Review
The Role of the Host in Driving Phenotypic Heterogeneity in Salmonella

https://doi.org/10.1016/j.tim.2019.01.004Get rights and content

Highlights

The intensity of the innate immune response varies depending on host tissue, cell type, and phase of infection.

Variability in immune stresses selects for diversity in Salmonella populations in vivo and gives rise to substantial heterogeneity in virulence gene expression.

Salmonella spreads in infected hosts by exploiting the innate immune system, using the natural antimicrobial mechanisms of a host as cues for virulence gene expression.

To maximize pathogenic fitness, Salmonella exhibits variation in the extent to which it evades the immune system, grows within and outside host cells, and acquires nutrients for efficient central metabolism.

Microbial phenotypic heterogeneity during infection is a likely cause of antimicrobial failure during therapy, as most antibiotics have single targets that may be dispensable in certain bacterial subpopulations with altered gene expression.

The complex infection environment within hosts exerts unique stresses across tissues and cell types, selecting for phenotypic heterogeneity in bacterial populations. Pathogens maintain variability during infection as a strategy to cope with fluctuating host immune conditions, leading to diversification of virulence phenotypes. Recent improvements in single-cell analyses have revealed that distinct bacterial subpopulations contribute unique colonization and growth strategies across infection sites. We discuss several examples of host-driven phenotypic heterogeneity in Salmonella populations throughout the course of infection, highlighting how variation in gene expression, growth rate, immune evasion, and metabolic activity contribute to overall bacterial success at the population level. We additionally focus our discussion on the implications of diversity within bacterial communities for antimicrobial efficacy.

Section snippets

Complexity across the Infection Landscape

During infection, the host environment diversifies into areas with varying degrees of inflammation. The detection of invading pathogens recruits several immune cells to multiple host tissues, which orchestrate the appropriate defense response through antigenic detection, modulation of gene expression, and establishment of immunological memory 1, 2. Traditionally, these processes have been quantified at the population level, contributing to an oversimplified view of the infection process and the

Modeling Infection Heterogeneity with Salmonella

Depending on host immune status and the infecting strain, exposure to different Salmonella serotypes can lead to either self-limiting gastroenteritis or systemic typhoid-like infection, which can both be investigated with several well established animal models [10]. Most of what we know of Salmonella pathogenicity has been gleaned from laboratory strains of the nontyphoidal Typhimurium serovar – LT2, SL1344, and ATCC14028s [11] – which produce lethal infections and significant pathology in the

Invasion and Inflammation of the Intestinal Tract

The initial invasion of the intestinal epithelium is central to Salmonella pathogenesis. After oral infection of streptomycin pretreated mice, bacterial colonization is first localized to the terminal ileum, cecum, and colon, inducing pathology and inflammation in these areas [20]. The process of intestinal invasion and colonization has been considered highly T3SS-1-dependent, as SPI-1 mutants are significantly attenuated for cultured epithelial cell invasion and the induction of intestinal

Survival and Replication in the Intracellular Environment

Irrespective of the mechanisms underlying epithelium traversal and extraintestinal exit, the next stage of Salmonella pathogenesis is dependent upon intracellular adaptation, with Salmonella populations mostly occupying dendritic cells, macrophages, neutrophils, and fibroblasts [61]. Once infected, these host cells attempt to restrict the growth of internalized Salmonella with several antimicrobial activities. Here we highlight only a few of the diverse outcomes of Salmonella–macrophage

Growth and Spread of Salmonella at Systemic Sites

During the first day after infection, the total Salmonella burden within infected hosts is thought to initially decrease, due to a net balance of host-mediated killing over bacterial replication 94, 95. However, as infection proceeds, bacterial survival is favored by the transcriptional reprogramming that occurs in intracellular Salmonella to express genes that confer resistance to the natural antimicrobial mechanisms of the host innate immune system. This includes the expression of enzymes

Concluding Remarks

The asynchronous nature of bacterial infection within hosts creates a pool of phenotypic diversity that permits the exploitation of a wide range of niches, as well as the evasion of environmental and immunological stresses. Consistent with this, distinct subpopulations of both immune and bacterial cells emerge in the complex landscape of infection, creating microenvironments with different host–pathogen interaction outcomes. Despite being one of the most well-studied pathogenic organisms, the

References (125)

  • L.A. Knodler

    Salmonella enterica: living a double life in epithelial cells

    Curr. Opin Microbiol.

    (2015)
  • C.L. Birmingham

    Autophagy controls Salmonella infection in response to damage to the Salmonella-containing vacuole

    J. Biol. Chem.

    (2006)
  • L.A. Knodler

    Noncanonical inflammasome activation of caspase-4/caspase-11 mediates epithelial defenses against enteric bacterial pathogens

    Cell Host Microbe

    (2014)
  • M.E. Sellin

    Epithelium-intrinsic NAIP/NLRC4 inflammasome drives infected enterocyte expulsion to restrict Salmonella replication in the intestinal mucosa

    Cell Host Microbe

    (2014)
  • I. Rauch

    NAIP-NLRC4 inflammasomes coordinate intestinal epithelial cell expulsion with eicosanoid and il-18 release via activation of caspase-1 and -8

    Immunity

    (2017)
  • A.J. Müller

    Salmonella gut invasion involves TTSS-2-dependent epithelial traversal, basolateral exit, and uptake by epithelium-sampling lamina propria phagocytes

    Cell Host Microbe

    (2012)
  • R. Avraham

    Pathogen cell-to-cell variability drives heterogeneity in host immune responses

    Cell

    (2015)
  • N.A. Eisele

    Salmonella require the fatty acid regulator PPARδ for the establishment of a metabolic environment essential for long-term persistence

    Cell Host Microbe

    (2013)
  • V. Liss

    Salmonella enterica remodels the host cell endosomal system for efficient intravacuolar nutrition

    Cell Host Microbe

    (2017)
  • B. