted in the dAGE-fed mice. Furthermore, the plasma levels of proinflammatory molecules (C5a, ICAM-1, IL-6, MCP-1, IL-1ß and TNF-α) were found to be elevated (3-fold) in dAGE-fed mice. mRNA expression analysis revealed a significant increase in the expression levels of inflammatory markers (Cox-2, iNOS, and NF-κB) (3-fold) in cardiac and renal tissues of dAGE-fed mice. Moreover, increased expression of RAGE and downregulation of AGER-1 (p < 0.001) were noticed in the heart and kidney tissues of dAGE-fed mice. Interestingly, the dAGE-induced proinflammatory genes and inflammatory responses were neutralized upon cotreatment with CU. The present study demonstrates that dietary supplementation with CU has the ability to neutralize dAGE-induced adverse effects and alleviate proinflammatory gene expression in the heart and kidney tissues of experimental mice.

Pathogenesis and host responses in lungs and kidneys following Canadian 4/91 infectious bronchitis virus (IBV) infection in chickens.

The infectious bronchitis virus (IBV) 4/91 was one of the common IBV variants isolated in Eastern Canada between 2013 and 2017 from chicken flocks showing severe respiratory and production problems. We designed an in vivo experiment, using specific pathogen free (SPF) chickens, to study the pathogenesis of, and host response to, Canadian (CAN) 4/91 IBV infection. At one week of age, the chickens were infected with 4/91 IBV/Ck/Can/17-038913 isolate. Swab samples were collected at predetermined time points. Five birds from the infected and the control groups were euthanized at 3, 7- and 10-days post-infection (dpi) to collect lung and kidney tissues. The results indicate IBV replication in these tissues at all three time points with prominent histological lesions, significant immune cell recruitment and up regulation of proinflammatory mediators. Overall, our findings add to the understanding of the pathogenesis of 4/91 infection and the subsequent host responses in the lungs and kidneys following experimental infection.

Ameliorate impacts of scopoletin against vancomycin-induced intoxication in rat model through modulation of Keap1-Nrf2/HO-1 and IκBα-P65 NF-κB/P38 MAPK signaling pathways: Molecular study, molecular docking evidence and network pharmacology analysis.

Nephrotoxicity is an indication for the damage of kidney-specific detoxification and excretion mechanisms by exogenous or endogenous toxicants. Exposure to vancomycin predominantly results in renal damage and losing the control of body homeostasis. Vancomycin-treated rats (200 mg/kg/once daily, for seven consecutive days, i.p.) revealed significant increase in serum pivotal kidney function, oxidative stress, and inflammatory biomarkers. Histologically, vancomycin showed diffuse acute tubular necrosis, denudation of epithelium and infiltration of inflammatory cells in the lining tubular epithelium in cortical portion. In the existing study, the conservative consequences of scopoletin against vancomycin nephrotoxicity was investigated centering on its capacity to alleviate oxidative strain and inflammation through streamlining nuclear factor (erythroid-derived-2) like 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling and prohibiting the nuclear factor kappa B (NF-κB)/mitogen-activated protein kinase (p38 MAPK) pathway. With respect to vancomycin group, scopoletin pretreatment (50 mg/kg/once daily, i.p.) efficiently reduced kidney function, oxidative stress biomarkers and inflammatory mediators. Moreover, histological and immunohistochemical examination of scopoletin-treated group showed remarkable improvement in histological structure and reduced vancomycin-induced renal expression of iNOS, NF-κB and p38 MAPK. In addition, scopoletin downregulated (Kelch Like ECH Associated Protein1) Keap1, P38MAPK and NF-κB expression levels while upregulated renal expression levels of regulatory protein (IκBα), Nrf2 and HO-1. Furthermore, molecular docking and network approach were constructed to study the prospect interaction between scopoletin and the targeted proteins that streamline oxidative stress and inflammatory pathways. The present investigations elucidated that scopoletin co-treatment with vancomycin may be a rational curative protocol for mitigation of vancomycin-induced renal intoxication.

Homodimeric Minimal Factor H: In Vivo Tracking and Extended Dosing Studies in Factor H Deficient Mice.

