1. Microbiology and Infectious Disease
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The Mla pathway in Acinetobacter baumannii has no demonstrable role in anterograde lipid transport

  1. Matthew J Powers
  2. Brent W Simpson
  3. M Stephen Trent  Is a corresponding author
  1. University of Georgia, United States
Research Article
  • Cited 6
  • Views 1,755
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Cite this article as: eLife 2020;9:e56571 doi: 10.7554/eLife.56571

Abstract

The asymmetric outer membrane (OM) of Gram-negative bacteria functions as a selective permeability barrier to the environment. Perturbations to OM lipid asymmetry sensitize the cell to antibiotics. As such, mechanisms involved in lipid asymmetry are fundamental to our understanding of OM lipid homeostasis. One such mechanism, the Maintenance of lipid asymmetry (Mla) pathway has been proposed to extract mislocalized glycerophospholipids from the outer leaflet of the OM and return them to the inner membrane (IM). Work on this pathway in Acinetobacter baumannii support conflicting models for the directionality of the Mla system being retrograde (OM to IM) or anterograde (IM to OM). Here we show conclusively that A. baumannii mla mutants exhibit no defects in anterograde transport. Furthermore, we identify an allele of the GTPase obgE that is synthetically sick in the absence of Mla; providing another link between cell envelope homeostasis and stringent response.

Data availability

Sequencing data (RNAseq) have been deposited to the database NCBI Gene Expression Omnibus. Accession number is GSE147139

The following data sets were generated

Article and author information

Author details

  1. Matthew J Powers

    Microbiology, University of Georgia, Athens, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Brent W Simpson

    Infectious Diseases, University of Georgia, Athens, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. M Stephen Trent

    Infectious Diseases, Microbiology, University of Georgia, Athens, United States
    For correspondence
    strent@uga.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6134-1800

Funding

National Institute of Allergy and Infectious Diseases (AI129940)

  • M Stephen Trent

National Institute of Allergy and Infectious Diseases (AI138576)

  • M Stephen Trent

National Institute of Allergy and Infectious Diseases (AI150098)

  • M Stephen Trent

National Science Foundation (049347-06)

  • Matthew J Powers

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Tâm Mignot, CNRS-Aix Marseille University, France

Publication history

  1. Received: March 3, 2020
  2. Accepted: September 2, 2020
  3. Accepted Manuscript published: September 3, 2020 (version 1)
  4. Version of Record published: September 18, 2020 (version 2)

Copyright

© 2020, Powers et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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Further reading

    1. Medicine
    2. Microbiology and Infectious Disease
    Alexander O Pasternak et al.
    Research Article Updated

    Background:

    It remains unclear whether combination antiretroviral therapy (ART) regimens differ in their ability to fully suppress human immunodeficiency virus (HIV) replication. Here, we report the results of two cross-sectional studies that compared levels of cell-associated (CA) HIV markers between individuals receiving suppressive ART containing either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI).

    Methods:

    CA HIV unspliced RNA and total HIV DNA were quantified in two cohorts (n = 100, n = 124) of individuals treated with triple ART regimens consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) plus either an NNRTI or a PI. To compare CA HIV RNA and DNA levels between the regimens, we built multivariable models adjusting for age, gender, current and nadir CD4+ count, plasma viral load zenith, duration of virological suppression, NRTI backbone composition, low-level plasma HIV RNA detectability, and electronically measured adherence to ART.

    Results:

    In both cohorts, levels of CA HIV RNA and DNA strongly correlated (rho = 0.70 and rho = 0.54) and both markers were lower in NNRTI-treated than in PI-treated individuals. In the multivariable analysis, CA RNA in both cohorts remained significantly reduced in NNRTI-treated individuals (padj = 0.02 in both cohorts), with a similar but weaker association between the ART regimen and total HIV DNA (padj = 0.048 and padj = 0.10). No differences in CA HIV RNA or DNA levels were observed between individual NNRTIs or individual PIs, but CA HIV RNA was lower in individuals treated with either nevirapine or efavirenz, compared to PI-treated individuals.

    Conclusions:

    All current classes of antiretroviral drugs only prevent infection of new cells but do not inhibit HIV RNA transcription in long-lived reservoir cells. Therefore, these differences in CA HIV RNA and DNA levels by treatment regimen suggest that NNRTIs are more potent in suppressing HIV residual replication than PIs, which may result in a smaller viral reservoir size.

    Funding:

    This work was supported by ZonMw (09120011910035) and FP7 Health (305522).

    1. Evolutionary Biology
    2. Microbiology and Infectious Disease
    Emily R Ebel et al.
    Research Article

    The replication of Plasmodium falciparum parasites within red blood cells (RBCs) causes severe disease in humans, especially in Africa. Deleterious alleles like hemoglobin S are well-known to confer strong resistance to malaria, but the effects of common RBC variation are largely undetermined. Here we collected fresh blood samples from 121 healthy donors, most with African ancestry, and performed exome sequencing, detailed RBC phenotyping, and parasite fitness assays. Over one third of healthy donors unknowingly carried alleles for G6PD deficiency or hemoglobinopathies, which were associated with characteristic RBC phenotypes. Among non-carriers alone, variation in RBC hydration, membrane deformability, and volume was strongly associated with P. falciparum growth rate. Common genetic variants in PIEZO1, SPTA1/SPTB, and several P. falciparum invasion receptors were also associated with parasite growth rate. Interestingly, we observed little or negative evidence for divergent selection on non-pathogenic RBC variation between Africans and Europeans. These findings suggest a model in which globally widespread variation in a moderate number of genes and phenotypes modulates P. falciparum fitness in RBCs.