Biology:Host-directed therapeutics
Host-directed therapeutics, also called host targeted therapeutics, act via a host-mediated response 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. Certain agents also have the ability to reduce bacterial load by enhancing host cell responses even in the absence of traditional antimicrobial agents.[4][5][6]
Types
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.[citation needed]
Enhanced 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,[7][8] and Francisella tularensis.[9][10]
Pathology modification
Modifying lung and macrophage pathology has been shown to have a role in the host-directed therapies for MTB.[1]
References
- ↑ 1.0 1.1 1.2 1.3 "Host-directed therapeutics for tuberculosis: can we harness the host?". Microbiology and Molecular Biology Reviews 77 (4): 608–27. December 2013. doi:10.1128/MMBR.00032-13. PMID 24296574.
- ↑ "Applying Precision Medicine and Immunotherapy Advances from Oncology to Host-Directed Therapies for Infectious Diseases". Frontiers in Immunology 8: 688. 2017. doi:10.3389/fimmu.2017.00688. PMID 28706516.
- ↑ "Immunotherapeutic approaches to treatment of fungal diseases". The Lancet. Infectious Diseases 17 (12): e393–e402. December 2017. doi:10.1016/S1473-3099(17)30442-5. PMID 28774700.
- ↑ "Delayed Administration of Recombinant Plasma Gelsolin Improves Survival in a Murine Model of Penicillin-Susceptible and Penicillin-Resistant Pneumococcal Pneumonia". The Journal of Infectious Diseases 220 (9): 1498–1502. September 2019. doi:10.1093/infdis/jiz353. PMID 31287867.
- ↑ "Free actin impairs macrophage bacterial defenses via scavenger receptor MARCO interaction with reversal by plasma gelsolin". American Journal of Physiology. Lung Cellular and Molecular Physiology 312 (6): L1018–L1028. June 2017. doi:10.1152/ajplung.00067.2017. PMID 28385809.
- ↑ "Plasma gelsolin improves lung host defense against pneumonia by enhancing macrophage NOS3 function". American Journal of Physiology. Lung Cellular and Molecular Physiology 309 (1): L11-6. July 2015. doi:10.1152/ajplung.00094.2015. PMID 25957291.
- ↑ "Eradication of intracellular Salmonella enterica serovar Typhimurium with a small-molecule, host cell-directed agent". Antimicrobial Agents and Chemotherapy 53 (12): 5236–44. December 2009. doi:10.1128/aac.00555-09. PMID 19805568.
- ↑ "Acetalated dextran encapsulated AR-12 as a host-directed therapy to control Salmonella infection". International Journal of Pharmaceutics 477 (1–2): 334–43. December 2014. doi:10.1016/j.ijpharm.2014.10.022. PMID 25447826.
- ↑ "Eradication of intracellular Francisella tularensis in THP-1 human macrophages with a novel autophagy inducing agent". Journal of Biomedical Science 16 (1): 110. December 2009. doi:10.1186/1423-0127-16-110. PMID 20003180.
- ↑ "Needle-Free Delivery of Acetalated Dextran-Encapsulated AR-12 Protects Mice from Francisella tularensis Lethal Challenge". Antimicrobial Agents and Chemotherapy 60 (4): 2052–62. April 2016. doi:10.1128/AAC.02228-15. PMID 26787696.
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