Repurposing Nucleoside Analogs for Human Coronaviruses.

Coronavirus disease 2019 (COVID-19) is a serious illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or CoV-2). Some reports claimed certain nucleoside analogs to be active against CoV-2 and thus needed confirmation. Here, we evaluated a panel of compounds and identified novel nucleoside analogs with antiviral activity against CoV-2 and HCoV-OC43 while ruling out others. Of significance, sofosbuvir demonstrated no antiviral effect against CoV-2, and its triphosphate did not inhibit CoV-2 RNA polymerase.

The TLR4 Agonist Monophosphoryl Lipid A Drives Broad Resistance to Infection via Dynamic Reprogramming of Macrophage Metabolism.

Monophosphoryl lipid A (MPLA) is a clinically used TLR4 agonist that has been found to drive nonspecific resistance to infection for up to 2 wk. However, the molecular mechanisms conferring protection are not well understood. In this study, we found that MPLA prompts resistance to infection, in part, by inducing a sustained and dynamic metabolic program in macrophages that supports improved pathogen clearance. Mice treated with MPLA had enhanced resistance to infection with Staphylococcus aureus and Candida albicans that was associated with augmented microbial clearance and organ protection. Tissue macrophages, which exhibited augmented phagocytosis and respiratory burst after MPLA treatment, were required for the beneficial effects of MPLA. Further analysis of the macrophage phenotype revealed that early TLR4-driven aerobic glycolysis was later coupled with mitochondrial biogenesis, enhanced malate shuttling, and increased mitochondrial ATP production. This metabolic program was initiated by overlapping and redundant contributions of MyD88- and TRIF-dependent signaling pathways as well as downstream mTOR activation. Blockade of mTOR signaling inhibited the development of the metabolic and functional macrophage phenotype and ablated MPLA-induced resistance to infection in vivo. Our findings reveal that MPLA drives macrophage metabolic reprogramming that evolves over a period of days to support a macrophage phenotype highly effective at mediating microbe clearance and that this results in nonspecific resistance to infection.

Borrelia burgdorferi chemotaxis toward tick protein Salp12 contributes to acquisition.

Lyme disease is a common tick-borne infection caused by the spirochete Borrelia burgdorferi sensu stricto (s.s.). B. burgdorferi s.s. may utilize chemotaxis, the directional migration towards or away from a chemical stimulus, for transmission, acquisition, and infection. However, the specific signals recognized by the spirochete for these events have not been defined. In this study, we identify an Ixodes scapularis salivary gland protein, Salp12, that is a chemoattractant for the spirochete. We demonstrate that Salp12 is expressed in the I. scapularis salivary glands and midgut and expression is not impacted by B. burgdorferi s.s. infection. Knockdown of Salp12 in the salivary glands or passive immunization against Salp12 reduces acquisition of the spirochete by ticks but acquisition is not completely prevented. Knockdown does not impact transmission of B. burgdorferi s.s. This work suggests a new role for chemotaxis in acquisition of the spirochete and suggests that recognition of Salp12 contributes to this phenomenon.