Kunkel Lecture: Fundamental immunodeficiency and its correction

Abstract

In the Kunkel Society Lecture, Nathan calls “fundamental immunodeficiency” the inability of the encoded immune system to protect us from every life-threatening infection. The remedy is “adopted immunity,” including antimicrobial agents. Immunologists can engage with drug developers to help overcome the rising problem of antimicrobial resistance.

Targeting the Proteostasis Network for Mycobacterial Drug Discovery

“… 17 Phenotypic drug tolerance may result from arrest of replication for individual bacteria within a larger population (Class I persistence) or synchronous arrest of replication of a population of bacteria in response to an extrinsic stress (Class II persistence). While often associated with nonreplication, Class I drug tolerance may also result from phenomena unrelated to nonreplication, 18 , 19 including stochastic expression of INH’s activating enzyme, catalase–peroxidase (KatG), 14 or mistranslation of RIF’s target, RNA polymerase subunit RpoB. 20 , 21 The mechanisms leading to Class II persistence are different from those leading to Class I persistence.…”

“… 20 , 21 The mechanisms leading to Class II persistence are different from those leading to Class I persistence. 19 For example, nonreplicating Class II persisters may have different uptake, retention, and metabolism of drugs. 6 , 19 , 22 The Class II definition of persistence is further demarcated by the ability of bacteria, upon removal of the persistence-inducing stress, to recover as colonies on solid agar (Class IIa) or recover exclusively in liquid medium upon serial dilution (Class IIb).…”

“… 19 For example, nonreplicating Class II persisters may have different uptake, retention, and metabolism of drugs. 6 , 19 , 22 The Class II definition of persistence is further demarcated by the ability of bacteria, upon removal of the persistence-inducing stress, to recover as colonies on solid agar (Class IIa) or recover exclusively in liquid medium upon serial dilution (Class IIb). 23 , 24 Bacteria exhibiting Class I phenotypic tolerance to one drug will often remain sensitive to other antibiotics, 25 while bacteria exhibiting Class II phenotypic tolerance are broadly resistant to numerous antibiotics.…”

“… 23 , 24 Bacteria exhibiting Class I phenotypic tolerance to one drug will often remain sensitive to other antibiotics, 25 while bacteria exhibiting Class II phenotypic tolerance are broadly resistant to numerous antibiotics. 19 , 26 − 29 Defining Class I and Class II persisters lays a foundation for designing rational strategies to treat human TB with antibiotics. 13 , 19 Thus, in addition to targeting actively replicating Mtb, decreasing the time of TB treatment will require additional antibiotics that eradicate Class I, IIa, and IIb drug-tolerant Mtb persisters.…”

“… 19 , 26 − 29 Defining Class I and Class II persisters lays a foundation for designing rational strategies to treat human TB with antibiotics. 13 , 19 Thus, in addition to targeting actively replicating Mtb, decreasing the time of TB treatment will require additional antibiotics that eradicate Class I, IIa, and IIb drug-tolerant Mtb persisters. 6 , 13 …”