Vol.:(0123456789) 1 3 Parasitology Research (2024) 123:60 https://doi.org/10.1007/s00436-023-08031-x REVIEW Apoptosis and its pathways as targets for intracellular pathogens to persist in cells Jorge Rodríguez‑González 1,2  · Laila Gutiérrez‑Kobeh 1 Received: 7 March 2023 / Accepted: 10 November 2023 © The Author(s) 2023 Abstract Apoptosis is a fnely programmed process of cell death in which cells silently dismantle and actively participate in several operations such as immune response, diferentiation, and cell growth. It can be initiated by three main pathways: the extrin- sic, the perforin granzyme, and the intrinsic that culminate in the activation of several proteins in charge of tearing down the cell. On the other hand, apoptosis represents an ordeal for pathogens that live inside cells and maintain a strong dependency with them; thus, they have evolved multiple strategies to manipulate host cell apoptosis on their behalf. It has been widely documented that diverse intracellular bacteria, fungi, and parasites can interfere with most steps of the host cell apoptotic machinery to inhibit or induce apoptosis. Indeed, the inhibition of apoptosis is considered a virulence property shared by many intracellular pathogens to ensure productive replication. Some pathogens intervene at an early stage by interfering with the sensing of extracellular signals or transduction pathways. Others sense cellular stress or target the apoptosis regulator proteins of the Bcl-2 family or caspases. In many cases, the exact molecular mechanisms leading to the interference with the host cell apoptotic cascade are still unknown. However, intense research has been conducted to elucidate the strategies employed by intracellular pathogens to modulate host cell death. In this review, we summarize the main routes of activation of apoptosis and present several processes used by diferent bacteria, fungi, and parasites to modulate the apoptosis of their host cells. Keywords Apoptosis · Bacteria · Fungi · Intracellular pathogens · Parasites · Signaling pathways Introduction Human health is continuously threatened by pathogens and in response to this, the immune system orchestrates multi- faceted defense strategies. As a result, pathogens have devel- oped multiple schemes to overcome human defense mecha- nisms. Among these, cell death is very important for the host because it eliminates infected cells and activates the immune system. However, cell death can become a double-edged sword: if uncontrolled, it may also lead to tissue damage, which might subsequently activate the pathogen dissemina- tion procedures. To avoid this, the major cell death pathways (apoptosis, pyroptosis, and necroptosis) are highly regulated. Recently, these three programed cell death pathways have been included in an entity named PANoptosis directed by a PANoptosome. The PANoptosome is a multimeric protein complex responsible for recruiting all the molecules neces- sary to carry out any of the three types of programmed cell death (Bedoui et al. 2020; D'Arcy 2019; Samir et al. 2020). Of these three types of programmed cell death, apoptosis has typically been described through morphological mark- ers such as chromatin condensation, cytoplasm contraction, formation and separation of apoptotic bodies, and the lack of infammation. Nevertheless, the Committee for Nomen- clature of Cell Death has determined that to have a clearer characterization of the diferent types of cell death quantif- able biochemical parameters must be used instead of mor- phological ones (Galluzzi et al. 2014). Handling Editor: Una Ryan * Laila Gutiérrez-Kobeh lgutierr@unam.mx 1 Unidad de Investigación UNAM-INC, División de Investigación, Facultad de Medicina, Universidad Nacional Autónoma de México-Instituto Nacional de Cardiología “Ignacio Chávez,”, Juan Badiano No. 1, Col. Belisario Domínguez, Sección XVI, Delegación Tlalpan, C.P. 14080 Ciudad de México, México 2 Present Address: Laboratorio de Estudios Epidemiológicos, Clínicos, Diseños Experimentales e Investigación, Facultad de Ciencias Químicas, Universidad Autónoma “Benito Juárez” de Oaxaca, Oaxaca, Mexico