Biology subjects

Rajadas, J.

Publications and source records attributed to Rajadas, J..

3 recordsLinked to original sources

bioRxiv2024

P66 is a bacterial mimic of CD47 that binds the anti-phagocytic receptor SIRPα and facilitates macrophage evasion by Borrelia burgdorferi

Summary ParagraphInnate immunity, the first line of defense against pathogens, relies on efficient elimination of invading agents by phagocytes. In the co-evolution of host and pathogen, pathogens developed mechanisms to dampen and evade phagocytic clearance. Here, we report that bacterial pathogens can evade clearance by macrophages through mimicry at the mammalian anti-phagocytic "dont eat me" signaling axis between CD47 (ligand) and SIRP (receptor). We identified a protein, P66, on the surface of Borrelia burgdorferi that, like CD47, is necessary and sufficient to bind the macrophage receptor SIRP. Expression of the gene encoding the protein is required for bacteria to bind SIRP or a high-affinity CD47 reagent. Genetic deletion of p66 increases phagocytosis by macrophages. Blockade of P66 during infection promotes clearance of the bacteria. This study demonstrates that mimicry of the mammalian anti-phagocytic protein CD47 by B. burgdorferi inhibits macrophage-mediated bacterial clearance. Such a mechanism has broad implications for understanding of host-pathogen interactions and expands the function of the established innate immune checkpoint receptor SIRP. Moreover, this report reveals P66 as a novel therapeutic target in the treatment of Lyme Disease.

immunology↗

bioRxiv2022

The pharmacokinetics and pharmacodynamics of 4-methylumbelliferone and its glucuronide metabolite in mice

Hyaluronan (HA) is an extracellular matrix glycosaminoglycan, with important roles in chronic inflammation, cancer and autoimmunity. 4-methylumbelliferone (4-MU), a small molecule inhibitor of HA synthases, is widely used to study HAs interactions with the surrounding tissues and the immune cells. There is substantial experimental and therapeutic interest in using oral 4-MU to inhibit HA synthesis, but pharmacokinetic and pharmacodynamic data on treatment routes have been lacking. Moreover, it recently became clear that the main metabolite of 4-MU, 4-methlyumbelliferyl glucuronide (4-MUG), is bioactive. We therefore sought to define the pharmacokinetics and pharmacodynamics of 4-MU and its active metabolite 4-MUG in mice. Single dose mouse studies showed that 4-MU administered intravenously (i.v.) resulted in 100-fold higher 4-MU exposure compared to oral (p.o.) administration. The 4-MU ratio AUC i.v./AUC p.o. was 96/1. 4-MUG exposures were much higher than 4-MU exposures after both 4-MU i.v. and p.o. administration, but only small differences in 4-MUG exposure were seen after 4-MU i.v. versus p.o. administration. The 4-MUG metabolite was also administered as a single dose both i.v. and p.o. and showed a 25.9% bioavailability. Compared to 4-MUG p.o. dosing, 1.14 higher 4-MUG exposures were seen after 4-MU p.o. dosing. 4-MU exposure after 4-MUG p.o. administration was minimal but similar to 4-MU exposure after 4-MU p.o. administration. In mice treated for several weeks with 4-MU in chow, the 4-MU concentration immediately drops after treatment was stopped, whereas the 4-MUG concentration showed a peak 1 hour after treatment stop. In a build-up study, 4-MU and 4-MUG treatment in mice lead to a plateau of 4-MU concentration starting at 4 days post treatment start. These 4-MU and 4-MUG concentration findings in vivo will inform future clinical studies and experimental work with 4-MU.

pharmacology and toxicology↗

bioRxiv2019

Repurposing disulfiram (Tetraethylthiuram Disulfide) as a potential drug candidate against Borrelia burgdorferi in vitro and in vivo

Lyme disease caused by the Borrelia burgdorferi (Bb or B. burgdorferi) is a most common vector-borne, multi-systemic disease in USA. Although, most Lyme disease patients can be cured with a course of antibiotic treatment, a significant percent of patient population fail to be disease-free post-treatment, necessitating the development of more effective therapeutics. We previously found several drugs including disulfiram having with good activity against B. burgdorferi. In current study, we evaluated the potential of repurposing the FDA approved disulfiram drug for its borreliacidal activity. Our in vitro results indicate disulfiram shows excellent borreliacidal activity against both the log and stationary phase B. burgdorferi. Subsequent mice studies have determined that the disulfiram eliminated B. burgdorferi completely from hearts and urinary bladder by day 28 post infection, demonstrating the practical application and efficacy of disulfiram against B. burgdorferi in vivo. Moreover, disulfiram treated mice showed reduced expression of inflammatory markers and protected against histopathology and organ damage. Furthermore, disulfiram treated mice showed significantly lower amounts of total antibody titers (IgM and IgG) at day 21 and total IgG2b at day 28 post infection. Mechanistically, cellular analysis of lymph nodes revealed a decrease in percentage of CD19+ B cells and increase in total percentage of CD3+ T cells, CD3+ CD4+ T helpers, and naive and effector memory cells in disulfiram-treated mice. Together, we demonstrate that disulfiram has the potential and could be repurposed as an effective antibiotic for treating Lyme disease in near future.

microbiology↗