Host-directed immunotherapy of viral and bacterial infections: past, present and future

Abstract

The advent of COVID-19 and the persistent threat of infectious diseases such as tuberculosis, malaria, influenza and HIV/AIDS remind us of the marked impact that infections continue to have on public health. Some of the most effective protective measures are vaccines but these have been difficult to develop for some of these infectious diseases even after decades of research. The development of drugs and immunotherapies acting directly against the pathogen can be equally challenging, and such pathogen-directed therapeutics have the potential disadvantage of selecting for resistance. An alternative approach is provided by host-directed therapies, which interfere with host cellular processes required for pathogen survival or replication, or target the host immune response to infection (immunotherapies) to either augment immunity or ameliorate immunopathology. Here, we provide a historical perspective of host-directed immunotherapeutic interventions for viral and bacterial infections and then focus on SARS-CoV-2 and Mycobacterium tuberculosis, two major human pathogens of the current era, to indicate the key lessons learned and discuss candidate immunotherapeutic approaches, with a focus on drugs currently in clinical trials.

Fig. 1. Timeline of key developments in host-directed immunotherapeutic interventions for infectious disease.

Indicated are the time of discovery or first description for corticosteroids, interferons, IL-2, IL-6 receptor antagonists and Janus kinase (JAK) inhibitors, together with their successful uses in humans as immunotherapies for the indicated non-infectious and infectious diseases. Asterisks indicate therapies that were ultimately adopted into routine clinical use^–. TB, tuberculosis.

Fig. 2. Host-directed immunotherapeutic intervention points for severe COVID-19.

If the initial interferon and inflammatory responses are insufficient to control SARS-CoV-2 infection, the inflammatory cascade may persist and become hyperactivated. This can lead to monocyte and neutrophil infiltration into the lung, high local and systemic levels of cytokines, tissue damage in the lung, formation of neutrophil extracellular traps (NETosis), complement hyperactivation, coagulation, and the formation of microthrombi. Immunotherapeutic interventions aim to improve virus control early in infection (indicated in green) or to limit immune-mediated tissue damage owing to uncontrolled inflammation (indicated in red). JAK, Janus kinase.

Fig. 3. Interferons and immunotherapeutic intervention: COVID-19 and tuberculosis.

Interferons are thought to have both protective and detrimental effects in COVID-19 and in tuberculosis. a | COVID-19. Lung epithelial cells produce type I interferon and type III interferon upon infection with SARS-CoV-2. Both types of interferon contribute to the establishment of an antiviral state in infected and adjacent cells through the induction of interferon-stimulated genes (ISGs). Immunotherapeutic intervention early after infection includes treatment with interferons, in particular with type III interferon, to reduce virus replication. Later in infection, type I interferon drives sustained inflammation, and type III interferon may contribute to impaired tissue repair. Therefore, late treatment with interferons should be avoided. Instead, monoclonal antibody-mediated interferon blockade may be considered, and treatment with Janus kinase (JAK) inhibitors may exert its beneficial effect partly through blocking the deleterious effects of interferons. b | In tuberculosis, type I interferon can promote disease by recruiting infection-permissive myeloid cells, by inhibiting intracellular control of bacterial growth in macrophages and by promoting immunopathology through necrosis of infected macrophages as well as neutrophils through the release of neutrophil extracellular traps (NETosis). By contrast, there is also evidence that type I interferon, under certain conditions, can enhance host resistance to Mycobacterium tuberculosis. The basis of these divergent effects of type I interferon on M. tuberculosis is poorly understood. As yet, there have been no published clinical trials that directly target this pathway in tuberculosis.

Fig. 4. Major candidates for host-directed immunotherapies and their targets in tuberculosis.

Host-directed immunotherapies for Mycobacterium tuberculosis infection can act early in the response to augment immunity or later in the response to reduce immunopathology. Although the control of M. tuberculosis infection clearly depends on both interferon-γ (IFNγ) production and T cell responses, immunotherapies targeting these elements — through IFNγ administration or PD1 blockade — have shown only limited promise in certain conditions or have proven detrimental, respectively. Administration of IL-2 to enhance T cell responses showed no clear benefit in clinical trials. Type I interferon blockade, despite having potent preclinical effects in ameliorating immunopathology, has unexplained effects on increasing the mycobacterial load in certain models. Also of note is that some interventions (such as mechanistic target of rapamycin (mTOR) inhibitors and anti-oxidants) have host-protective effects by both inhibiting pathogen growth and ameliorating immunopathology despite their original intended target being to augment immunity. Nearly all clinical trials of candidates for host-directed immunotherapy of tuberculosis are carried out adjunctively with antibiotics. COX2, cyclooxygenase 2; JAK, Janus kinase.