C3 glomerulopathy (C3G) is associated with dysregulation of the alternative pathway (AP) of complement and treatment options remain inadequate. Factor H (FH) is a potent regulator of the AP. An in-depth analysis of FH-related protein dimerised minimal (mini)-FH constructs has recently been published. This analysis showed that addition of a dimerisation module to mini-FH not only increased serum half-life but also improved complement regulatory function, thus providing a potential treatment option for C3G. Herein, we describe the production of a murine version of homodimeric mini-FH [mHDM-FH (mFH1-5^18-20^R1-2)], developed to reduce the risk of anti-drug antibody formation during long-term experiments in murine models of C3G and other complement-driven pathologies. Our analysis of mHDM-FH indicates that it binds with higher affinity and avidity to WT mC3b when compared to mouse (m)FH (mHDM-FH KD=505 nM; mFH KD=1370 nM) analogous to what we observed with the respective human proteins. The improved binding avidity resulted in enhanced complement regulatory function in haemolytic assays. Extended interval dosing studies in CFH-/- mice (5mg/kg every 72hrs) were partially effective and bio-distribution analysis in CFH-/- mice, through in vivo imaging technologies, demonstrates that mHDM-FH is preferentially deposited and remains fixed in the kidneys (and liver) for up to 4 days. Extended dosing using an AAV- human HDM-FH (hHDM-FH) construct achieved complete normalisation of C3 levels in CFH-/- mice for 3 months and was associated with a significant reduction in glomerular C3 staining. Our data demonstrate the ability of gene therapy delivery of mini-FH constructs to enhance complement regulation in vivo and support the application of this approach as a novel treatment strategy in diseases such as C3G.

Potential Efficacy of Chitosan-Poly (Lactide-Co-Glycolide)-Encapsulated Trivalent Immersion Vaccine in Olive Flounder (Paralichthys olivaceus) Against Viral Hemorrhagic Septicemia Virus, Streptococcus parauberis Serotype I, and Miamiensis avidus (Scuticociliate).

Olive flounder (Paralichthys olivaceus) is the most valuable aquaculture species in Korea, corresponding to ~60% of its total production. However, infectious diseases often break out among farmed flounders, causing high mortality and substantial economic losses. Although some deleterious pathogens, such as Vibrio spp. and Streptococcus iniae, have been eradicated or contained over the years through vaccination and proper health management, the current disease status of Korean flounder shows that the viral hemorrhagic septicemia virus (VHSV), Streptococcus parauberis, and Miamiensis avidus are causing serious disease problem in recent years. Furthermore, these three pathogens have differing optimal temperature and can attack young fingerlings and mature fish throughout the year-round culture cycle. In this context, we developed a chitosan-poly(lactide-co-glycolide) (PLGA)-encapsulated trivalent vaccine containing formalin-killed VHSV, S. parauberis serotype-I, and M. avidus and administered it to olive flounder fingerlings by immersion route using a prime-boost strategy. At 35 days post-initial vaccination, three separate challenge experiments were conducted via intraperitoneal injection with the three targeted pathogens at their respective optimal temperature. The relative percentages of survival were 66.63%, 53.3%, and 66.75% in the group immunized against VHSV, S. parauberis serotype-I, and M. avidus, respectively, compared to the non-vaccinated challenge (NVC) control group. The immunized fish also demonstrated significantly (p < 0.05) higher specific antibody titers in serum and higher transcript levels of Ig genes in the mucosal and systemic tissues than those of NVC control fish. Furthermore, the study showed significant (p < 0.05) upregulation of various immune genes in the vaccinated fish, suggesting induction of strong protective immune response, ultimately leading to improved survival against the three pathogens. Thus, the formulated mucosal vaccine can be an effective prophylactic measure against VHS, streptococcosis, and scuticociliatosis diseases in olive flounder.

CD38 Defines a Subset of B Cells in Rainbow Trout Kidney With High IgM Secreting Capacities.

