Silva-Gomes, R. | Search bioRxiv

bioRxiv2022

Regulation of inflammation and protection against invasive pneumococcal infection by the long pentraxin PTX3

Streptococcus pneumoniae is a major pathogen in children, elderly subjects and immunodeficient patients. PTX3 is a fluid phase pattern recognition molecule (PRM) involved in resistance to selected microbial agents and in regulation of inflammation. The present study was designed to assess the role of PTX3 in invasive pneumococcal infection. In a murine model of invasive pneumococcal infection, PTX3 was strongly induced in non-hematopoietic (particularly, endothelial) cells. The IL-1{beta}/MyD88 axis played a major role in regulation of the Ptx3 gene expression. Ptx3-/- mice were more susceptible to invasive pneumococcal infection. Although high concentrations of PTX3 had opsonic activity in vitro, no evidence of PTX3-enhanced phagocytosis was obtained in vivo. In contrast, Ptx3-deficient mice showed enhanced recruitment of neutrophils and inflammation. Using P-selectin deficient mice, we found that protection against pneumococcus was dependent upon PTX3-mediated regulation of neutrophil inflammation. In humans, PTX3 genetic polymorphisms were associated with invasive pneumococcal infections. Thus, this fluid phase PRM plays an important role in tuning inflammation and resistance against invasive pneumococcal infection.

immunology↗

bioRxiv2018

Antimicrobial activity of Mycobacteriophage D29 Lysin B during Mycobacterium ulcerans infection

Buruli Ulcer (BU) is a cutaneous disease caused by Mycobacterium ulcerans. The pathogenesis of this disease is closely related to the secretion of the toxin mycolactone that induces extensive destruction of the skin and soft tissues. Although the World Health Organization recommends a combination of rifampicin and streptomycin for the treatment of BU, clinical management of advanced stages often requires extensive surgical resection of the infected tissue. Therefore, it is important to develop alternative strategies for the treatment of BU.\n\nEndolysins (lysins) are phage encoded enzymes that degrade peptidoglycan of bacterial cell walls. Over the past years, lysins have been emerging as alternative antimicrobial agents against Gram-positive bacteria. Amongst Gram-positive bacteria, mycobacteria have an unusual outer membrane that is covalently attached to the mycolylarabinogalactan-peptidoglycan complex. To overcome this additional barrier to phage-mediated lysis, some mycobacteriophages encode a lipolytic enzyme, Lysin B (Lys B).\n\nIn this study, we demonstrated for the first time that recombinant Lys B displays lytic activity against M. ulcerans isolates. Moreover, using a mouse model of M. ulcerans footpad infection, we show that subcutaneous treatment with Lys B leads to a reduction in bacterial burdens, associated with IFN-{gamma} and TNF production in the draining lymph node. These findings highlight the potential use of lysins as a novel therapeutic approach against this neglected tropical disease.\n\nAUTHOR SUMMARYBuruli Ulcer (BU) is a necrotizing skin disease caused by Mycobacterium ulcerans. Standard treatment for BU lesions consists of a combination of rifampicin and streptomycin for 8 weeks. However, clinical management of advanced stages of the disease often requires extensive surgical resection of the infected tissue. Therefore, it is important to develop alternative strategies for the treatment of BU. In that sense, we tested the efficacy of Lysin B (Lys B), a phage encoded lipolytic enzyme that degrades the mycolylarabinogalactan-peptidoglycan complex present in the mycobacterial cell wall. In this study, we show that Lys B not only displays lytic activity against M. ulcerans isolates in vitro, but also leads to a reduction in bacterial burdens in M. ulcerans-infected mouse footpads. These findings highlight the potential use of lysins as a novel therapeutic approach against this neglected tropical disease.

microbiology↗