Host-directed therapies for infectious diseases: current status, recent progress, and future prospects

Abstract

Despite extensive global efforts in the fight against killer infectious diseases, they still cause one in four deaths worldwide and are important causes of long-term functional disability arising from tissue damage. The continuing epidemics of tuberculosis, HIV, malaria, and influenza, and the emergence of novel zoonotic pathogens represent major clinical management challenges worldwide. Newer approaches to improving treatment outcomes are needed to reduce the high morbidity and mortality caused by infectious diseases. Recent insights into pathogen-host interactions, pathogenesis, inflammatory pathways, and the host's innate and acquired immune responses are leading to identification and development of a wide range of host-directed therapies with different mechanisms of action. Host-directed therapeutic strategies are now becoming viable adjuncts to standard antimicrobial treatment. Host-directed therapies include commonly used drugs for non-communicable diseases with good safety profiles, immunomodulatory agents, biologics (eg monoclonal antibodies), nutritional products, and cellular therapy using the patient's own immune or bone marrow mesenchymal stromal cells. We discuss clinically relevant examples of progress in identifying host-directed therapies as adjunct treatment options for bacterial, viral, and parasitic infectious diseases.

Figure 1

The main types of host-directed therapies Host-directed therapies focus on ameliorating the severity of disease and improving treatment outcomes. Host-directed therapies constitute a range of therapeutic agents such as repurposed drugs, small molecules, synthetic nucleic acids, biologics (such as monoclonal antibodies), cytokines, cellular therapy, recombinant proteins, and micronutrients.

Figure 2

Host-directed therapies as a means to counteract antimicrobial resistance Pathogens develop resistance to antimicrobial therapy via various factors, including modification of cell-surface proteins and intracellular enzymes (bacteria and parasites), modification of envelope proteins (viruses), secretion of toxins (bacteria and parasites), sporulation and dormancy (bacteria, viruses, and fungi), activation of efflux pumps (bacteria, fungi, and parasites), and decreased permeability of cell wall (bacteria and fungi). These virulence factors impede cellular functions (solid blockade), which are required to successfully eradicate the pathogen. Host-directed therapies can counter these mechanisms by targeting impaired intracellular processes in affected host cells (blue arrow), by mechanisms such as activation of autophagy and apoptosis, induction of oxidative and nitrosative stress, and increased antigen processing and presentation, which in turn trigger necessary adaptive immune responses. Novel host-directed therapeutic strategies target host surface receptors, such as programmed death-ligand 1 (PD-L1; involved in immune exhaustion) and sialic acid-containing receptor (SAR; enhances entry of pathogens into host cells). Histone modification is done by targeting genes involved in pathogen replication and induction of apoptosis, autophagy, and antigen processing and presentation. Fatty-acid metabolism might have a role in maintenance of memory CD8 cytotoxic T-lymphocyte pools in the host. Responses induced by host-directed therapies might counteract microbial virulence factors (dotted blockade), in addition to neutralising tissue damage.

Figure 3

Possible biological pathways and mechanisms for host-directed interventions against infectious diseases Pharmacological activation of autophagy or apoptosis, or both, drives improved intracellular killing of pathogens and enhanced antigen presentation. Activation and recruitment of antigen-presenting cells (ie, dendritic cells and macrophages) via therapy with the pro-inflammatory cytokines interferon γ (IFNγ), granulocyte-macrophage colony-stimulating factor (GM-CSF), and IFNγ-induced protein (IP-10), among others, could amplify the antimicrobial immune response. Several anticancer drugs (ie, cisplatin, gemcitabine, and paclitaxel) can potentiate antigen-specific CD8 cytotoxic T-lymphocyte (CTL) responses in patients by inducing production of interleukin (IL) 12, tumour necrosis factor γ (TNFγ), and IL 6. Immune checkpoint inhibition by blocking the programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway activates antigen-specific T cells. In-vitro selection and expansion of pathogen-specific autologous T-cell subsets (antigen-specific CD4 T cells and CD8 CTLs) can allow for reinfusion into the patient after confirmation of activity. Blockade of cell surface-bound signalling molecules, such as the receptors for IL 6 and neuropilin 1 (NRP-1), may potentiate specific T-cell responses. Removal of excess inflammatory cytokines by use of monoclonal antibodies, or depletion of regulatory T cells (Treg) with cytotoxic agents (eg, cyclophosphamide and etoposide) dampens destructive inflammation in the target organs, and might re-orientate Mycobacterium tuberculosis-targeted immune responses (T-helper-1 [Th1] and CD8 CTLs). Histone deacetylase inhibitors, valproic acid, and vorinostat, might reprogramme non-productive Th2 cells to antigen-specific Th1 cells. Infusion of autologous mesenchymal stromal cells (MSCs) could neutralise the local cytokine milieu, promote tissue repair, and orchestrate antigen-specific T-cell responses, in multidrug-resistant tuberculosis. Host-cell surface receptors used by pathogens for entry could be targeted by host-directed therapies. AMP=antimicrobial peptide. BCR=B-cell receptor. M-CSF=macrophage colony-stimulating factor. PGE2=prostaglandin E2. TCR=T-cell receptor. TGF=transforming growth factor. TGFβ=TGF β. VD3=vitamin D3. VEGF=vascular endothelial growth factor.