Host-directed therapeutics
Host-directed therapeutics, also called host targeted therapeutics, act via a host-mediated responses to pathogens rather than acting directly on the pathogen, like traditional antibiotics. They can change the local environment in which the pathogen exists to make it less favorable for the pathogen to live and/or grow. With these therapies, pathogen killing, e.g.bactericidal effects, will likely only occur when it is co-delivered with a traditional agent that acts directly on the pathogen, such as an antibiotic, antifungal, or antiparasitic agent.[1][2][3] Several antiviral agents are host-directed therapeutics, and simply slow the virus progression rather than kill the virus. Host-directed therapeutics may limit pathogen proliferation, e.g., have bacteriostatic effects.
Mechanism of Action
- Immunomodulatory: Intracellular pathogens often reside in immune cells like macrophages. These pathogens can be obligate or facultative intracellular pathogens. Changing the innate immune response of these host-cells can alter the pathogen's ability to live inside the cell. Many of these immunomodulatory host-directed therapies are adjuvants or pathogen-associated molecular patterns. They can include Toll-like receptors (TLRs), NOD-like receptors (NLRs), C-type lectin receptors (CLRs), mannose receptor (MR), dendritic cell-specific intracellular adhesion molecule 3 (ICAM3)-grabbing nonintegrin (DC-SIGN), complement receptors, Fc receptors, and DNA sensors (e.g., STING). Epithelial cells also host pathogens, like Salmonella enterica. These immunomodulatory agents can also alter the epithelial cell environments, since they also have a role in innate signalling.
- Enhance host cell function: Autophagy modulators are one type of method to enhance host cell functions. Pathogens like Mycobacterium tuberculosis (MTB), will be degraded in the autophagosome during an effective host response that will clear the bacteria. Because bacteria and other pathogens like MTB can take over cellular responses like autophagy, they can increase their survival in the body. By reactivating effective autophagy processes the pathogen could be cleared. Examples of this has been shown with MTB,[1] and Listeria monocytogenes.[1] OSU-03012 is thought to modulate autophagy in its effect on Salmonella enterica,[4][5] and Francisella tularensis.[6][7]
- Modify pathology: Modifying lung and macrophage pathology has been shown to have a role in the host-directed therapies for MTB.[1]
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References
- Hawn, TR; Matheson, AI; Maley, SN; Vandal, O (2013). "Host-directed therapeutics for tuberculosis: can we harness the host?". Microbiol Mol Biol Rev. 77 (4): 608. doi:10.1128/MMBR.00032-13. PMC 3973381. PMID 24296574.
- Mahon, RN; Hafner, R (2017). "Applying Precision Medicine and Immunotherapy Advances from Oncology to Host-Directed Therapies for Infectious Diseases". Front Immunol. 8: 688. doi:10.3389/fimmu.2017.00688. PMC 5489679. PMID 28706516.
- Armstrong-James, D; Brown, GD; Netea, MG; Zelante, T; Gresnigt MS, MS; van de Veerdonk, FL; Levitz, SM (2017). "Immunotherapeutic approaches to treatment of fungal diseases". Lancet Infect Dis. 17: e393–e402. doi:10.1016/S1473-3099(17)30442-5. hdl:10044/1/57316. PMID 28774700.
- Chiu, HC; Kulp, SK; Soni, S; Wang, D; Gunn, JS; Schlesinger, LS; Chen, CS (Dec 2009). "Eradication of intracellular Salmonella enterica serovar Typhimurium with a small-molecule, host cell-directed agent". Antimicrob Agents Chemother. 53 (12): 5236. doi:10.1128/aac.00555-09. PMC 2786354. PMID 19805568.
- Hoang, KV; Borteh, HM; Rajaram, MV; Peine, KJ; Curry, H; Collier, MA; Homsy, ML; Bachelder, EM; Gunn, JS; Schlesinger, LS; Ainslie, KM (Dec 2014). "Acetalated dextran encapsulated AR-12 as a host-directed therapy to control Salmonella infection". Int J Pharm. 477 (1–2): 334. doi:10.1016/j.ijpharm.2014.10.022. PMC 4267924. PMID 25447826.
- Chiu, HC; Soni, S; Kulp, SK; Curry, H; Wang, D; Gunn, JS; Schlesinger, LS; Chen, CS (Dec 2009). "Eradication of intracellular Francisella tularensis in THP-1 human macrophages with a novel autophagy inducing agent". J Biomed Sci. 16: 110. doi:10.1186/1423-0127-16-110. PMC 2801672. PMID 20003180.
- Hoang, KV; Curry, H; Collier, MA; Borteh, H; Bachelder, EM; Schlesinger, LS; Gunn, JS; Ainslie, KM (Mar 25, 2016). "Needle-Free Delivery of Acetalated Dextran-Encapsulated AR-12 Protects Mice from Francisella tularensis Lethal Challenge". Antimicrob Agents Chemother. 60 (4): 2052–2062. doi:10.1128/AAC.02228-15. PMC 4808193. PMID 26787696.
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