Table 1. Selection of infectious diseases and their aetiological agents targeted by host-directed therapy.
| Disease | Relevance | Pathogen | Immunology and persistence strategies | Pathogenesis | Antimicrobials and antimicrobial resistance |
|---|---|---|---|---|---|
| TB: 80% pulmonary, 10% extra-pulmonary and 10% both | In 2015, 10.4 m new cases, 1.8 m deaths. 0.5 m new MDR TB cases and 0.2 m MDR TB deaths | Mycobacterium tuberculosis (Mycobacterium africanum, Mycobacterium bovis and Mycobacterium caprae) | Intracellular bacteria persisting in macrophages; T cells activate macrophages to inhibit mycobacterial growth but fail to achieve sterile eradication; role of antibodies questionable | Immunopathology; granulomas as hallmark; solid granulomas: bacterial containment; necrotic or caseous granulomas: tissue damage | Three or four drugs over 6 months; increasing incidence of MDR and XDR |
| Sepsis | Leading cause of death in ICUs in industrialized countries; 750,000 cases annually in the United States | Gram-positive and Gram-negative bacteria and fungal organisms | Initial hyper-inflammation, followed by immunosuppression; apoptotic depletion of T, B and dendritic cells, increased T regulatory cells, T cell exhaustion, shift to TH2 phenotype, type 2 macrophages, secretion of regulatory cytokines (IL-10) | Immune activation by PAMPs and DAMPs. Crosstalk between innate and adaptive immunity directs host response | Increasing development of antimicrobial resistance with MDR organisms and 'super-bugs', such as ESBL-producing Gram-negative bacteria and VRE |
| Chronic viral hepatitis | ~130 m chronic HCV and ~240 m chronic HBV infections; ~5% of chronic HBV infections are also chronically infected with HDV. Chronic hepatitis E is rarely found in immune compromised patients; no chronic hepatitis A | HBV, HCV and HDV |
• HBV: cccDNA; T cell exhaustion, probably induced by excessive amounts of subviral particles (HBsAg) • HDV: stable circular ssRNA genome persisting in nucleus of infected cells • HCV: T cell exhaustion; immune escape variants; continuous intrahepatic IFN response; cell-to-cell spread |
• Predominantly mediated by cellular immune response. Likelihood of end-stage liver disease depending on virus type • HBV: integration of viral genome (fragments) into host cell chromosomes possible • HBV–HDV coinfection: higher risk of end-stage liver disease |
• HBV: nucleoside and nucleotide analogue (life-long) or IFN; resistance depending on drug used; rarely virus elimination • HDV: no approved therapy available • HCV: combination of two or three drugs, mostly for 12 weeks; resistance is rare |
| AIDS | In 2015, 36.7 m people living with HIV or AIDS; 1.1 m died of AIDS-related illnesses worldwide | HIV-1, groups M, N and O; HIV-2 (mostly confined to West Africa) | Mostly acute lytic infection of immune cells, notably CD4+ T cells; obligatory integration into the host cell genome as provirus; latency in provirus-containing resting CD4+ T cells; cell-to-cell spread | Infection and hyper-activation or destruction of CD4+ T cells; successive loss of cell-mediated adaptive immune response and progressive susceptibility to opportunistic infections | ART: dose depends on prior treatment experience, patient age and other conditions. For treatment-naive patients, three drugs from two different classes, eventually together with a pharmacokinetic booster (for example, ritonavir) |
ART, antiretroviral therapy; cccDNA, covalently closed circular DNA; DAMPs, damage-associated molecular patterns; ESBL, extended-spectrum β-lactamase; HBsAg, HBV surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; HDT, host-directed therapy; HDV, hepatitis D virus; ICUs, intensive care units; IFN, interferon; IL-10, interleukin-10; m, million; MDR, multidrug-resistant; PAMPs, pathogen-associated molecular patterns; ssRNA, single-stranded RNA; TB, tuberculosis; TH2, T helper 2; VRE, vancomycin-resistant enterococci; XDR, extensively drug-resistant.