Nephritis-associated plasmin receptor (NAPlr) positive glomerulonephritis caused by Aggregatibacter actinomycetemcomitans bacteremia: A case report.

Infection-related glomerulonephritis (IRGN) develops after various infections. It was previously thought to be caused by Streptococcus species alone but can also be caused by other pathogens. Nephritis-associated plasmin receptor (NAPlr) was discovered as a candidate nephritis-inducing factor in acute post-streptococcal glomerulonephritis. More recently, renal lesions caused by other pathogens were found to be positive for the same molecular marker. We report the case of a 64-year-old man who experienced repeated fever for several months and presented with progressively-deteriorating renal function. He had previously undergone aortic valve replacement. Aggregatibacter actinomycetemcomitans, a component of the oral flora, was detected in a blood culture. Renal biopsy showed diffuse proliferative glomerulonephritis. Immunofluorescence staining of the kidney specimen was positive for immunoglobulins, complements, and NAPlr. The patient was diagnosed with infectious endocarditis and IRGN. Six weeks of intravenous antibiotic therapy improved the patient's clinical condition and kidney function. In this case, IRGN was caused by a rare pathogen. This is the first published case to show NAPlr positivity in the glomeruli after systemic infection with the periodontal bacteria, Aggregatibacter actinomycetemcomitans. This case and subsequent research might expand the concept of IRGN, anchored by NAPlr as a key diagnostic biomarker.
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Protective effects of the angiotensin type 1 receptor antagonist losartan in infection-induced and arthritis-associated alveolar bone loss.

BACKGROUND AND OBJECTIVE: The angiotensin type 1 (AT1) receptor has been implicated in the pathogenesis of inflammatory bone disorders. This study aimed to investigate the effect of an AT1 receptor antagonist in infection-induced and arthritis-associated alveolar bone loss in mice. MATERIAL AND METHODS: Mice were subjected to Aggregatibacter actinomycetemcomitans oral infection or antigen-induced arthritis and treated daily with 10 mg/kg of the prototype AT1 antagonist, losartan. Treatment was conducted for 30 d in the infectious condition and for 17 d and 11 d in the preventive or therapeutic regimens in the arthritic model, respectively. The mice were then killed, and the maxillae, serum and knee joints were collected for histomorphometric and immunoenzymatic assays. In vitro osteoclast assays were performed using RAW 264.7 cells stimulated with A. actinomycetemcomitans lipopolysacharide (LPS). RESULTS: Arthritis and A. actinomycetemcomitans infection triggered significant alveolar bone loss in mice and increased the levels of myeloperoxidase and of TRAP(+) osteoclasts in periodontal tissues. Losartan abolished such a phenotype, as well as the arthritis joint inflammation. Both arthritis and A. actinomycetemcomitans conditions were associated with the release of tumor necrosis factor alpha (TNF-α), interferon-gamma, interleukin-17 and chemokine (C-X-C motif) ligand 1 and an increased RANKL/osteoprotegerin ratio in periodontal tissues, but such expression decreased after losartan treatment, except for TNF-α. The therapeutic approach was as beneficial as the preventive one. In vitro, losartan prevented LPS-induced osteoclast differentiation and activity. CONCLUSION: The blockade of AT1 receptor exerts anti-inflammatory and anti-osteoclastic effects, thus protecting periodontal tissues in distinct pathophysiological conditions of alveolar bone loss.

Inflammatory bone loss in experimental periodontitis induced by Aggregatibacter actinomycetemcomitans in interleukin-1 receptor antagonist knockout mice.

