Combinations of registered drugs reduce treatment times required to deplete Wolbachia in the Litomosoides sigmodontis mouse model.

Filarial parasites can be targeted by antibiotic treatment due to their unique endosymbiotic relationship with Wolbachia bacteria. This finding has led to successful treatment strategies in both, human onchocerciasis and lymphatic filariasis. A 4-6 week treatment course using doxycycline results in long-term sterility and safe macrofilaricidal activity in humans. However, current treatment times and doxycycline contraindications in children and pregnant women preclude widespread administration of doxycycline in public health control programs; therefore, the search for shorter anti-wolbachial regimens is a focus of ongoing research. We have established an in vivo model for compound screening, using mice infected with Litomosoides sigmodontis. We could show that gold standard doxycycline treatment did not only deplete Wolbachia, it also resulted in a larval arrest. In this model, combinations of registered antibiotics were tested for their anti-wolbachial activity. Administration of rifamycins in combination with doxycycline for 7 days successfully depleted Wolbachia by > 2 log (>99% reduction) and thus resulted in a significant reduction of the treatment duration. Using a triple combination of a tetracycline (doxycycline or minocycline), a rifamycin and a fluoroquinolone (moxifloxacin) led to an even greater shortening of the treatment time. Testing all double combinations that could be derived from the triple combinations revealed that the combination of rifapentine (15mg/kg) and moxifloxacin (2 x 200mg/kg) showed the strongest reduction of treatment time in intraperitoneal and also oral administration routes. The rifapentine plus moxifloxacin combination was equivalent to the triple combination with additional doxycycline (>99% Wolbachia reduction). These investigations suggest that it is possible to shorten anti-wolbachial treatment times with combination treatments in order to achieve the target product profile (TPP) requirements for macrofilaricidal drugs of no more than 7-10 days of treatment.

Spleen tyrosine kinase (SYK) is a potential target for the treatment of cutaneous lupus erythematosus patients.

Spleen tyrosine kinase (SYK) is a protein kinase involved in cell proliferation and the regulation of inflammatory pathways. Due to the increasing evidence that kinase inhibitors have potential as specific anti-inflammatory drugs, we have investigated the potential for SYK inhibition as a therapeutic target in autoimmune diseases, particularly cutaneous lupus erythematosus (CLE). Skin samples of patients with different CLE subtypes and appropriate controls were analysed for the expression of SYK and SYK-associated pro-inflammatory mediators via gene expression analysis and immunohistochemistry. The functional role of SYK in keratinocytes was investigated in vitro, using LE-typical pro-inflammatory stimuli and a selective inhibitor of SYK. SYK-associated genes are strongly upregulated in CLE skin lesions. Importantly, phosphorylated SYK (pSYK) is strongly expressed by several immune cell types and also keratinocytes in CLE skin. In vitro, immunostimulatory nucleic acids are capable of inducing SYK phosphorylation in keratinocytes leading to the induction of pro-inflammatory cytokines, while small-molecule SYK inhibition decreases the expression of these proteins. The results demonstrate that pSYK is expressed by immune cells and keratinocytes in skin lesions of CLE patients. LE-typical stimuli induce the expression of pSYK in vitro. Small-molecule SYK inhibition leads to a reduction of pSYK expression and downregulation of pro-inflammatory cytokines in keratinocytes. We therefore believe that pSYK provides a potential future drug target for the treatment of patients who suffer from CLE and related skin disorders. Specifically, our study reveals evidence supporting the use of topical SYK inhibitors in treating lupus.

IL-36γ (IL-1F9) is a biomarker for psoriasis skin lesions.

In recent years, different genes and proteins have been highlighted as potential biomarkers for psoriasis, one of the most common inflammatory skin diseases worldwide. However, most of these markers are not only psoriasis-specific but also found in other inflammatory disorders. We performed an unsupervised cluster analysis of gene expression profiles in 150 psoriasis patients and other inflammatory skin diseases (atopic dermatitis, lichen planus, contact eczema, and healthy controls). We identified a cluster of IL-17/tumor necrosis factor-α (TNFα)-associated genes specifically expressed in psoriasis, among which IL-36γ was the most outstanding marker. In subsequent immunohistological analyses, IL-36γ was confirmed to be expressed in psoriasis lesions only. IL-36γ peripheral blood serum levels were found to be closely associated with disease activity, and they decreased after anti-TNFα-treatment. Furthermore, IL-36γ immunohistochemistry was found to be a helpful marker in the histological differential diagnosis between psoriasis and eczema in diagnostically challenging cases. These features highlight IL-36γ as a valuable biomarker in psoriasis patients, both for diagnostic purposes and measurement of disease activity during the clinical course. Furthermore, IL-36γ might also provide a future drug target, because of its potential amplifier role in TNFα- and IL-17 pathways in psoriatic skin inflammation.