Apoptosis and its pathways as targets for intracellular pathogens to persist in cells

Abstract

Apoptosis is a finely programmed process of cell death in which cells silently dismantle and actively participate in several operations such as immune response, differentiation, and cell growth. It can be initiated by three main pathways: the extrinsic, 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 different bacteria, fungi, and parasites to modulate the apoptosis of their host cells.

Keywords: Apoptosis; Bacteria; Fungi; Intracellular pathogens; Parasites; Signaling pathways.

Fig. 1

Modulation of the extrinsic pathway by intracellular pathogens. The induction of apoptosis through the extrinsic pathway occurs through the activation of death receptors of the TNF family such as TNFR or FAS. When death receptors bind to their ligands, adaptor proteins, such as TRADD or FADD, are recruited to the receptor intracellular domain and, in turn, recruit other proteins to form multiproteic complexes that activate initiation caspases, mainly caspase 8. Caspase 8 activates executioner caspases, mainly caspase 3, which finally conducts to cell apoptosis. Some intracellular pathogens modulate the extrinsic pathway of apoptosis. For example, C. trachomatis and Salmonella inhibit host cell apoptosis through the inhibition of TNFR or TNF, respectively. It is also known that Brucella, M. tuberculosis, T. gondii, and Y. pestis block host cell apoptosis through the inhibition of FAS or FASL. However, and in a very interesting way, it is known that M. tuberculosis and T. gondii can induce host cell apoptosis by enhancing TNF secretion or FASL expression. Besides, it has been observed that M. tuberculosis can also induce the expression of TNFR in order to capture the extracellular TNF and in this way inhibits apoptosis

Fig. 2

Modulation of signaling pathways. Apoptosis is a highly regulated process in which it is known that several signaling pathways participate, where the best studied are Akt, NF-κB, or MAPK. Generally, the activation of these signaling pathways conducts to the synthesis of proteins that inhibit apoptosis or to the inhibition of proteins that induce apoptosis. It has been observed that some pathogenic microorganisms can activate or inhibit these pathways in order to modulate host cell apoptosis. For example, C. trachomatis, Leishmania, and Shigella can activate Akt signaling pathway, while Leishmania and S. pneumoniae activate MAPK in order to inhibit host cell apoptosis. Interestingly, Salmonella can inhibit both NF-κB as well as JNK to delay the proapoptotic innate immune response. On the other hand, L. pneumophila and M. tuberculosis can activate NF-κB and in this way inhibit apoptosis. Contrarily, Y. pestis can inhibit both NF-κB and MAPK, which results in the induction of host cell apoptosis

Fig. 3

Modulation through the interference with caspases. The induction of apoptosis through both the extrinsic and the intrinsic pathway leads to the activation of the executioner caspases 3 and 7. Due to this, many intracellular pathogenic microorganisms modulate host cell apoptosis through the interference with caspases. For example, it has been observed that Leishmania and P. gingivalis inhibit caspase 3. On the other hand, it has been observed that E. coli, L. pneumophila, and Y. pestis inhibit caspase 3, and E. coli can also inhibit caspase 9

Fig. 4

Modulation of proteins that regulate MOMP by intracellular pathogens. The induction of apoptosis through the intrinsic pathway leads to the loss of the mitochondrial outer membrane permeability (MOMP), which permits the release of lethal molecules, as for example cytochrome c, that along with APAF1 form the apoptosome, which permits the autoactivation of caspase 9 and finally the activation of caspases 3 and 7. Interestingly, the activation of the intrinsic pathway can occur through the extrinsic pathway thanks to a positive feedback loop that depends on the formation of tBID from BID. MOMP is a mechanism characterized by a fine regulation carried out by different proteins, mainly by proteins that belong to the Bcl-2 family that participate in regulatory processes such as post-translational modifications and regulation of the expression of different genes, as those of the Bcl-2 family, that finally will decide the fate of the cell. Due to all this, intracellular pathogens have developed different strategies to modulate the MOMP, the molecules released from the mitochondria, and proteins from the Bcl-2 family. For example, it has been observed that Leishmania, M. tuberculosis, N. algerae, and T. cruzi induce the overexpression of the antiapoptotic proteins Bcl-2, Bcl-xL, and Mcl-1 and in this way inhibit host cell apoptosis, although it has also been observed that M. tuberculosis can induce apoptosis through the proapoptotic protein Bim. On the other hand, it has been shown that both C. burnetii and Leishmania can inhibit MOMP. In addition, it is known that A. phagocytophilum, C. trachomatis, Leishmania, T. gondii, and Salmonella inhibit the release of cytochrome c