Review Host-directed therapies for infectious diseases: current status, recent progress, and future prospects Alimuddin Zumla, Martin Rao, Robert S Wallis, Stefan H E Kaufmann, Roxana Rustomjee, Peter Mwaba, Cris Vilaplana, Dorothy Yeboah-Manu, Jeremiah Chakaya, Giuseppe Ippolito, Esam Azhar, Michael Hoelscher, Markus Maeurer, for the Host-Directed Therapies Network consortium* Despite extensive global eff orts in the fi ght against killer infectious diseases, they still cause one in four deaths Lancet Infect Dis 2016; worldwide and are important causes of long-term functional disability arising from tissue damage. The continuing 16: e47–63 epidemics of tuberculosis, HIV, malaria, and infl uenza, and the emergence of novel zoonotic pathogens represent *List of consortium partners is major clinical management challenges worldwide. Newer approaches to improving treatment outcomes are needed to available from http://www.unza- uclms.org/hdt-net-partners reduce the high morbidity and mortality caused by infectious diseases. Recent insights into pathogen–host interactions, Centre for Clinical pathogenesis, infl ammatory pathways, and the host’s innate and acquired immune responses are leading to Microbiology, Division of identifi cation and development of a wide range of host-directed therapies with diff erent mechanisms of action. Host- Infection and Immunity, directed therapeutic strategies are now becoming viable adjuncts to standard antimicrobial treatment. Host-directed University College London therapies include commonly used drugs for non-communicable diseases with good safety profi les, immunomodulatory (UCL), London, UK (Prof A Zumla FRCP); National agents, biologics (eg monoclonal antibodies), nutritional products, and cellular therapy using the patient’s own Institute for Health Research immune or bone marrow mesenchymal stromal cells. We discuss clinically relevant examples of progress in identifying Biomedical Research Centre, host-directed therapies as adjunct treatment options for bacterial, viral, and parasitic infectious diseases. UCL Hospitals NHS Foundation Trust, London, UK (Prof A Zumla); Division of Introduction mortality, and end-organ damage, and long-term Therapeutic Immunology, Infectious diseases are leading causes of morbidity functional recovery. A range of host-directed therapies Department of Laboratory and mortality worldwide.1 In high-income countries, have been identifi ed with diff erent mechanisms of action Medicine, Karolinska Institutet, mortality from respiratory tract infections remains high (fi gure 1), and they are now regarded as viable adjuncts to Stockholm, Sweden (M Rao PhD, despite access to quality health services and availability of standard antimicrobial treatment. Host-directed Prof M Maeurer PhD); Centre for antibiotic therapy.1 The intermittent emergence of new therapies can improve host cellular responses to Allogeneic Stem Cell zoonotic pathogens and the increasing incidence of pathogens, target disease-causing virulence factors Transplantation, Karolinska treatment-resistant infections draws attention to the (fi gure 2), and activate innate and adaptive immune University Hospital Huddinge, Stockholm, Sweden (M Rao, 2 limits of the current antimicrobial treatment portfolio responses and immunological memory (fi gure 3). Prof M Maeurer); and the urgent need for alternative management strategies. In evolutionary terms, host–pathogen interactions are Key messages dependent on the microbe surviving without causing • Despite the availability of antimicrobial drugs, infectious diseases are leading causes of harm to the host. The host’s innate and adaptive immune morbidity and mortality worldwide. surveillance mechanisms govern whether the infection • The widespread emergence of antimicrobial resistance calls for novel interventions in will be contained or progress to clinical disease with addition to new antimicrobial development. either recovery or death. Several host factors aff ect • A range of host factors are responsible for development of disease, poor treatment antimicrobial treatment outcome and are responsible for response, and increased mortality. These include immune dysregulation from any progression of disease after infection, poor treatment cause and comorbidity with non-communicable diseases such as diabetes, cancer, response, tissue damage, long-term functional disability, smoking, and chronic obstructive pulmonary disease. and increased mortality. These factors include immune • During the past 4 years, a renaissance of scientifi c research strategies targeting host dysregulation from any cause (aberrant or excess factors—rather than pathogen components directly—is leading to development of a host infl ammatory response to infection, stress, wide range of host-directed therapies that target and modify biological pathways to immunosuppressive drugs, poor living conditions, achieve a positive clinical treatment outcome. socioeconomic factors, micronutrient defi ciencies, HIV, • Host-directed therapies can augment host cellular responses to pathogens, target malnutrition, and alcohol or substance misuse) and disease-causing virulence factors, activate innate and adaptive protective immune comorbidity with non-communicable diseases such as responses, or modulate excessive infl ammation, leading to reduced morbidity, diabetes, cancer, smoking, and chronic obstructive mortality, and end-organ damage. 