Targeting host-specific metabolic pathways—opportunities and challenges for anti-infective therapy

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TL;DR

This review explores host-directed therapy (HDT) targeting lipid metabolism enzymes LCAT and LPL as an emerging anti-infective strategy. It details how intracellular pathogens hijack these host pathways for replication and persistence, and discusses the dual challenge of developing activators for cardiovascular disease while avoiding unintended promotion of microbial virulence. The clinical significance lies in the need to carefully monitor patients on lipid-modulating therapies to prevent complications from co-infections.

Full summary

3,242 CHARS

**Background:** Lipids are essential for cell maintenance, energy production, and immune signaling. Intracellular pathogens (bacteria, viruses, fungi, protozoa) hijack host lipid metabolism to support their replication, entry, egress, and persistence. Host-directed therapy (HDT) is an emerging anti-infective strategy that targets host metabolic pathways rather than the pathogen directly. This review focuses on two key enzymes in cholesterol and triglyceride metabolism—lecithin-cholesterol acyltransferase (LCAT) and lipoprotein lipase (LPL)—and their roles in both cardiovascular disease (CVD) and infectious processes.

**Methods:** The authors conducted a narrative review of the literature, summarizing current knowledge on LCAT and LPL in host lipid homeostasis, their modulation by pathogens, and the development of small-molecule activators for these enzymes. They also discuss microbial enzymes that mimic LCAT and LPL, and the implications for drug development.

**Key Results:** - LCAT is critical for HDL maturation and reverse cholesterol transport. Genetic LCAT deficiency (familial LCAT deficiency, FLD) has an incidence <1 in 200,000, causing corneal opacities, anemia, and renal disease. Recombinant human LCAT (rhLCAT) has been tested in phase I/II trials (NCT02601560, NCT03578809, NCT03773172). Small-molecule activators (e.g., DS-8190a) increase LCAT activity up to 2.0-fold in cynomolgus monkeys and prevent plaque progression in atherosclerosis models. - LPL hydrolyzes triglycerides in chylomicrons and VLDL. Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder (~1:1,000,000) caused by LPL mutations. Evinacumab (anti-ANGPTL3 monoclonal antibody) was FDA-approved in 2021 for homozygous familial hypercholesterolemia. Volanesorsen (antisense oligonucleotide) is approved in Europe for FCS. Small-molecule LPL activators (e.g., NO-1886/Ibrolipim) showed efficacy in animal models but were halted due to adrenal side effects. - Pathogens modulate host LCAT and LPL: In leptospirosis, LCAT fractional activity was 3.6 times lower than in healthy individuals. In HIV and HCV infections, decreased LCAT activity and apoA-I levels reduce reverse cholesterol transport. SARS-CoV-2 infection impairs HDL function, reducing apoA-I and apoE, increasing serum amyloid A, and leading to oxidized LDL/HDL that activate LOX-1 and promote inflammation. - Some pathogens produce LCAT-like enzymes (e.g., GCAT from Aeromonas, LCAT from Plasmodium falciparum) and LPL-like enzymes (e.g., S. aureus Lpls). S. aureus Lpl1 binds host HSP90α/β, potentiating invasion 2- to 5-fold. β-lactam antibiotics upregulate lpl expression in MRSA via sarA, increasing virulence.

**Clinical Implications:** HDT targeting LCAT and LPL offers potential for both CVD and infectious diseases, but careful monitoring is needed because activators of these enzymes may inadvertently enhance pathogen survival or virulence. For example, β-lactam-induced LPL upregulation in MRSA could worsen treatment outcomes. Drug repurposing and combination therapies must consider these host-pathogen interactions. The review underscores the need for further research to inform dosing and avoid complications in patients with co-morbidities.