Histoplasma Virulence and Host Responses

Histoplasma capsulatum is the most prevalent cause of fungal respiratory disease. The disease extent and outcomes are the result of the complex interaction between the pathogen and a host's immune system. The focus of our paper consists in presenting the current knowledge regarding the multiple facets of the dynamic host-pathogen relationship in the context of the virulence arsenal displayed by the fungus and the innate and adaptive immune responses of the host

Nitric Oxide Releasing Nanoparticles Are Therapeutic for Staphylococcus aureus Abscesses in a Murine Model of Infection

Staphylococcus aureus (SA) is a leading cause of a diverse spectrum of bacterial diseases, including abscesses. Nitric oxide (NO) is a critical component of the natural host defense against pathogens such as SA, but its therapeutic applications have been limited by a lack of effective delivery options. We tested the efficacy of a NO-releasing nanoparticle system (NO-np) in methicillin-resistant SA (MRSA) abscesses in mice. The results show that the NO-np exert antimicrobial activity against MRSA in vitro and in abscesses. Topical or intradermal NO-np treatment of abscesses reduces the involved area and bacterial load while improving skin architecture. Notably, we evaluated pro- and anti-inflammatory cytokines that are involved in immunomodulation and wound healing, revealing that NO-np lead to a reduction in angiogenesis preventing bacterial dissemination from abscesses. These data suggest that NO-np may be useful therapeutics for microbial abscesses

THE IMPACT OF ANTIFUNGALS ON TOLL-LIKE RECEPTORS

Fungi are increasingly recognized as major pathogens in immunocompromised individuals. The most common invasive fungal infections are caused by Candida spp., Aspergillus spp. and Cryptococcus spp. Amphotericin B has remained the cornerstone of therapy against many fulminant fungal infections but its use is limited by its multitude of side effects. Echinocandins are a newer class of antifungal drugs with activity against Candida spp. and Aspergillus spp. and constitutes an alternative to amphotericin B due to superior patient tolerability and fewer side effects. Due to their excellent bioavailability and oral availability, azoles continue to be heavily used for simple, such as fluconazole for candidal vaginitis, and complex diseases, such as voriconazole for aspergilloisis. The objective of this paper is to present current knowledge regarding the multiple interactions between the broad spectrum antifungals and the innate immune response, primarily focusing on the toll-like receptors

Sustained Nitric Oxide-Releasing Nanoparticles Interfere with Methicillin-Resistant Staphylococcus aureus Adhesion and Biofilm Formation in a Rat Central Venous Catheter Model.

Staphylococcus aureus is frequently isolated in the setting of infections of indwelling medical devices, which are mediated by the microbe\u27s ability to form biofilms on a variety of surfaces. Biofilm-embedded bacteria are more resistant to antimicrobial agents than their planktonic counterparts and often cause chronic infections and sepsis, particularly in patients with prolonged hospitalizations. In this study, we demonstrate that sustained nitric oxide-releasing nanoparticles (NO-np) interfere with S. aureus adhesion and prevent biofilm formation on a rat central venous catheter (CVC) model of infection. Confocal and scanning electron microscopy showed that NO-np-treated staphylococcal biofilms displayed considerably reduced thicknesses and bacterial numbers compared to those of control biofilms in vitro and in vivo, respectively. Although both phenotypes, planktonic and biofilm-associated staphylococci, of multiple clinical strains were susceptible to NO-np, bacteria within biofilms were more resistant to killing than their planktonic counterparts. Furthermore, chitosan, a biopolymer found in the exoskeleton of crustaceans and structurally integrated into the nanoparticles, seems to add considerable antimicrobial activity to the technology. Our findings suggest promising development and translational potential of NO-np for use as a prophylactic or therapeutic against bacterial biofilms on CVCs and other medical devices

NO-np killed MR<i>SA</i> in subcutaneous abscesses.

<p>(<b>A</b>) Abscess bacterial burden (CFU; colony forming units) in mice infected subcutaneously with 10⁷ MR<i>SA</i> and treated with NO-np is significantly lower than untreated or np-treated mice (<i>n</i> = 20 abscesses per group). Each point represents an abscess. Dashed lines are the averages of the results and error bars denote standard deviations. Asterisks denote <i>P</i> value significance (** <i>P</i><0.001) calculated by analysis of variance and adjusted by use of the Bonferroni correction. (<b>B</b>) Histological analysis of Balb/c mice untreated MR<i>SA</i>-infected, np-treated MR<i>SA</i>-infected, and MR<i>SA</i>-infected treated with NO, day 4. Mice were infected with 10⁷ MR<i>SA</i>. Representative H&E-stained sections of the skin lesions are shown with the <i>Insets</i> showing Gram staining of MR<i>SA</i>. Scale bars: 25 µm.</p

NO-np prevents MR<i>SA</i> collagen degradation in subcutaneous abscesses.

<p>(<b>A</b>) Histological analysis of Balb/c mice untreated MR<i>SA</i>-infected, np-treated MR<i>SA</i>-infected, and MR<i>SA</i>-infected treated with NO-np, day 4. Mice were infected with 10⁷ bacterial cells. The blue stain indicates collagen. Scale bar: 25 µm. (<b>B</b>) Quantitative measurement of collagen intensity in 20 representative fields of the same size for untreated MR<i>SA</i>-infected, np-treated MR<i>SA</i>-infected, and MR<i>SA</i>-infected treated with NO-np. Bars are the averages of the results, and error bars denote standard deviations. Asterisks denote <i>P</i> value significance (*, <i>P</i><0.05 in comparing MR<i>SA</i>-infected np and untreated control groups; **, <i>P</i><0.001 in comparing MR<i>SA</i>-infected NO-np and untreated control groups; #, <i>P</i><0.01 in comparing MR<i>SA</i>-infected np and NO-np groups) calculated by analysis of variance and adjusted by use of the Bonferroni correction.</p

Cytokine levels in abscesses of mice.

<p><i>n</i> = 7 mice per group.</p>a<p>Value significantly greater than the value for control mice (<i>P</i><0.05).</p>b<p>Value significantly less than the value for control mice (<i>P</i><0.05).</p

NO-np inhibits MR<i>SA</i> growth <i>in vitro</i>.

<p>The effect of NO in MR<i>SA</i> growth kinetics after 24 h co-culture was determined using Bioscreen C analysis. MR<i>SA</i> was grown in the absence or presence of nanoparticles with NO (NO-np) or without NO (np). Each point represents the average of four measurements and error bars denote standard deviations.</p

NO-np decreases vascularization in the setting of MR<i>SA</i> abscesses.

<p>Histological analysis of untreated, np-treated and NO-np treated MR<i>SA</i>-infected Balb/c mice, day 4. Mice were infected with 10⁷ MR<i>SA</i>. The brown staining indicates vascularization. Representative CD34-immunostained sections of the skin lesions are shown with the <i>Insets</i> representing Gram of MR<i>SA</i>. White arrows denote Gram positive cocci. Scale bars: 25 µm.</p