The interleukin-1 receptor antagonist (IL-1Ra) binds to IL-1 receptors and inhibits IL-1 activity. However, it is not clear whether IL-1Ra plays a protective role in periodontal disease. This study was undertaken to compare experimental periodontitis induced by Aggregatibacter actinomycetemcomitans in IL-1Ra knockout (KO) mice and wild-type (WT) mice. Computed tomography (CT) analysis and hematoxylin-and-eosin (H&E) and tartrate-resistant acid phosphatase (TRAP) staining were performed. In addition, osteoblasts were isolated; the mRNA expression of relevant genes was assessed by real-time quantitative PCR (qPCR); and calcification was detected by Alizarin Red staining. Infected IL-1Ra KO mice exhibited elevated (P, <0.05) levels of antibody against A. actinomycetemcomitans, bone loss in furcation areas, and alveolar fenestrations. Moreover, protein for tumor necrosis factor alpha (TNF-α) and IL-6, mRNA for macrophage colony-stimulating factor (M-CSF), and receptor activator of NF-κB ligand (RANKL) in IL-1Ra KO mouse osteoblasts stimulated with A. actinomycetemcomitans were increased (P, <0.05) compared to in WT mice. Alkaline phosphatase (ALP), bone sialoprotein (BSP), osteocalcin (OCN)/bone gla protein (BGP), and runt-related gene 2 (Runx2) mRNA levels were decreased (P, <0.05). IL-1α mRNA expression was increased, and calcification was not observed, in IL-1 Ra KO mouse osteoblasts. In brief, IL-1Ra deficiency promoted the expression of inflammatory cytokines beyond IL-1 and altered the expression of genes involved in bone resorption in A. actinomycetemcomitans-infected osteoblasts. Alterations consistent with rapid bone loss in infected IL-Ra KO mice were also observed for genes expressed in bone formation and calcification. In short, these data suggest that IL-1Ra may serve as a potential therapeutic drug for periodontal disease.

Bacterial promotion of bisphosphonate-induced osteonecrosis in Wistar rats.

Clinically, bisphosphonate-related osteonecrosis (BRON) only occurs in the jaw (BRONJ). We aimed to determine differences between the jaw and other bones, as well as the relationship between periodontal pathogens and BRON. Twelve male Wistar rats were divided into two groups: group Z (n=6) were subcutaneously injected with zoledronic acid weekly for 4 weeks; group C (n=6) were injected with saline. One week after the final injection, rats in both groups were divided into three subgroups: Aa subgroup was injected with freeze-dried Aggregatibacter actinomycetemcomitans into bone marrow of the mandibles and femurs, while CFA and saline subgroups were injected with complete Freund's adjuvant (CFA) or saline using the same protocol. Four weeks after those injections, the rats were euthanized. Areas of osteonecrosis were measured histologically. Statistically, rats in group Z showed significantly wider osteonecrosis areas in both mandibles and femurs with each type of local injection than rats in group C. In group Z, mandibles and femurs stimulated with A. actinomycetemcomitans or CFA had significantly wider osteonecrosis areas than those stimulated with saline. We have developed a rat model with BRONJ-like lesions. Our results showed BRON to develop not only in the jaw but also in other types of bone following an inflammatory stimulus.

Actinobacillus endocarditis associated with hypertrophic cardiomyopathy.

Infective endocarditis can be associated with complex clinical presentations, sometimes with a difficult multi-disciplinary management. Actinobacillus actinomycetemcomitans belongs to the Haemophilus species, Actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens and Kingella species group, responsible for 5% to 10% of infective endocarditis in native heart valves. These organisms have slow fastidious growth pattern, often associated with negative cultures, and cause systemic embolism with abscess formation. The authors present the case of a 59-year-old man, admitted due to fever of unknown origin, with a personal history of obstructive hypertrophic cardiomyopathy and recent dental manipulation. The diagnosis of mitral valve's endocarditis was established after a transoesophageal ecocardiography, with a late isolation of A actinomycetemcomitans in blood culture. Despite the institution of antibiotic therapy, the patient suffered from multiple episodes of septic embolism: skin, mucosae, cerebral abscesses, spondylodiscitis and uveitis. He was submitted to heart surgery with miectomy and replacement of the native mitral valve by a mechanical prosthesis, while on antibiotics.

