Antibacterial agents and innate immunity

On their own, antibacterial agents cannot cure an infectious disease. They need help from the innate immune response followed by the adaptive immune response and inflammatory response. An overview of Toll-Like Receptors (TLR) as key players in the innate immune response is given followed by a review of published results obtained in the authors laboratory related to the effect of several antibacterial agents on the action of bacterial lipopolysaccharide (LPS), a ligand for TLR-4. The results indicated that the antibacterial agents tested were anti-inflammatory. Inflammation is a two edged sword; in moderation it is beneficial, but deleterious if in excess. It is suggested that infectious disease specialists monitor serum proinflammatory cytokine and/or nitric oxide levels of their patients on antibacterial therapy and when needed, treat with a cytokine, a TLR agonist or a TLR antagonist where indicated.Antibacterial agents on their own are not capable of eradicating infections efficiently. Help coming from the patient’s innate immune response followed by the adaptive immune response and inflammatory response is needed. This has been observed in patients with immunodeficiency diseases such as X-Linked Agammaglobulinemia, Chronic Granulomatous Disease and CD40 Ligand Deficiency (1). Treatment of these patients with antibacterial agents might temporarily control the infection. However, recurrences’ always occur

Circulating immune complexes and complement C3 and C4 levels in a selected group of patients with rhinitis in Lebanon

BACKGROUND: A number of reports indicate that circulating immune complexes (CIC) and activation of the complement system contribute to the pathogenesis of Type I allergy. The aim of this study was to investigate the status of CIC in 113 patients with rhinitis in Lebanon and determine complement components C3 and C4 serum levels in the CIC-positive patients. Serum specific IgE antibodies were previously detected and reported in 74 of the 113 patients. METHODS: CIC were detected by polyethylene glycol precipitation and serum C3 and C4 levels quantified by radial immunodiffusion. RESULTS: CIC was positive in 20 of the specific IgE-positive and 13 of the specific IgE-negative patients. C3 and C4 levels were within the normal range in all the 33 CIC-positive patients. CONCLUSIONS: The antibody class that constitutes the complexes does not seem to be IgG or IgM. Moreover, complement activation does not seem to be involved in the allergic reaction since both C3 and C4 levels were normal in all patients. The role of these complexes, if any, in the pathogenesis of rhinitis is yet to be determined

Decrease in Shiga toxin expression using a minimal inhibitory concentration of rifampicin followed by bactericidal gentamicin treatment enhances survival of Escherichia coli O157:H7-infected BALB/c mice

<p>Abstract</p> <p>Background</p> <p>Treatment of <it>Escherichia coli </it>O157:H7 infections with antimicrobial agents is controversial due to an association with potentially fatal sequelae. The production of Shiga toxins is believed to be central to the pathogenesis of this organism. Therefore, decreasing the expression of these toxins prior to bacterial eradication may provide a safer course of therapy.</p> <p>Methods</p> <p>The utility of decreasing Shiga toxin gene expression in <it>E. coli </it>O157:H7 with rifampicin prior to bacterial eradication with gentamicin was evaluated <it>in vitro </it>using real-time reverse-transcription polymerase chain reaction. Toxin release from treated bacterial cells was assayed for with reverse passive latex agglutination. The effect of this treatment on the survival of <it>E. coli </it>O157:H7-infected BALB/c mice was also monitored.</p> <p>Results</p> <p>Transcription of Shiga toxin-encoding genes was considerably decreased as an effect of treating <it>E. coli </it>O157:H7 <it>in vitro </it>with the minimum inhibitory concentration (MIC) of rifampicin followed by the minimum bactericidal concentration (MBC) of gentamicin (> 99% decrease) compared to treatment with gentamicin alone (50-75% decrease). The release of Shiga toxins from <it>E. coli </it>O157:H7 incubated with the MIC of rifampicin followed by addition of the MBC of gentamicin was decreased as well. On the other hand, the highest survival rate in BALB/c mice infected with <it>E. coli </it>O157:H7 was observed in those treated with the <it>in vivo </it>MIC equivalent dose of rifampicin followed by the <it>in vivo </it>MBC equivalent dose of gentamicin compared to mice treated with gentamicin or rifampicin alone.</p> <p>Conclusions</p> <p>The use of non-lethal expression-inhibitory doses of antimicrobial agents prior to bactericidal ones in treating <it>E. coli </it>O157:H7 infection is effective and may be potentially useful in human infections with this agent in addition to other Shiga toxin producing <it>E. coli </it>strains.</p

HLA Allele Associations and V-Beta T-Lymphocyte Expansions in Patients With Psoriasis, Harboring Toxin-Producing Staphylococcus aureus

HLA alleles have been associated with psoriasis. Toxin-producing strains of Staphylococcus aureus behave as superantigens, and if present in patients, might play a role in the exacerbation of psoriatic lesions by activating certain V-beta (Vβ) T-lymphocyte subsets. Allele frequencies in 22 patients and 22 controls (alleles determined by DNA/SSP typing) were used to calculate a relative risk of 4.7 (P < .05) for HLA-Cw6. S aureus was isolated from the throat of 11 patients. Enterotoxins A and C were detected by agglutination in the culture filtrate of one isolate. The enterotoxin A and/or C genes were detected by PCR in 9 isolates, and transcripts were detected by RT-PCR in 7 of them. None of the isolates from controls harbored enterotoxin genes. Vβ expansions were detected by RT-PCR in all 22 patients. Low or no Vβ expansions were obtained in controls. The association of HLA-Cw6 with psoriasis in Lebanese concurs with that reported for other ethnic groups. Toxin-producing isolates that colonize patients might play a role in the exacerbation of psoriatic lesions

