Infections With the Tick-Borne Bacterium "Candidatus Neoehrlichia mikurensis” Mimic Noninfectious Conditions in Patients With B Cell Malignancies or Autoimmune Diseases

We present a comprehensive study of a new infectious disease in immune compromised patients, neoehrlichiosis. The clinical picture of the disease can be misleading because the symptoms may be misinterpreted to be a worsening of the underlying diseas

The Staphylococcus aureus Response to Unsaturated Long Chain Free Fatty Acids: Survival Mechanisms and Virulence Implications

Staphylococcus aureus is an important human commensal and opportunistic pathogen responsible for a wide range of infections. Long chain unsaturated free fatty acids represent a barrier to colonisation and infection by S. aureus and act as an antimicrobial component of the innate immune system where they are found on epithelial surfaces and in abscesses. Despite many contradictory reports, the precise anti-staphylococcal mode of action of free fatty acids remains undetermined. In this study, transcriptional (microarrays and qRT-PCR) and translational (proteomics) analyses were applied to ascertain the response of S. aureus to a range of free fatty acids. An increase in expression of the σB and CtsR stress response regulons was observed. This included increased expression of genes associated with staphyloxanthin synthesis, which has been linked to membrane stabilisation. Similarly, up-regulation of genes involved in capsule formation was recorded as were significant changes in the expression of genes associated with peptidoglycan synthesis and regulation. Overall, alterations were recorded predominantly in pathways involved in cellular energetics. In addition, sensitivity to linoleic acid of a range of defined (sigB, arcA, sasF, sarA, agr, crtM) and transposon-derived mutants (vraE, SAR2632) was determined. Taken together, these data indicate a common mode of action for long chain unsaturated fatty acids that involves disruption of the cell membrane, leading to interference with energy production within the bacterial cell. Contrary to data reported for other strains, the clinically important EMRSA-16 strain MRSA252 used in this study showed an increase in expression of the important virulence regulator RNAIII following all of the treatment conditions tested. An adaptive response by S. aureus of reducing cell surface hydrophobicity was also observed. Two fatty acid sensitive mutants created during this study were also shown to diplay altered pathogenesis as assessed by a murine arthritis model. Differences in the prevalence and clinical importance of S. aureus strains might partly be explained by their responses to antimicrobial fatty acids

Modulation of the inflammatory responses in Staphylococcus aureus arthritis and sepsis

Bacterial arthritis is a severe, rapidly progressing erosive disease with high mor-bidity and mortality. Staphylococcus aureus is the most common bacterium causing this ailment. Systemic antibiotic treat-ment, with or without drainage, is the dominant therapeutic procedure. However, despite the use of antimicrobial treatment, a mortality rate of up to 20% and joint destruction are typical. The host immune response accounts for many of the consequences of infection.Using the model of haematogenously acquired S. aureus arthritis and sepsis we analysed host response mechanisms, and performed therapeutic approaches. Manipulations directed towards mediators of inflammation affect the course of the disease. Inhibitors of nitric oxide synthase aggravated S. aureus arthritis, presumably by impairing bactericidal capacity of macrophages. Furthermore, complement depletion disturbed the opsonization of bacteria yielding impaired phagocytic activity of phagocytes, and interacted with the process of extravasation and migration of polymorphonuclear cells, thus aggravating the clinical course of the disease. Blocking of complement receptor 1 (CD35) induced an increased severity of arthritis, probably via vasodilatation and neutrophil migration/extravasation augmenting action. Treatment with heparin aggravated S. aureus arthritis, possibly interacting with the complement system and opsonophagocytosis. We provide the evidence that co-treatment of systemic corticosteroids with the conventional therapy of septic arthritis diminishes disability and severity of the disease and increases survival. This effect seems to be dependent on the downregulatory effect of corticosteroids on the proliferation/differentiation of lymphocytes.Altogether, this thesis adds to the comprehension of the overall complexity of immune responses during sepsis and septic arthritis and indicates potential therapeutic modalities

Inhibition of nitric oxide synthase (NOS) aggravates Staphylococcus aureus septicaemia and septic arthritis