CD38 is a multifunctional molecule that functions both as a transmembrane signaling receptor and as an ectoenzyme with important roles in cell adhesion, calcium regulation and signal transduction. Within the B cell linage, CD38 is expressed in diverse murine B cell subsets, with highest levels in innate B cell subpopulations such as marginal zone (MZ) B cells or B1 cells. In humans, however, CD38 is transiently expressed on early lymphocyte precursors, is lost on mature B cells and is consistently expressed on terminally differentiated plasma cells. In the present work, we have identified two homologues of mammalian CD38 in rainbow trout (Oncorhynchus mykiss), designating them as CD38A and CD38B. Although constitutively transcribed throughout different tissues in homeostasis, both CD38A and CD38B mRNA levels were significantly up-regulated in head kidney (HK) in response to a viral infection. In this organ, after the generation of a specific monoclonal antibody (mAb) against CD38A, the presence of CD38A+ populations among IgM+ B cells and IgM- leukocytes was investigated by flow cytometry. Interestingly, the percentage of IgM+CD38A+ B cells increased in response to an in vitro stimulation with inactivated Aeromonas salmonicida. Finally, we demonstrated that HK IgM+CD38A+ B cells had an increased IgM secreting capacity than that of cells lacking CD38A on the cell surface, also showing increased transcription levels of genes associated with B cell differentiation. This study strongly suggests a role for CD38 on the B cell differentiation process in teleosts, and provides us with novel tools to discern between B cell subsets in these species.

Acute kidney injury in a mouse model of meningococcal disease.

INTRODUCTION: Meningococcal disease is associated with high mortality. When acute kidney injury (AKI) occurs in patients with severe meningococcal disease, it is typically attributable to sepsis, although meningococcal disease and lipopolysaccharide release are rarely investigated. Therefore, we evaluated renal tissue in a mouse model of meningococcal disease. METHODS: Female BALB/c mice were induced to AKI by meningococcal challenge. Markers of renal function were evaluated in infected and control mice. RESULTS: In the infected mice, serum concentrations of tumor necrosis factor alpha, interferon gamma, interleukins (IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-10, and IL-12), and granulocyte-macrophage colony-stimulating factor were elevated, as was renal interstitial infiltration with lymphocytes and neutrophils (p < 0.01 for the latter). Histological analysis showed meningococcal microcolonies in the renal interstitium, without acute tubular necrosis. Infected mice also showed elevated renal expression of toll-like receptor 2, toll-like receptor 4, and Tamm-Horsfall protein. The expression of factors in the intrinsic pathway of apoptosis was equal to or lower than that observed in the control mice. Urinary sodium and potassium were also lower in infected mice, probably due to a tubular defect. CONCLUSION: Our findings corroborate those of other studies of AKI in sepsis. To our knowledge, this is the first time that meningococci have been identified in renal interstitium and that the resulting apoptosis and inflammation have been evaluated. However, additional studies are needed in order to elucidate the mechanisms involved.

COVID-19 Modulates Inflammatory and Renal Markers That May Predict Hospital Outcomes among African American Males.

BACKGROUND AND OBJECTIVES: African Americans and males have elevated risks of infection, hospitalization, and death from SARS-CoV-2 in comparison with other populations. We report immune responses and renal injury markers in African American male patients hospitalized for COVID-19. METHODS: This was a single-center, retrospective study of 56 COVID-19 infected hospitalized African American males 50+ years of age selected from among non-intensive care unit (ICU) and ICU status patients. Demographics, hospitalization-related variables, and medical history were collected from electronic medical records. Plasma samples collected close to admission (≤2 days) were evaluated for cytokines and renal markers; results were compared to a control group (n = 31) and related to COVID-19 in-hospital mortality. RESULTS: Among COVID-19 patients, eight (14.2%) suffered in-hospital mortality; seven (23.3%) in the ICU and one (3.8%) among non-ICU patients. Interleukin (IL)-18 and IL-33 were elevated at admission in COVID-19 patients in comparison with controls. IL-6, IL-18, MCP-1/CCL2, MIP-1α/CCL3, IL-33, GST, and osteopontin were upregulated at admission in ICU patients in comparison with controls. In addition to clinical factors, MCP-1 and GST may provide incremental value for risk prediction of COVID-19 in-hospital mortality. CONCLUSIONS: Qualitatively similar inflammatory responses were observed in comparison to other populations reported in the literature, suggesting non-immunologic factors may account for outcome differences. Further, we provide initial evidence for cytokine and renal toxicity markers as prognostic factors for COVID-19 in-hospital mortality among African American males.