Infectious microbes & diseases最新文献

Nipah virus (NiV) and Langya virus (LayV) are emerging zoonotic henipaviruses with serious public health risks. However, no vaccine or drug is available for either disease. To address the persistent threats posed by NiV and LayV, we preliminarily developed indirect ELISAs based on truncated fusion glycoprotein (F) and attachment glycoprotein (G) expressed in a mammalian expression system. We validated these assays using immunized BALB/c mice (for both NiV and LayV), immunized Syrian golden hamsters (for NiV), and goats and a dog that were naturally infected (for LayV). Specificity was assessed using negative sera from mice, ferrets, African green monkeys, hamsters and swine. The ELISAs demonstrated high sensitivity (1:64,000) for both viruses in immunized BALB/c mice, high specificity (approximately 95% in mice and 100% in ferrets, African green monkeys, hamsters and swine), and strong concordance with commercial NiV ELISA kits (>93%). The NiV ELISAs were further validated using immunized Syrian golden hamsters, which had sensitivities of 1:51,200 (F-based) and 1:6400 (G-based). The LayV ELISAs successfully detected antibodies in the sera of goats and a dog naturally infected with LayV. These preliminary indirect ELISAs serve as proof-of-concept tools and may be valuable for vaccine and therapeutic development, serological surveillance studies and future diagnostic platform development.

Listeria monocytogenes is a human and veterinary pathogen, one of the most common agents of foodborne infections worldwide. It can cause severe complications such as meningitis or miscarriage. Anti-virulence therapies, which target virulence factors such as pore-forming toxins, offer an alternative approach to combating infections. In this study, cholesterol-containing liposomal nanotraps effectively neutralized L. monocytogenes exotoxins, particularly listeriolysin O (LLO), thereby protecting mammalian cells. Notably, toxin neutralization was observed under both neutral and acidic conditions, where LLO activity is optimized to facilitate bacterial escape from the phagosome. Liposomal nanotraps were phagocytosed by macrophages and colocalized with intracellular Listeria, increasing the clearance rate of intracellular bacteria. These findings expand the potential use of broad-spectrum liposomal nanotrap therapy, which could be employed alongside current standard of care treatments to assist the immune system in controlling virulent pathogens.

Infections refractory to standard antibiotic therapy are contributing to adverse treatment outcomes in patients suffering from deep-seated bacterial infections caused by increasingly resistant pathogens. Adjunctive strategies targeting bacterial virulence factors have been considered to supplement the host immune response in fighting the infection. Previous studies suggest that the FDA-approved anti-inflammatory drug diflunisal inhibits Staphylococcus aureus (SA) α-toxin expression by its interaction with the response regulator AgrA. We investigated the broader anti-virulence properties of diflunisal against pathogenic strains of SA and established proof-of-concept for its efficacy in blocking SA virulence. Our studies reveal that diflunisal inhibits α-toxin production, sensitizes SA to cationic antibiotics and human antimicrobial peptides, inhibits the production of the golden pigment staphyloxanthin, and reduces biofilm formation. Molecular docking simulations revealed potential interactions between diflunisal and AgrA binding sites. In addition, sequence alignment of the SA AgrA response regulator demonstrated similarities to other response regulators involved in controlling virulence factor expression. Appreciation of the antivirulence properties of diflunisal supports a therapeutic strategy distinct from structurally similar compounds, such as salicylic acid. The repurposing of diflunisal may mitigate disease severity and provide a unique adjunctive tool in the treatment of SA infection.

Vitamin A and its biologically active derivative, retinoic acid (RA), are important for many immune processes. RA, in particular, is essential for the development of immune cells, including neutrophils, which serve as a front-line defense against infection. While vitamin A deficiency has been linked to higher susceptibility to infections, the precise role of vitamin A/RA in host-pathogen interactions remains poorly understood. Here, we provided evidence that RA boosts neutrophil killing of methicillin-resistant Staphylococcus aureus (MRSA). RA treatment stimulated primary human neutrophils to produce reactive oxygen species, neutrophil extracellular traps, and the antimicrobial peptide cathelicidin (LL-37). Because RA treatment was insufficient to reduce MRSA burden in an in vivo murine model of skin infection, we expanded our analysis to other infectious agents. RA did not affect the growth of a number of common bacterial pathogens, including MRSA, Escherichia coli K1 and Pseudomonas aeruginosa; however, RA directly inhibited the growth of group A Streptococcus (GAS). This antimicrobial effect, likely in combination with RA-mediated neutrophil boosting, resulted in substantial GAS killing in neutrophil killing assays conducted in the presence of RA. Furthermore, in a murine model of GAS skin infection, topical RA treatment showed therapeutic potential by reducing both skin lesion size and bacterial burden. These findings suggest that RA may hold promise as a therapeutic agent against GAS and perhaps other clinically significant human pathogens.