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Review
. 2023 Sep 29:14:1227467.
doi: 10.3389/fimmu.2023.1227467. eCollection 2023.

Host-directed therapy for bacterial infections -Modulation of the phagolysosome pathway

Toshihiko Taya  1 , Fumiya Teruyama  2   3 , Satoshi Gojo  3
Affiliations
Review

Host-directed therapy for bacterial infections -Modulation of the phagolysosome pathway

Toshihiko Taya et al. Front Immunol. .

Abstract

Bacterial infections still impose a significant burden on humanity, even though antimicrobial agents have long since been developed. In addition to individual severe infections, the f fatality rate of sepsis remains high, and the threat of antimicrobial-resistant bacteria grows with time, putting us at inferiority. Although tremendous resources have been devoted to the development of antimicrobial agents, we have yet to recover from the lost ground we have been driven into. Looking back at the evolution of treatment for cancer, which, like infectious diseases, has the similarity that host immunity eliminates the lesion, the development of drugs to eliminate the tumor itself has shifted from a single-minded focus on drug development to the establishment of a treatment strategy in which the de-suppression of host immunity is another pillar of treatment. In infectious diseases, on the other hand, the development of therapies that strengthen and support the immune system has only just begun. Among innate immunity, the first line of defense that bacteria encounter after invading the host, the molecular mechanisms of the phagolysosome pathway, which begins with phagocytosis to fusion with lysosome, have been elucidated in detail. Bacteria have a large number of strategies to escape and survive the pathway. Although the full picture is still unfathomable, the molecular mechanisms have been elucidated for some of them, providing sufficient clues for intervention. In this article, we review the host defense mechanisms and bacterial evasion mechanisms and discuss the possibility of host-directed therapy for bacterial infection by intervening in the phagolysosome pathway.

Keywords: V-ATPase; antimicrobial resistance; bacterial infection; host-directed therapy; immune evasion; lysosome; phagocytosis; sepsis.

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Conflict of interest statement

