Efficacy of PTX3 and Posaconazole Combination in a Rat Model of Invasive Pulmonary Aspergillosis

Abstract

Posaconazole is currently used for the prophylaxis of invasive pulmonary aspergillosis (IPA). Limitations to posaconazole usage are drug-drug interactions and side effects. PTX3 is an innate immunity glycoprotein with opsonic activity, proven to be protective in IPA animal models. This study investigated the combination of posaconazole with PTX3. The results indicate synergy between PTX3 and posaconazole against aspergillosis, suggesting that a combination of reduced doses of posaconazole with the immune response enhancer PTX3 might represent a treatment option with a higher therapeutic index than posaconazole.

Host Genetic Signatures of Susceptibility to Fungal Disease

“…Although data in the clinical setting is so far lacking, these observations support the potential applicability of PTX3 in novel prophylactic or therapeutic approaches for IPA in patients at-risk (Carvalho et al 2012a). As stated above, the combined use of antifungal therapy and PTX3 treatment has been found to improve the efficacy of the drug alone in animal models of IPA (Lo Giudice et al 2012;Marra et al 2014).…”

“…The proficiency of fungal recognition and interaction with the membrane-associated PRRs also relies to a large extent on the opsonization by different families of soluble pattern recognition molecules, including collectins, pentraxins, ficolins and components of the complement pathway (Bidula and Schelenz 2016). Of note, studies have highlighted that these molecules may be exploited as a possible alternative or adjuvants to currently available antifungal therapy to increase their efficacy (Lo Giudice et al 2012;Marra et al 2014). Besides pathogen-derived molecules, PRRs are also critically important in responding to products released from damaged host cells during infection, including nucleic acids, alarmins and metabolic products, collectively termed damage-associated molecular patterns (DAMPs) .…”

The complement system in Aspergillus fumigatus infections and its crosstalk with pentraxins

“…Furthermore, PTX3 protected BM-transplanted and murine cytomegalovirus (MCMV)-infected mice from A. fumigatus superinfections [137], and had therapeutic activity in animal models of chronic lung infection by Pseudomonas aeruginosa, a major cause of morbidity in cystic fibrosis, a condition that predisposes to IPA [138]. Noticeably, the exogenous protein retained its protective properties in the combination therapy, whereby in rodent models of IPA it enhanced or even synergized with clinically established antifungal drugs, including the polyene amphotericin B [139], and the triazole voriconazole [140] and posaconazole [141]. Given the current limitations to the use of antifungals, mostly due to drug-drug interactions and both acute and chronic toxicity [14], these observations are of great clinical significance.…”

Role of Deficits in Pathogen Recognition Receptors in Infection Susceptibility

“…Clinical translation is more likely to result from the characterization of the molecular and cellular pathways involved in disease and the identification of novel targets for immunomodulatory drugs or vaccines, especially in the context of monogenic defects. Another interesting example regards the identification of the gene defect in PTX3 underlying IA, which raises the possibility to use recombinant PTX3 treatment to supplement antifungal agents, as demonstrated in animal models of infection [99,100]. Furthermore, the application of systems biology to integrate genome-wide studies, including genomic, transcriptomic, proteomic, or metabolomic profiles, and their integration with clinical data may be a particularly powerful approach for identifying novel therapeutic targets [101].…”