Lipid droplets (LDs) are cellular organelles rich in neutral lipids such as triglycerides and cholesterol esters that are coated by a phospholipid monolayer and associated proteins. LDs are known to play important roles in the storage and availability of lipids in the cell and to serve as a source of energy reserve for the cell. However, these structures have also been related to oxidative stress, reticular stress responses, and reduced antigen presentation to T cells. Importantly, LDs are also known to modulate viral infection by participating in virus replication and assembly. Here, we review and discuss the interplay between neutral lipid metabolism and LDs in the replication cycle of different DNA viruses, identifying potentially new molecular targets for the treatment of viral infections.

Lipids play essential roles in the cell as components of cellular membranes, signaling molecules, and energy storage sources. Lipid droplets are cellular organelles composed of neutral lipids, such as triglycerides and cholesterol esters, and are also considered as cellular energy reserves, yet new functions have been recently associated with these structures, such as regulators of oxidative stress and cellular lipotoxicity, as well as modulators of pathogen infection through immune regulation. Lipid metabolism and lipid droplets participate in the infection process of many RNA viruses and control their replication and assembly, among others. Here, we review and discuss the contribution of lipid metabolism and lipid droplets over the replication cycle of RNA viruses, altogether pointing out potentially new pharmacological antiviral targets associated with lipid metabolism.

Oxygen is essential for aerobic cells, and thus its sensing is critical for the optimal maintenance of vital cellular and tissue processes such as metabolism, pH homeostasis, and angiogenesis, among others. Hypoxia-inducible factors (HIFs) play central roles in oxygen sensing. Under hypoxic conditions, the α subunit of HIFs is stabilized and forms active heterodimers that translocate to the nucleus and regulate the expression of important sets of genes. This process, in turn, will induce several physiological changes intended to adapt to these new and adverse conditions. Over the last decades, numerous studies have reported a close relationship between viral infections and hypoxia. Interestingly, this relation is somewhat bidirectional, with some viruses inducing a hypoxic response to promote their replication, while others inhibit hypoxic cellular responses. Here, we review and discuss the cellular responses to hypoxia and discuss how HIFs can promote a wide range of physiological and transcriptional changes in the cell that modulate numerous human viral infections.

Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) infections are highly prevalent in the human population and produce mild to life-threatening diseases. These viruses interfere with the function and viability of dendritic cells (DCs), which are professional antigen-presenting cells that initiate and regulate the host’s antiviral immune responses. Heme oxygenase-1 (HO-1) is an inducible host enzyme with reported antiviral activity against HSVs in epithelial cells and neurons. Here, we sought to assess whether HO-1 modulates the function and viability of DCs upon infection with HSV-1 or HSV-2. We found that the stimulation of HO-1 expression in HSV-inoculated DCs significantly recovered the viability of these cells and hampered viral egress. Furthermore, HSV-infected DCs stimulated to express HO-1 promoted the expression of anti-inflammatory molecules, such as PDL-1 and IL-10, and the activation of virus-specific CD4⁺ T cells with regulatory (Treg), Th17 and Treg/Th17 phenotypes. Moreover, HSV-infected DCs stimulated to express HO-1 and then transferred into mice, promoted the activation of virus-specific T cells and improved the outcome of HSV-1 skin infection. These findings suggest that stimulation of HO-1 expression in DCs limits the deleterious effects of HSVs over these cells and induces a favorable virus-specific immune response in the skin against HSV-1.

An important virulence trait of Salmonella enterica serovar Typhimurium (S. Typhimurium) is the ability to avoid the host immune response, generating systemic and persistent infections. Host cells play a crucial role in bacterial clearance by expressing the enzyme heme oxygenase 1 (Hmox1), which catalyzes the degradation of heme groups into Fe²⁺, biliverdin, and carbon monoxide (CO). The role of Hmox1 activity during S. Typhimurium infection is not clear and previous studies have shown contradictory results. We evaluated the effect of pharmacologic modulation of Hmox1 in a mouse model of acute and persistent S. Typhimurium infection by administering the Hmox1 activity inductor cobalt protoporphyrin-IX (CoPP) or inhibitor tin protoporphyrin-IX (SnPP) before infection. To evaluate the molecular mechanism involved, we measured the colocalization of S. Typhimurium and autophagosome and lysosomal markers in macrophages. Administering CoPP reduced the bacterial burden in organs of mice 5 days post-infection, while SnPP-treated mice showed bacterial loads similar to vehicle-treated mice. Furthermore, CoPP reduced bacterial loads when administered after infection in macrophages in vitro and in a persistent infection model of S. Typhimurium in vivo, while tin protoporphyrin-IX (SnPP) treatment resulted in a bacterial burden similar to vehicle-treated controls. However, we did not observe significant differences in co-localization of green fluorescent protein (GFP)-labeled S. Typhimurium with the autophagic vesicles marker microtubule-associated protein 1A/1B-light chain 3 (LC3) and the lysosomal marker lysosomal-associated membrane protein 1 (LAMP-1) in macrophages treated with CoPP. Our results suggest that CoPP can enhance antimicrobial activity in response to Salmonella infection, reducing bacterial dissemination and persistence in mice, in a CO and autophagy- independent manner.