FT is an employee of Kowa Corporation, but Kowa Corporation is not involved in any aspect of this study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Pathways of bacterial eradication by phagocytes and immune evasion strategies by bacteria. A: The encounter between the bacteria and the host phagocyte is the initial site of rivalry that determines whether infection is established or not, and begins with the sensing of the bacteria by the host. Bacteria LPS is sensed by PPRs, and if opsonized by immunoglobulin and complement, by Fc or complement receptors, respectively. In the case of opsonization by complement, some bacteria evade detection by the complement receptor by mimicking the regulatory mechanism of complement. In the case of opsonization by antibodies, some bacteria prevent binding to the Fc receptor by secreting an enzyme that digests the antibody. Some bacteria alter the structure recognized by PRRs by phosphorylation or other means to escape from the PRRs. B: The process from phagocytic ruffle through cup closure and scission to phagosome formation requires dramatic changes in the cytoskeleton and in membrane phosphatidylinositides, which are regulated by many signals such as phosphorylation. Bacteria prevent phagocytosis formation by disrupting these signals through the secretion of dephosphorylases. On the other hand, there are viruses that produce substances that mimic the “Don’t eat me” signal as phagocytosis checkpoints. C: Phagolysosome pathway (Middle): Nascent phagosomes undergo fusion with early/late endosomes, hydrolase increases toward full set and V-ATPase also increases. As a result, the phagosome lumen becomes acidified and moves along the cytoskeleton toward the site of lysosome presence, where it fuses with the lysosome. The resulting phagolysosome reaches a pH near 4.6, the optimum pH for many hydrolases, to carry out complete bacterial degradation. D: Xenophagy (Left): When the phagosome is damaged by a bacterial escape mechanism, galectin, which is only exposed in the lumen, is exposed in the cytoplasm, which triggers autophagy initiation. If the cargo is a pathogen such as a bacterium, the autophagy is called xenophagy. The vesicles also eventually fuse with the lysosomes, resulting in complete digestion of the pathogen. E: LAP (Right): LAPosomes, in which LC3, which plays an important role in autophagy, engages the nascent phagosome, recruits NOX2 and produces reactive oxygen species. Reactive oxygen species are formed most efficiently in a neutral environment, and they damage pathogen-forming lipids, proteins, and nucleic acids more rapidly than phagolysosomes. The final disposition of the inclusions of this pathway is also completed by fusion with lysosomes. Created in BioRender.
Figure 2
Figure 2
Checkpoint Inhibition (A) Immune checkpoint: T cells exercise T cell activation, clonal expansion, and effector function by transmitting signals via the TCR and signals from CD28 through binding to CD80/86 as costimulatory signals. On the other hand, inhibitory signals from CTLA-4 through binding to CD80/86 result in T cell deactivation. T cells expressing PD-1, which is also recognized as a T cell exhaustion marker, transmit inhibitory signals by engaging its ligand PD-L1, causing T cell deactivation similar to that of CTLA-4. Antibodies against molecules that comprise this immune checkpoint (immune checkpoint inhibitors: ICIs) shield the target antigen and cause T cell activation by releasing the T cell brake. Host-directed therapy with ICIs for cancer is an important anti-tumor strategy that works in tandem with anticancer drugs that kill the cancer cells themselves. (B) Phagocytosis checkpoint: Phagocytes, like T cells, have receptors with intracellular domains that transmit inhibitory signals to control their activity. The lignads, also called “Don’t eat me” signals, include CD47 and PD-L1, whose receptors are SIRPα and PD-1, respectively. Cells infected with pathogens show enhanced expression of CD47 as the main inducer of INF-g, while cells in apoptosis express PD-L1 and escape clearance by phagocytes. These phagocytosis checkpoint inhibitors may promote phagosytosis and, in the case of bacterial infection, may promote bacterial killing. Created in BioRender.
Figure 3
Figure 3
Regulated assembly/Reversible disassembly of V-ATPase. V-ATPase is composed of a membrane-integrated V0 complex and a V1 complex that can exist free in the cytoplasm. PI3K/AKT, EGF signal, and in mammals, glucose starvation and high glucose induce regulated assembly. On the other hand, glucose starvation induces reversible disassembly in yeast. In the case of amino acid deficiency, TRiC, which holds the V1 complex in the cytoplasm, releases the V1 complex and leans toward V-ATPase assembly. Rbc3 recruits V1 to V0 as a chaperone molecule. The dimer formation of V1E and V1G, which form the peripheral stalk of the V1 complex, is inhibited by the phosphorylation of V1G by ATM, resulting in inhibition of V-ATPase assembly. KU-60019, which inhibits ATM, promotes V-ATPase assembly. Created in BioRender.
Figure 4
Figure 4
Rpresentative mechanisms by which pathogens evade from the host phagolysosomal system. (A) Representative mechanisms by which the host senses pathogens include TLRs, FcγRs, and complement receptors, and we show bacteria that possess mechanisms that counteract this sensing. (B). It shows bacteria with an evade mechanism by inhibiting the process of phagocytosis, phagosome maturation, and fusion with lysosomes. (C). The point of action at which the function of V-ATPase is attacked and the bacteria that carry it out. Four typical mechanisms are shown. Direct inhibition of pump function, elimination of the pump from the membrane, loss of proton concentration differences by generating pores, and production of enzymes that alkalinize acidified intralumens. (D). The point of action at which the function of NOX2 is attacked and the bacteria that carry it out. Three typical mechanisms are shown: direct inhibition of the mechanism that produces superoxide, elimination of the complex from the membrane, and detoxification of the produced reactive oxygen species.
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The authors declare that this review was supported by funding from Remiges Ventures, Inc. (Tokyo, Japan). The funder was not involved in the concept of this review; writing of this article; or decision to submit it for publication.
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