Pyogenic cervical spondylitis caused by Pasteurella haemolytica attributed to excessive contact with dogs.

The bacterium Pasteurella haemolytica is resident in the oral cavities of dogs and cats and is often a cause of zoonotic infection. However, it is rare for it to be the pathogenic bacteria behind pyogenic spondylitis, and few studies have been conducted on it. This article reports a case of pyogenic cervical spondylitis thought to be caused by excessive contact with pet dogs.A 52-year-old man reported neck pain and pain in the right upper limb. He was admitted after plain radiographs and magnetic resonance imaging suggested pyogenic spondylitis. Pasteurella haemolytica was detected by needle aspiration biopsy of the intervertebral disk. Because the patient owned 2 dogs and frequently kissed them on the mouth, the cause of infection was thought to be excessive contact with pet dogs. Symptoms were alleviated with bed rest and administration of antibiotics with a higher sensitivity to this bacterium.

Experimental infection of Peste des Petit Ruminant virus and Mannheimia haemolytica A2 in goats: immunolocalisation of Mannheimia haemolytica antigens.

Nigerian strain of Peste des Petit Ruminant (PPR) virus and Mannheimia haemolytica (MH) biotype A serotype 2, was used successfully to reproduce a concurrent disease in West African Dwarf goats. The development of the various pathological features were studied at regular intervals following infection. The acute inflammatory reaction which had developed by day 3 after initial infection was characterised by flooding of the alveoli by neutrophils, oedema, hemorrhage and syncytial cells together with a moderate bronchial and bronchiolar epithelial necrosis. This progressed to a milder acute broncho interstitial pneumonia with giant cells. At this stage, the mucosal immunity were well developed especially the aggregate form of NALT and more of nodular forms of BALT. The organisms were demonstrated with strong immunostaining in the necrotic center, necrotic alveolar wall, fibrin, serous exudate, and degenerated leukocyte in the alveoli and respiratory airways. The bacterial antigens were observed as a strong immunostaining in the blood vessels of the nasal septum, sinusoid in the liver and interstium of the kidney, cytoplasm of alveolar macrophages, pneumocytes, bronchial and bronchiolar epithelium, in the monocytes in the blood vessels. These findings confirmed the enhancement of MH tropism especially in the respiratory tract, liver and kidney. It also showed that West african dwarf goats are highly susceptible to the intratracheal combined infection of PPR virus and MH. The fact that the infection induces strong mucosal responses, this phenomenon can be explored in Africa with the use of combined PPR virus and MH intranasal vaccines to curtail the menace of pneumonia associated with the combined infection on field.

Aggregatibacter actinomycetemcomitans accelerates atherosclerosis with an increase in atherogenic factors in spontaneously hyperlipidemic mice.

Cariogenic and periodontal pathogens are thought to be etiological factors in the development of cardiovascular disease. We assessed the involvement of the periodontal pathogen Aggregatibacter actinomycetemcomitans and cariogenic pathogen Streptococcus mutans in the development of atherosclerosis in apolipoprotein E-deficient spontaneously hyperlipidemic (Apoe(shl)) mice. The mice were treated intravenously with A. actinomycetemcomitans HK1651, S. mutans GS-5, or phosphate-buffered saline three times a week for 3 weeks and killed at 15 weeks of age. The areas of the aortic sinus that were covered with atherosclerotic plaque were significantly larger in Apoe(shl) mice challenged with A. actinomycetemcomitans compared with S. mutans- or vehicle-challenged mice. Aggregatibacter actinomycetemcomitans challenge increased serum high-sensitive C-reactive protein and lipopolysaccharide levels. Bacterial DNA was detected in the blood, heart, and spleen, but not in the liver. Furthermore, serum interleukin-6 (IL-6), IL-8, tumor necrosis factor alpha, and MCP-1 levels and Toll-like receptor (TLR)2, TLR4, ICAM-1, E-selectin, P-selectin, LOX-1, HSP60, CCL19, CCL21, CCR7, and MCP-1 expressions in the aorta were significantly increased in mice challenged with A. actinomycetemcomitans. These results suggest that systemic infection with A. actinomycetemcomitans accelerates atherosclerosis in Apoe(shl) mice by exposing the whole microorganisms or their products, followed by initiating inflammation. Increases in proatherogenic factors may explain the aggravation of atherosclerosis by A. actinomycetemcomitans infection.

