Macrophages use a bet-hedging strategy for antimicrobial activity in phagolysosomal acidification
Open Access
- 1 July 2020
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 130 (7), 3805-3819
- https://doi.org/10.1172/jci133938
Abstract
Microbial ingestion by a macrophage results in the formation of an acidic phagolysosome but the host cell has no information on the pH susceptibility of the ingested organism. This poses a problem for the macrophage and raises the fundamental question of how the phagocytic cell optimizes the acidification process to prevail. We analyzed the dynamical distribution of phagolysosomal pH in murine and human macrophages that had ingested live or dead Cryptococcus neoformans cells, or inert beads. Phagolysosomal acidification produced a range of pH values that approximated normal distributions, but these differed from normality depending on ingested particle type. Analysis of the increments of pH reduction revealed no forbidden ordinal patterns, implying that the phagosomal acidification process was a stochastic dynamical system. Using simulation modeling, we determined that by stochastically acidifying a phagolysosome to a pH within the observed distribution, macrophages sacrificed a small amount of overall fitness to gain the benefit of reduced variation in fitness. Hence, chance in the final phagosomal pH introduces unpredictability to the outcome of the macrophage-microbe, which implies a bet-hedging strategy that benefits the macrophage. While bet hedging is common in biological systems at the organism level, our results show its use at the organelle and cellular level.Keywords
Funding Information
- NIH (5R01AI033774,R01HL059842,5R37AI033142,5R01AI052733)
This publication has 74 references indexed in Scilit:
- Macrophage M1/M2 Polarization Dynamically Adapts to Changes in Cytokine Microenvironments in Cryptococcus neoformans InfectionmBio, 2013
- Candida albicans Infection Affords Protection against Reinfection via Functional Reprogramming of MonocytesCell Host & Microbe, 2012
- Control and Measurement of Plasma pH in Equilibrium Dialysis: Influence on Drug Plasma Protein BindingDrug Metabolism and Disposition, 2010
- Bet-hedging as an evolutionary game: the trade-off between egg size and numberProceedings. Biological sciences, 2009
- NADPH oxidase controls phagosomal pH and antigen cross-presentation in human dendritic cellsBlood, 2008
- Phagosome maturation: going through the acid testNature Reviews Molecular Cell Biology, 2008
- Direct cell-to-cell spread of a pathogenic yeastBMC Immunology, 2007
- Cell-to-cell spread and massive vacuole formation after Cryptococcus neoformans infection of murine macrophagesBMC Immunology, 2007
- Recruitment of CD63 toCryptococcus neoformansphagosomes requires acidificationProceedings of the National Academy of Sciences of the United States of America, 2006
- Chloroquine Antagonizes the Proinflammatory Cytokine Response to Opportunistic Fungi by Alkalizing the Fungal PhagolysosomeThe Journal of Infectious Diseases, 2001