1 pulmonary disease. • Host-directed therapies include commonly used, safe, and cheap drugs for During the past 4 years, a renaissance of scientifi c non-communicable diseases; biologics; nutritional products; and cellular therapy, research strategies targeting host factors, rather than using the patient’s own immune or mesenchymal stromal cells. pathogen components directly, has opened up novel • The broad spectrum effi cacy of host-directed therapies could also be useful for treatment approaches termed host-directed therapies. A treatment of infectious diseases with epidemic potential, which are associated with host-directed therapy is any product that can augment high mortality. host defence mechanisms or modulate excessive • Host-directed therapies have the additional unique benefi t of preventing or reducing infl ammation, or both, leading to improved clinical the development of antibiotic resistance. treatment outcomes as shown by reduced morbidity, www.thelancet.com/infection Vol 16 April 2016 e47 Review Aurum Institute, Johannesburg, South Africa (Prof R S Wallis MD); Max Planck Institute for Infection Biology, Berlin, Germany (Prof S H E Kaufmann PhD); Monoclonal antibodies Vitamins Repurposed drugs South African Medical Research Council, Cape Town, South CH H Africa (R Rustomjee PhD); NH NH H C University of Zambia-UCL H 3 H N NH2 Medical School (UNZA-UCLMS) H CH3 Research and Training Project, H0 CH University Teaching Hospital, Lusaka, Zambia (P Mwaba PhD); Ministry of Health, Lusaka, Amelioration Zambia (P Mwaba); Unitat de Tuberculosi Experimental Host-directed therapies Fundació Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol CIBER Enfermedades Respiratorias, Can Ruti Campus, Edifici Laboratoris de Disease Recerca, Barcelona, Spain (C Vilaplana PhD); Bacteriology Department, Noguchi Memorial Institute for Medical Research, University of Ghana, Cytokines Cellular therapy Recombinant proteins Legon, Ghana (Prof D Yeboah-Manu PhD); Kenya Medical Research Clinical cure Institute, Nairobi, Kenya (J Chakaya PhD); National Institute for Infectious Figure 1: The main types of host-directed therapies Diseases, Lazzaro Spallanzani, Host-directed therapies focus on ameliorating the severity of disease and improving treatment outcomes. Host-directed therapies constitute a range of therapeutic Rome, Italy (Prof G Ippolito MD); agents such as repurposed drugs, small molecules, synthetic nucleic acids, biologics (such as monoclonal antibodies), cytokines, cellular therapy, recombinant Special Infectious Agents Unit, proteins, and micronutrients. King Fahd Medical Research Centre, and Medical Laboratory Technology Department, Examples of host-directed therapies include commonly with WHO-recommended combination antituberculosis Faculty of Applied Medical used and aff ordable drugs for non-communicable antibiotic therapy. This focus still thrives, although there Sciences, King Abdulaziz diseases with good safety profi les, immunomodulatory are about 2 billion people in the world with latent University, Jeddah, Saudi 89 Arabia (E Azhar PhD); Division agents, biologics, nutritional products, and cellular tuberculosis infection who do not develop active disease. of Infectious Diseases and therapy using the patient’s own immune or mesenchymal Furthermore, the substantial decline in tuberculosis in Tropical Medicine, Medical stromals cells (table 1). See appendix for discussion of Europe and North America in the fi rst half of the Centre of the University of potential host factors for targets of host-directed therapy 19th century occurred well before the antibiotic era. In Munich, Munich, Germany (Prof M Hoelscher PhD); and against infectious disease. 2014, an estimated 1·5 million people died of tuberculosis DZIF German Centre for Studies of host-directed therapies also enable new and there were an estimated 450 000 cases of multidrug- Infection Research, Munich, insights into underlying mechanisms of pathogenesis, resistant (MDR) and extensively drug-resistant (XDR) Germany (Prof M Hoelscher) infl ammatory pathways, and the host’s innate and tuberculosis,89 suggesting that host