The aim of this study was to assess the role of NO and its metabolites in bacterial arthritis. The murine model of haematogenously acquired septic arthritis was used. Swiss mice treated with NOS inhibitors (NG-monomethyl-l-arginine or Nω-nitro-l-arginine methyl ester) were injected intravenously with toxic shock syndrome toxin-1 (TSST-1) producing Staphylococcus aureus LS-1. Arthritis was evaluated clinically and histopathologically. Serum cytokine levels, bacterial isolates and intracellular capacity of macrophages to kill bacteria were also analysed. The frequency of arthritis in mice treated with NOS inhibitors was three to four-fold higher than that in non-treated controls (75% versus 20%). The severity of arthritis, expressed as mean arthritic index, was 1.4 and 0.4, respectively. Cartilage and/or bone destruction occurred in 63% of NOS inhibitor-treated mice, but only in 10% of controls. Also, the cumulative septicaemia-induced mortality was clearly higher in mice treated with NOS inhibitors compared with non-treated controls. Intracellular killing capacity of the peritoneal macrophages, treated in vitro with NOS inhibitors, was decreased. Thus, 24 h after bacterial inoculation peritoneal macrophages pretreated with NOS inhibitors killed more than 10 times less bacteria than the control ones (P < 0.01). We conclude that NOS inhibitors aggravate S. aureus arthritis, possibly by inducing impairment of the intracellular killing capacity of macrophages

Cloxacillin control of experimental arthritis induced by SEC +

Staphylococcus aureus is the most common agent of septic arthritis (SA) that is a severe, rapidly progressive and erosive disease. In this work we investigated the clinical, histopathological and immunological characteristics of the SA triggered by an enterotoxin C producer S. aureus strain. The effect of a β-lactamic antibiotic over disease evolution and cytokine production was also evaluated. After confirmation that ATCC 19095 SEC+ strain preserved its ability to produce enterotoxin C, this bacteria was used to infect C57BL/6 male mice. Body weight, clinical score and disease prevalence were daily evaluated during 14 days. Cytokine production by splenocytes, cytokine mRNA expression in arthritic lesions, transcription factors mRNA expression in inguinal lymph nodes and histopathological analysis were performed 7 and 14 days after infection. ATCC 19095 SEC+ strain caused a severe arthritis characterized by weight loss, high clinical scores and a 100% disease prevalence. Histopathological analysis revealed inflammation, pannus formation and bone erosion. Arthritis aggravation was associated with elevated production of pro-inflammatory cytokines, higher local mRNA expression of these cytokines and also higher mRNA expression of T-bet, ROR-γ and GATA-3. Disease control by cloxacillin was associated with decreased production of pro-inflammatory cytokines but not of IL-10. These findings indicate that the ATCC 19095 SEC+ strain is able to initiate a severe septic arthritis in mice associated with elevated cytokine production that can be, however, controlled by cloxacillin

Infections with the tick-borne bacterium "Candidatus Neoehrlichia mikurensis" mimic noninfectious conditions in patients with B cell malignancies or autoimmune diseases

BACKGROUND Candidatus Neoehrlichia mikurensis is a newly discovered noncultivatable bacterium spread among ticks and rodents in Europe and Asia that can infect humans, particularly immunocompromised patients. METHODS We compiled clinical and laboratory data from 11 patients with hematological malignances or autoimmune diseases who were diagnosed with Candidatus N. mikurensis infection in Europe 2010-2013. Both published (6) and unpublished cases (5) were included. RESULTS The patients had a median age of 67, were mostly male (8/11), and resided in Sweden, Switzerland, Germany, and the Czech Republic. All but one had ongoing or recent immune suppressive treatment and a majority were splenectomized (8/11). Less than half of them recalled tick exposure. The most frequent symptoms were fever (11/11), localized pain afflicting muscles and/or joints (8/11), vascular and thromboembolic events (6/11), that is, deep vein thrombosis (4), transitory ischemic attacks (2), pulmonary embolism (1), and arterial aneurysm (1). Typical laboratory findings were elevated C-reactive protein, leukocytosis with neutrophilia, and anemia. Median time from onset of symptoms to correct diagnosis was 2 months. In at least 4 cases, the condition was interpreted to be due to the underlying disease, and immunosuppressive therapy was scheduled. All patients recovered completely when doxycycline was administered. CONCLUSIONS Candidatus N. mikurensis is an emerging tick-borne pathogen that may give rise to a systemic inflammatory syndrome in persons with hematologic or autoimmune diseases that could be mistaken for recurrence of the underlying disease and/or unrelated arteriosclerotic vascular events. Awareness of this new pathogen is warranted among rheumatologists, hematologists, oncologists, and infectious disease specialists