Effects of exposure to calves persistently infected with bovine viral diarrhea virus type 1b and subsequent infection with Mannheima haemolytica on clinical signs and immune variables: model for bovine respiratory disease via viral and bacterial interaction.

The objective was to determine effects of an intratracheal Mannheimia haemolytica challenge after 72-h exposure to bovine viral diarrhea virus type 1b (BVDV1b) persistently infected (PI) calves on serum antibody production, white blood cell count (WBC), cytokine concentrations, and blood gases in feedlot steers. Twenty-four steers (initial BW = 314 +/- 31 kg) were randomly allocated to 1 of 4 treatments (6 steers/treatment) arranged as a 2 x 2 factorial. Treatments were 1) steers not exposed to steers PI with BVDV nor challenged with M. haemolytica (control; CON); 2) steers exposed to 2 steers PI with BVDV for 72 h (BVD); 3) steers intratracheally challenged with M. haemolytica (MH); and 4) steers exposed to 2 steers PI with BVDV for 72 h and challenged with M. haemolytica (BVD+MH). There were 12 h between exposure to PI steers and challenge with M. haemolytica. Rectal temperature was increased (P < 0.001) for MH and BVD+MH during the initial 24 h after the M. haemolytica challenge. For MH and BVD+MH, total WBC count was increased (P < 0.01) at 36 h post M. haemolytica challenge compared with CON, whereas in BVD steers, WBC count was decreased (P < 0.01). Total lymphocyte count was increased (P = 0.004) during the initial 72 h post BVDV exposure for the BVD and BVD+MH groups compared with MH and CON, and this difference remained at 96 h post M. haemolytica challenge. An increased (P < 0.001) total neutrophil count was observed during the initial 36 h for the MH group and at 72 h for the BVD+MH challenge group. Interleukin 1beta, IL-6, and tumor necrosis factor alpha (TNFalpha) concentrations were greater (P

Mixed infection involving Actinomyces, Aggregatibacter, and Fusobacterium species presenting as perispinal tumor.

A representative case in which a polymicrobial infection involving Fusobacterium nucleatum, Actinomyces israelii and Aggregatibacter (formerly Actinobacillus) actinomycetemcomitans was initially diagnosed as malignancy in an edentulous patient. Additional history obtained after the nature of the syndrome was elucidated revealed that he had had his two remaining teeth extracted four months prior to this episode.

Molecular and ultrastructural studies of the fibrotic lesions of bovine focal proliferative fibrogranulomatous panniculitis (Lechiguana).

This work aimed to investigate some aspects related to the pathogenicity of Lechiguana, a bovine fibroproliferative lesion characterized by rapid collagen accumulation. Light and transmission electron microscopy and in situ hybridization studies were performed in order to elucidate the fibrogenic activity of this lesion. The characterization of fibroblastic plasticity in the lesion was done by immunohistochemical study for alpha-smooth-muscle cell actin. The ovoid-shaped cells presented positive reaction for alpha-smooth-muscle cell actin in their cytoplasm and, at the electron-microscopic level demonstrated basal lamina-like material adjacent to the external surface and collagen fibrils that corresponded to a cell population phenotypically similar to the myofibroblast. We also investigated alpha1 collagen type I mRNA at different times of evolution of Lechiguana lesions, using isotopic and non-isotopic in situ hybridization. The results strongly suggest the involvement of a myofibroblast-like cell population that expresses mRNA for type I collagen and is probably associated with the increase of collagen deposition.