Review study on external-hospital bacteria as a source of infection and antimicrobial resistance in Lebanon

Most studies done on bacteria in Lebanon are on hospital isolates. However, someof the sources of hospital isolates might be from contaminated foods and waterthat are imported into hospitals. Studies done in the Department of ExperimentalPathology, Immunology and Microbiology at the American University of Beirut onbacteria isolated from seafood, fruits, vegetables and poultry are reviewed, andattempts made to isolate V. cholerae from various water sources is reported. Theuse of antibacterial agents as food additives for poultry as a contributing factorfor the increase in resistant isolates is demonstrated. Methods to decontaminatefoods prior to getting into the kitchens of hospitals and homes are recommended

Birth weight and melanoma risk: a population-based case–control study

We investigated whether lower birth weight was associated with lower risk of melanoma later in life. This population-based case–control study included all incident cases of histologically verified invasive melanoma diagnosed until 31 December 2003 in the Norwegian population born between 1967 and 1986 (n=709). The control group without malignant disease was established by random sampling from the same source population as the cases (n=108 209). Data on birth weight, gender, mother's residence and parental age at the time of birth were collected from the Medical Birth Registry of Norway and data on cancer from the Cancer Registry of Norway. The Mantel–Haenszel test of linear trend showed no trend in risk across the birth weight categories: individuals in the highest quartile of birth weight (⩾3860 g) had an odds ratio (OR) of 1.19 (95% confidence interval, CI: 0.77–1.84) compared to individuals with birth weight <2500 g. The adjusted OR was 0.81 (95% CI: 0.52–1.26) for birth weight below 2500 g (exposed). Though not statistically significant, the results suggest that low birth weight might influence the risk of melanoma later in life

Bone marrow colony-stimulating factor and tumor resistance-enhancing activity of postendotoxin mouse sera

The passive transfer of postendotoxin mouse serum could enhance nonspecific resistance to the development of TA3-Ha transplantable ascites tumor in mice. The postendotoxin serum was not directly cytotoxic to TA3-Ha tumor cells in vitro, nor did it contain significant amounts of residual endotoxin, but it was rich in colony-stimulating factors (CSFs). High-titer CSF serum could be induced by endotoxic lipopolysaccharide (LPS). Nonendotoxic, lipid-free, and polysaccharide-rich hydrolytic breakdown product of LPS (called PS) was less potent but still active in CSF induction. There was a correlation between the level of CSF stimulation and the capacity of the sera to transfer tumor resistance (TUR). Those LPS preparations that had the highest CSF-inducing capacity were the most potent in TUR enhancement. Suppression of CSF production by treatment with theophylline or epinephrine, enhancers of cyclic AMP/cyclic GMP ratios, lowered the enhancement of TUR by endotoxic LPS. The infection of serum donor mice with bacillus Calmette-Guérin (BCG) 18 days prior to LPS treatment gave the highest serum CSF levels and the most potent TUR-inducing serum preparation. Even more notable was the finding that the nontoxic PS preparation could replace toxic LPS in the above BCG-LPS system. The serum harvested from BCG-infected mice 2 hr after PS injection was similarly effective in the passive transfer of TUR

Epstein-Barr virus DNA modulates regulatory T-cell programming in addition to enhancing interleukin-17A production via Toll-like receptor 9.

Infection with the Epstein-Barr virus (EBV) has been associated with several autoimmune diseases including rheumatoid arthritis (RA). We have previously reported that DNA from this virus enhances production of the pro-autoimmune interleukin 17A (IL-17A) in mice. In this study we assessed the effect of EBV DNA on regulatory T cell programming and examined whether it mediated its effects via Toll-like receptor 9 (TLR9) in mice; moreover, we evaluated whether EBV DNA in humans had similar effects to those seen in mice. For this purpose, we assessed the linearity of the correlation between EBV DNA and IL-17A levels in RA subjects and matched controls. A modulatory effect for the viral DNA was observed for regulatory T cell markers with an inhibitory effect observed for CTLA4 expression in the EBV DNA-treated mice. To examine whether TLR9 mediated the detection of EBV DNA and enhancement of IL-17A production, mouse peripheral blood mononuclear cells were treated with the DNA in the presence or absence of the TLR9 inhibitor ODN 2088. Subsequently, IL-17A production from these cells was assessed. Treatment with the TLR9 inhibitor resulted in a significant decrease in IL-17A production indicating that TLR9 is involved in this pathway. In human subjects, examining the linearity of the correlation between EBV DNA and IL-17A levels in RA subjects showed a propensity for linearity that was not observed in controls. Our data thus indicates that EBV DNA itself acts as a modulator of the Th17 compartment as well as that of regulatory T cell mechanisms. The involvement of TLR9 in the EBV DNA-triggered induction of IL-17A suggests therapeutic targeting of this endosomal receptor in EBV positive subjects with an autoimmune flare-up or possibly for prophylactic purposes