Host-directed therapies for bacterial and viral infections

Abstract

Despite the recent increase in the development of antivirals and antibiotics, antimicrobial resistance and the lack of broad-spectrum virus-targeting drugs are still important issues and additional alternative approaches to treat infectious diseases are urgently needed. Host-directed therapy (HDT) is an emerging approach in the field of anti-infectives. The strategy behind HDT is to interfere with host cell factors that are required by a pathogen for replication or persistence, to enhance protective immune responses against a pathogen, to reduce exacerbated inflammation and to balance immune reactivity at sites of pathology. Although HDTs encompassing interferons are well established for the treatment of chronic viral hepatitis, novel strategies aimed at the functional cure of persistent viral infections and the development of broad-spectrum antivirals against emerging viruses seem to be crucial. In chronic bacterial infections, such as tuberculosis, HDT strategies aim to enhance the antimicrobial activities of phagocytes and to curtail inflammation through interference with soluble factors (such as eicosanoids and cytokines) or cellular factors (such as co-stimulatory molecules). This Review describes current progress in the development of HDTs for viral and bacterial infections, including sepsis, and the challenges in bringing these new approaches to the clinic.

Figure 1. Replication cycles of HCV, HBV and HIV and points of intervention by HDTs.

a I Upon entry of hepatitis C virus (HCV) into the cell, viral RNA is translated at the endoplasmic reticulum (ER) and a membranous replication factory is formed (a membranous web). There, viral RNA (vRNA) is amplified and packaged into nucleocapsids that bud into the ER. Enveloped virions are secreted out of the cell. b I In the case of HBV, upon virus entry, the partially double-stranded viral DNA genome is converted into the covalently closed circular DNA (cccDNA) form that persists as an episome in the nucleus. vRNAs are transcribed and used for protein synthesis. Within the nucleocapsids the vRNA pre-genome is reverse transcribed by the viral polymerase (red circle) and virions are formed by budding into the ER lumen. Virions are secreted from the cell, along with subviral particles (SVPs) that lack a nucleocapsid and so are non-infectious. SVPs are composed of the same envelope (Env) proteins as infectious HBV particles. c I HIV enters upon interaction with the CD4 receptor and a co-receptor (such as CCR5) by direct fusion of the viral envelope with the plasma membrane. Nucleocapsids that contain the RNA genome are released into the cytoplasm and upon reverse transcription a pre-integration complex (PIC) containing the viral integrase (green bar) is formed. The viral DNA genome (blue) is inserted into the host cell genome (light purple) and this provirus serves as a template for the transcription of all viral mRNAs (vRNAs). These are translated in the cytoplasm and give rise to HIV proteins; some of them (the Gag and Gag–Pol polyprotein precursors) are transported to the plasma membrane to trigger the formation of nucleocapsids. These nucleocapsids acquire their envelope by budding at the plasma membrane. The viral polyproteins are cleaved within the released virions, thus inducing a rearrangement of the structural proteins, visible by morphological conversion into a conical nucleocapsid. Only these particles are infectious. CypA, cyclophilin A; HBIGs, hepatitis B immunoglobulins; HDT, host-directed therapy; ISGs, interferon-stimulated genes; TCR, T cell receptor. PowerPoint slide

Figure 2. HDTs that target macrophages in TB.

Mycobacterium tuberculosis (Mtb) is phagocytosed by macrophages and interferes with endosomal maturation. Bacilli block the fusion of the phagosome with lysosomes, egress into the cytosol, restrict autophagy and induce the accumulation of lipid bodies. The anti-mycobacterial activity of the macrophage is enhanced by stimulation with cytokines, as well as with factors that promote the secretion of antimicrobial peptides, such as vitamins. Several host-directed therapies (HDTs) have been directed at each stage of the macrophage life cycle of Mtb to overcome resistance to microbial killing. Each box indicates drugs or classes of drugs with proven effects on antimicrobial immunity. HDAC, histone deacetylase; IFNγ, interferon-γ; mTOR, mammalian target of rapamycin; PDE, phosphodiesterase; TB, tuberculosis; TNF, tumour necrosis factor. PowerPoint slide

Figure 3. HDTs that target inflammatory responses and granulomas in TB.

