Various Facets of Pathogenic Lipids in Infectious Diseases: Exploring Virulent Lipid-Host Interactome and Their Druggability

Abstract

Lipids form an integral, structural, and functional part of all life forms. They play a significant role in various cellular processes such as membrane fusion, fission, endocytosis, protein trafficking, and protein functions. Interestingly, recent studies have revealed their more impactful and critical involvement in infectious diseases, starting with the manipulation of the host membrane to facilitate pathogenic entry. Thereafter, pathogens recruit specific host lipids for the maintenance of favorable intracellular niche to augment their survival and proliferation. In this review, we showcase the lipid-mediated host pathogen interplay in context of life-threatening viral and bacterial diseases including the recent SARS-CoV-2 infection. We evaluate the emergent lipid-centric approaches adopted by these pathogens, while delineating the alterations in the composition and organization of the cell membrane within the host, as well as the pathogen. Lastly, crucial nexus points in their interaction landscape for therapeutic interventions are identified. Lipids act as critical determinants of bacterial and viral pathogenesis by altering the host cell membrane structure and functions.

Keywords: Drug development; Host–pathogen interactions; Lipid biosynthesis; Lipid rafts; Membrane organization; Virulence-associated lipids.

Fig. 1

Schematic representation of the cell membrane architectures in E. coli and M. tuberculosis along with structures of key virulence-associated lipids

Fig. 2

Lipid-mediated cellular effects pertaining to Shiga toxin producing E. coli and Mtb infection

Fig. 3

Schematic depicting HIV life cycle within the host cells. The entry process begins with the binding of viral spike protein gp120 to CD4 receptors and CCR5 and CXCR4 co-receptors situated within the host lipid raft domains, followed by a conformational change that exposes the fusion peptide of gp41. Upon fusion, the virus releases its single-stranded RNA-genome along with its reverse transcriptases for the formation of viral DNA, followed by integration with the host DNA and replication leading to the release of m-RNA. In the cytosol, the structural and enzymatic viral proteins are expressed including Pr55^Gag, which are critical for the viral assembly and budding. HIV RNA assembles at the inner leaflet of the cell membrane and form an immature HIV virus. The subdomains of Gag protein are involved at different stages of the budding process. The MA domain is anchored to the cell membrane via a myristate along with basic amino acids that preferentially interact with acidic lipids of the host raft domains. The capsid domain (CA) contains amino acids that promote Gag-Gag interactions (multimerization) that invaginate the membrane, initiating the budding process. The nucleocapsid domain (NC) binds to viral RNA that are packaged in the virus particle. Before release, viral proteases cleave Gag to form a mature virus. Upon maturation, the new virus buds out from the infected host cell along with a part of the host cell membrane as its own viral membrane

Fig. 4

Schematic representing major events in the SARS-CoV life cycle in the host cell. Entry of SARS-CoV occurs through the binding of spike protein with the host ACE receptors facilitated by transmembrane serine protease 2 (TMPRSS2), embedded in the host cell raft domains. Once the viral genome is released, transcription-replication complex (RTC) carries out the expression of viral structural and non-structural proteins. The entire RTC is known to be situated in the viral-induced compartments formed by the rearrangement of cellular membranes. The schematic shows formation of DMVs (Double-membrane vesicles), CMs (convoluted membranes) and VPs (vesicle pockets) through rough endoplasmic reticulum (RER) in conjunction with a complex interplay of viral non-structural proteins, nsp3-4–6. The presence of double-stranded RNA (dsRNA) as observed by Knoops et al. is also shown within the compartments of the reticulo-vesicular network