Viruses are obligatory intracellular pathogens that depend on cellular machinery for replication and dissemination [1]. Since their first investigation by Dmitri Ivanovsky and Martinus Beijerinck in the 19th century, it has been proposed that viruses have shaped evolutionary events, such as the transition from RNA to DNA genomes and the development of adaptive protective responses through viral genome incorporation into host cells [2]. Furthermore, viruses have also significantly changed human history through devastating pandemics, such as the Spanish flu and, recently, COVID-19, causing an alarming number of deaths 3, 4. These outbreaks highlight the adaptive capacity of viruses and the complexity of virus–host interactions, which are challenges to global health 1, 5.

The emergence of new viruses, often associated with zoonotic events, is driven by genetic adaptations enabling infection of new host species [1]. Virus–receptor interactions, mediated by specific viral binding proteins, often located on the virion surface, are crucial for cellular infection [5]. Mutations in these proteins can alter the range of susceptible hosts and pathogen virulence [5]. The specificity of viral binding to cellular receptors, such as sialic acid, cell adhesion molecules, and phosphatidylserine, determines viral tropism and, consequently, the clinical manifestations of disease 1, 5. Furthermore, some viruses may have additional mediators of cellular receptor binding, such as fusion glycoproteins and protein projections, present in enveloped and nonenveloped viruses, respectively [6].

Within infected organisms, viruses are exposed to many immune cells and proteins, which aim to hinder infection spreading and repair eventual tissue damage, thereby ensuring systemic homeostasis. Immune responses are didactically divided into adaptive and innate components: while the former acts by modulating and targeting inflammatory responses against specific pathogen antigens, the latter is actively responsible for the containment and destruction of microorganisms. Innate immune cells may act by sensing, engulfing, and eliminating pathogen- or damage-associated molecular patterns (PAMPs/DAMPs) sources, while also having a pivotal role in antigen processing and presentation and secreting a multitude of cytokines, which are key for many cell signaling pathways and the induction of an appropriate adaptive immune response [7].

The sensing capacity of innate immune cells, as well as their effector functions, is mediated by the activation of a series of pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), RIG-like receptors (RLRs), NOD-like receptors (NLRs), and the cGAS/STING signaling pathway [7]. These PRRs are located on the cell surface, anchored to vesicle membranes, or within the cytosol and interact with PAMPs and DAMPs, initiating cell signaling cascades and ultimately resulting in differential gene expression and cellular metabolic modulation, which are necessary for proper immune responses [7]. Such PRRs are not limited to innate immune cells and are also present in different cell types, such as lymphocytes, hepatocytes, fibroblasts, endothelial cells, and other cell types [7].

Virus–host interactions involve a complex network of molecular events that go beyond the viral binding to cellular receptors. For instance, many viruses have evolved sophisticated immune evasion mechanisms to prevent antigen presentation, modulate co-stimulation, suppress interferon responses, and perform molecular mimicry, among others, allowing viruses to persist in host cells [8]. Furthermore, some pathogens can drive changes in the expression or activity of metabolically active proteins, creating and exploiting adequate replication conditions within host cells 2, 9•. This has resulted in growing interest in the role of viral receptors and virally modulated proteins in regulating cellular metabolism and subsequent immune responses. Despite their growing importance, we still do not fully comprehend the molecular mechanisms underlying such interactions. This review aims to explore various facets of virus–host interactions, with a particular focus on metabolic alterations triggered by viral binding to specific receptors and the immune evasion strategies of viruses that manipulate metabolic pathways in their favor. Additionally, we discuss how these interactions can induce inflammatory responses and immune cell function, providing a comprehensive overview of the complexity of virus–host interactions and their implications for the development of new therapeutic strategies.