Editors' ChoiceInfectious Disease

Ironing out the mechanisms of chronic bacterial infection

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Science Translational Medicine  10 Oct 2018:
Vol. 10, Issue 462, eaav3885
DOI: 10.1126/scitranslmed.aav3885

Abstract

Molecular evaluation reveals an important role for nutrient-dependent intracellular trafficking in chronic bacterial otitis media.

Nontypeable Haemophilus influenzae (NTHI) infections have increased dramatically over the past decade and now account for a sizeable fraction of COPD exacerbations, otitis media, and bacterial sinusitis. Although it is most frequently present as an innocuous commensal, under certain environmental conditions, such as nutrient stress or viral infection, NTHI can emerge as an invasive pathogen. Furthermore, in a subset of cases, NTHI causes chronic, treatment-refractory disease by seeking intracellular refuge from the host immune system.

Despite its public health importance, the mechanisms underlying NTHI pathogenicity and intracellular survival remain incompletely understood. To address this gap, Hardison and colleagues first evaluated the impact of heme-iron nutrient deprivation on intracellular bacterial trafficking. Using immunofluorescence in both animal and airway cell culture models, they demonstrated that transient heme-iron restriction promoted intracellular invasion of NTHI and that this used both clathrin- and lipid raft–dependent mechanisms. Intriguingly, they found that nutrient restriction permitted survival and formation of intracellular bacterial communities by enabling NTHI to evade endolysosomal degradation. This suggested that NTHI causes chronic, treatment-refractory disease by usurping endogenous vesicle trafficking pathways to relocate intracellularly and evade host immune surveillance.

Important clues to the underlying biology emerged when pharmacologic inhibition of micropinocytosis was found to reduce the intracellular persistence of NTHI. Further examination revealed that the mechanism involved bacterial redirection through the endolysosomal pathway, resulting in degradation. Proteomic analysis of NTHI with and without nutrient deprivation identified 15 candidate proteins that may influence endolysosomal evasion and intracellular survival, including TehB and LipB, which also facilitate the intracellular adaptation of other bacteria.

Together, these findings illuminate a role for micropinocytosis in the intracellular invasion and survival of NTHI, and suggest that modulation of this process could afford a new therapeutic target for chronic infections of the ear and upper respiratory tract. Furthermore, this work expands our understanding of nutrient deprivation and intracellular sequestration in the context of immune evasion, which may apply broadly to other human pathogens. It would be interesting to evaluate the effects of other environmental factors—such as viral infections or particulate air pollutants, including tobacco smoke—on the intracellular survival of NTHI. In addition, comparative genomics and transcriptomics may help clarify the microbial and host factors governing endolysosomal evasion and intracellular survival after nutrient deprivation.

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