Listeria monocytogenes insertion mutants defective in hemolysin production were generated using the conjugative transposons Tn916 and Tn1545. All of the nonhemolytic mutants (hly-) lacked a secreted 58-kD polypeptide, presumedly hemolysin, and were avirulent in a mouse model. An intracellular multiplication assay was established in monolayers of mouse bone marrow-derived macrophages, the J774 macrophage-like cell line, the CL.7 embryonic mouse fibroblast cell line, and the Henle 407 human epithelial cell line. The hly+ strain grew intracellularly in all of the tissue culture cells with a doubling time of approximately 60 min. In contrast, the hly- mutants failed to grow in the murine-derived tissue culture cells, but retained the ability to grow in the human tissue culture cells examined. Hemolytic-positive revertants were selected after passage of the hly- mutants through monolayers of J774 cells. In each case, the hemolytic revertants possessed the 58-kD polypeptide, were capable of intracellular growth in tissue culture monolayers and were virulent for mice.

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In the wake of the COVID-19 pandemic many countries implemented containment measures to reduce disease transmission. Studies using digital data sources show that the mobility of individuals was effectively reduced in multiple countries. However, it remains unclear whether these reductions caused deeper structural changes in mobility networks and how such changes may affect dynamic processes on the network. Here we use movement data of mobile phone users to show that mobility in Germany has not only been reduced considerably: Lockdown measures caused substantial and long-lasting structural changes in the mobility network. We find that long-distance travel was reduced disproportionately strongly. The trimming of long-range network connectivity leads to a more local, clustered network and a moderation of the “small-world” effect. We demonstrate that these structural changes have a considerable effect on epidemic spreading processes by “flattening” the epidemic curve and delaying the spread to geographically distant regions.

Toxoplasma gondii is a widely distributed protozoan pathogen that causes devastating ocular and central nervous system disease. We show that the endochin-like quinolone (ELQ) class of compounds contains extremely potent inhibitors of T. gondii growth in vitro and is effective against acute and latent toxoplasmosis in mice. We screened 50 ELQs against T. gondii and selected two lead compounds, ELQ-271 and ELQ-316, for evaluation. ELQ-271 and ELQ-316, have in vitro IC 50 values of 0.1 nM and 0.007 nM, respectively. ELQ-271 and ELQ-316 have ED 50 values of 0.14 mg/kg and 0.08 mg/kg when administered orally to mice with acute toxoplasmosis. Moreover, ELQ-271 and ELQ-316 are highly active against the cyst form of T. gondii in mice at low doses, reducing cyst burden by 76-88% after 16 d of treatment. To investigate the ELQ mechanism of action against T. gondii, we demonstrate that endochin and ELQ-271 inhibit cytochrome c reduction by the T. gondii cytochrome bc 1 complex at 8 nM and 31 nM, respectively. We also show that ELQ-271 inhibits the Saccharomyces cerevisiae cytochrome bc 1 complex, and an M221Q amino acid substitution in the Q i site of the protein leads to >100-fold resistance. We conclude that ELQ-271 and ELQ-316 are orally bioavailable drugs that are effective against acute and latent toxoplasmosis, likely acting as inhibitors of the Q i site of the T. gondii cytochrome bc 1 complex.antiparasitic agents | electron transport | antimalarial | quinoline | opportunistic infection