**1. Introduction**

Cellular membranes are selective, permeable barriers, consisting of a phospholipid bilayer. They operate by physically separating two compartments within the cell or separate the contents of the cell from the external environment, and they regulate the exchange of chemicals, ions, and biomolecules across them. Cellular membranes thus define organelles and delineate vesicles in intracellular cargo transport systems, such as the endo-lysosomal or the exocytosis pathway. They are both fluid and dynamic, as well as solid and impermeable if necessary [1]. Therefore, membrane integrity is an essential part of cellular homeostasis, which is constantly challenged by pathogens (bacteria, virus, fungi), protein aggregates, or chemicals. Cells have evolutionary conserved surveillance systems to detect and respond to membrane damage and secure cell survival. As outlined in this review, a hallmark of membrane damage is the transient exposure of complex glycosylated proteins in the cytosolic compartment, which are detected by galectins (Gal). Galectins are small cytosolic carbohydrate binding proteins, which cluster at the site of membrane damage. Galectins also coordinate differential responses such as autophagy, to remove membrane remnants [2,3], and the activation of the endosomal sorting complex required for transport (ESCRT) machinery, favoring membrane repair [4,5]. There is increasing evidence that pathogens, including viruses, take control of the cell response to membrane damage and the associated machinery for their own benefit. Therefore, provoking membrane damage upon infection may not be just an accidental by-product of the pathogen entry process. Instead, eliciting membrane

damage could be purposeful and part of a sophisticated entry strategy. This review will discuss this possibility and provide an overview of current knowledge on the relationship between membrane damage, cellular response, and pathogen entry. While briefly summarizing observations made for bacterial pathogens and membrane damage in general, our focus is on the entry of the membrane lytic adenovirus (Ad), and other non-enveloped viruses. We discuss the limited existing knowledge about how viruses manipulate and exploit the cellular membrane damage response. We apologize in advance to the many authors who contribute to the emerging field of membrane damage and whose work we cannot cite due to limited space.

### *1.1. Virus Inflicted Membrane Damage*

Most viruses are taken up by receptor-mediated endocytosis and enter cells through the endo-lysosomal compartment. From here, they have to penetrate into the cytosol to reach their site of replication. For most RNA viruses, replication takes place in the cytosol, while most DNA viruses replicate in the nucleus. The endosome is a dynamic entry compartment, and while it provides some protection from cytosolic innate immune sensors, viruses need to escape before they are either sorted to the lysosome or recycled back to the cell surface [6]. Most enveloped viruses fuse their lipid shell (viral envelope) with the endosomal membrane and release their capsid to the cytosol. This strategy is e fficient and topologically simple: it does, *a priori*, not require any kind of membrane rupture [7]. In contrast, non-enveloped viruses, with their hydrophilic capsids, have to cross cell membranes by inflicting membrane damage. This approach risks exposure of the luminal content of the endosome to the cytosol, which can trigger inflammation. To penetrate the cellular membrane, most non-enveloped viruses undergo conformational changes and/or proteolytic processing that allow them to use membrane lytic/modulating factors. Strategies include lipid modification, pore insertion, or large-scale membrane disruption (Figure 1). Still, not much is known about the structural and mechanistic details of the process how non-enveloped viruses inflict membrane damage to cross membranes and even less is known how they engage in the cellular response [8,9].
