Host-directed therapies for bacterial and viral infections

• Published in: Nature reviews. Drug discovery Vol. 17; no. 1; pp. 35 - 56
• Main Authors: Kaufmann, Stefan H. E., Dorhoi, Anca, Hotchkiss, Richard S., Bartenschlager, Ralf
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2018; Nature Publishing Group
• Subjects: 631/250/255/234/2513; 631/250/255/2514; 631/92/609; 639/638/309/2144; 692/308/153; 692/699; 692/699/255; 692/699/255/1856; 692/700/565/1436; Anti-Infective Agents - therapeutic use; Antimicrobial agents; Bacterial infections; Bacterial Infections - immunology; Bacterial Infections - therapy; Biomedicine; Biotechnology; Cancer Research; Communicable diseases; Drug Resistance - drug effects; Drug targeting; Drug therapy; Host-parasite relationships; Host-Pathogen Interactions - drug effects; Host-Pathogen Interactions - immunology; Humans; Infections; Medicinal Chemistry; Methods; Molecular Medicine; Pharmaceutical Research; Pharmacology/Toxicology; review-article; Viral infections; Virus Diseases - immunology; Virus Diseases - therapy; United States
• ISSN: 1474-1776; 1474-1784; 1474-1784
• DOI: 10.1038/nrd.2017.162

Key Points Host-directed therapy (HDT) is a novel approach in the field of anti-infectives for overcoming antimicrobial resistance. HDT aims 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. HDTs encompassing the 'shock and kill' strategy or the delivery of recombinant interferons are possible approaches to treat HIV infections. HDTs that suppress the cytokine storm that is induced by some acute viral infections represent a promising concept. In tuberculosis, HDT aims to enhance the antimicrobial activities of phagocytes through phagosomal maturation, autophagy and antimicrobial peptides. HDTs also curtail inflammation through interference with soluble (such as eicosanoids or cytokines) or cellular (co-stimulatory molecules) factors and modulate granulomas to allow the access of antimicrobials or to restrict tissue damage. Numerous parallels between the immunological abnormalities that occur in sepsis and cancer indicate that the HDTs that are effective in oncology may also hold promise in sepsis. Advances in immune phenotyping, genetic screening and biosignatures will help to guide drug therapy to optimize the host response. Combinations of canonical pathogen-directed drugs and novel HDTs will become indispensable in treating emerging infections and diseases caused by drug-resistant pathogens. Host-directed therapy (HDT) aims to interfere with host cell factors that are required by a pathogen for replication or persistence. In this Review, Kaufmann et al . describe recent progress in the development of HDTs for the treatment of viral and bacterial infections and the challenges in bringing these approaches to the clinic. 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.