TY - JOUR
T1 - Host-Directed Therapies
T2 - Modulating Inflammation to Treat Tuberculosis
AU - Krug, Stefanie
AU - Parveen, Sadiya
AU - Bishai, William R.
N1 - Funding Information:
The authors gratefully acknowledge the support of NIH grants AI 152688, 155602, 130595 and HL 140812.
Publisher Copyright:
© Copyright © 2021 Krug, Parveen and Bishai.
PY - 2021/4/19
Y1 - 2021/4/19
N2 - Following infection with Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), most human hosts are able to contain the infection and avoid progression to active TB disease through expression of a balanced, homeostatic immune response. Proinflammatory mechanisms aiming to kill, slow and sequester the pathogen are key to a successful host response. However, an excessive or inappropriate pro-inflammatory response may lead to granuloma enlargement and tissue damage, which may prolong the TB treatment duration and permanently diminish the lung function of TB survivors. The host also expresses certain anti-inflammatory mediators which may play either beneficial or detrimental roles depending on the timing of their deployment. The balance between the timing and expression levels of pro- and anti-inflammatory responses plays an important role in the fate of infection. Interestingly, M. tuberculosis appears to manipulate both sides of the human immune response to remodel the host environment for its own benefit. Consequently, therapies which modulate either end of this spectrum of immune responses at the appropriate time may have the potential to improve the treatment of TB or to reduce the formation of permanent lung damage after microbiological cure. Here, we highlight host-directed TB therapies targeting pro- or anti-inflammatory processes that have been evaluated in pre-clinical models. The repurposing of already available drugs known to modulate these responses may improve the future of TB therapy.
AB - Following infection with Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), most human hosts are able to contain the infection and avoid progression to active TB disease through expression of a balanced, homeostatic immune response. Proinflammatory mechanisms aiming to kill, slow and sequester the pathogen are key to a successful host response. However, an excessive or inappropriate pro-inflammatory response may lead to granuloma enlargement and tissue damage, which may prolong the TB treatment duration and permanently diminish the lung function of TB survivors. The host also expresses certain anti-inflammatory mediators which may play either beneficial or detrimental roles depending on the timing of their deployment. The balance between the timing and expression levels of pro- and anti-inflammatory responses plays an important role in the fate of infection. Interestingly, M. tuberculosis appears to manipulate both sides of the human immune response to remodel the host environment for its own benefit. Consequently, therapies which modulate either end of this spectrum of immune responses at the appropriate time may have the potential to improve the treatment of TB or to reduce the formation of permanent lung damage after microbiological cure. Here, we highlight host-directed TB therapies targeting pro- or anti-inflammatory processes that have been evaluated in pre-clinical models. The repurposing of already available drugs known to modulate these responses may improve the future of TB therapy.
KW - MDSCs
KW - MMPs (metalloproteinases)
KW - PARP inhibition (PARPi)
KW - diphtheria fusion protein toxin
KW - host-directed therapies
KW - immunotherapy
KW - tuberculosis
UR - http://www.scopus.com/inward/record.url?scp=85104956093&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85104956093&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2021.660916
DO - 10.3389/fimmu.2021.660916
M3 - Review article
C2 - 33953722
AN - SCOPUS:85104956093
SN - 1664-3224
VL - 12
JO - Frontiers in immunology
JF - Frontiers in immunology
M1 - 660916
ER -