During latent tuberculosis (TB), lung lesions may be absent or may present as solid, eventually fibrotic and mineralized granulomas. During active TB, granulomas progress towards necrosis and caseation, leading to cavitation and bacterial expectoration. Such lesions contain Mycobacterium tuberculosis (Mtb) in distinct metabolic and replicative stages: replicating and metabolically active bacilli in caseous granulomas; and non-replicative, dormant bacteria in the hypoxic environment of solid granulomas. In a single patient, different granuloma types coexist that harbour Mtb with an active or a dormant phenotype. Hence, strategies to restrict or to promote inflammation are envisaged as potential host-directed therapy (HDT) for TB. The selection of a particular HDT depends on the rationale for applying it as stand-alone treatment, for example, to limit exacerbated tissue damage, or as an adjunct to canonical TB therapy to promote inflammation and facilitate killing of actively replicating Mtb. Interference with arachidonic acid (AA) metabolism, which generates both pro- and anti-inflammatory metabolites and which also modulates patterns of cell death in infected cells, and interference with cytokine signalling and selected cellular therapies, such as the maturation of myeloid-derived suppressor cells (MDSCs) and the infusion of mesenchymal stem cells (MSCs), can correct exacerbated inflammation. The amendment of immune suppression by checkpoint blockade can restrict inflammation by correcting levels of protective interferon-γ (IFNγ); however, this may facilitate hyper-inflammation once pathological levels of the cytokine are achieved. Drugs interfering with such mechanisms limit immunopathology and help to preserve tissue functionality. Immune-suppressive drugs, notably glucocorticoids and biologics, besides limiting life-threatening inflammation, reduce the local abundance of host-protective cytokines and thereby facilitate lesion caseation and promote the resuscitation of dormant Mtb. Metabolically active bacteria can be targeted by canonical TB chemotherapy. Limiting vasculogenesis restricts nutrient supply and access of Mtb-permissive cells to granulomas. Metformin, glycolytic agents and kinase inhibitors interfere with metabolic pathways activated under hypoxic conditions that support bacillary replication, and inhibition of matrix metalloproteinases (MMPs) limits collateral damage and Mtb spread. Boxes indicate drugs that interfere with angiogenesis, metabolic pathways and factors that promote tissue damage. AICAR, 5-aminoimidazole-4- carboxamide ribonucleotide; AMPK, 5′ adenosine monophosphate- activated protein kinase; COX, cyclooxygenase; CTLA4, cytotoxic T lymphocyte associated protein 4; GAL9, galectin 9; LOX, lipoxygenase; MHC, major histocompatibility complex; mTOR, mammalian target of rapamycin; NK, natural killer; NSAID, non-steroidal anti-inflammatory drug; PDE, phosphodiesterase; PD1, programmed cell death protein 1; PDL1, PD1 ligand 1; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; TCR, T cell receptor; TIM3, T cell immunoglobulin mucin receptor 3; TNF, tumour necrosis factor; VEGF, vascular endothelial growth factor. PowerPoint slide

Figure 4. HDT of sepsis.

During protracted sepsis, several mechanisms and pathways that impair the host's ability to defend against sepsis become activated with limited collateral damage and lower survival rates. Drugs that activate host immunity or that block inhibitory pathways offer new therapeutic approaches in sepsis. The four boxes on the top and left indicate potential immuno-adjuvant therapies that enhance host immunity. The three boxes on the right with inhibitory arrows indicate drugs that prevent inhibitory pathways from impairing host immunity. Bacteria are indicated by the orange rod-shaped structures that are shown engulfed inside the macrophage and at the bottom of the figure. CTLA4, cytotoxic T lymphocyte protein 4; FLT3L, FMS-like tyrosine kinase 3 ligand; GM-CSF, granulocyte–macrophage colony-stimulating factor; HDT, host-directed therapy; IFNγ, interferon-γ; MDSC, myeloid-derived suppressor cell; MØ, macrophage; PD1, programmed cell death 1; PDL1, PD1 ligand 1; PMN, polymorphonuclear leukocyte; RNS, reactive nitrogen species; TGFβ, transforming growth factor-β; T_H2, T helper 2; T_reg, T regulatory cell. PowerPoint slide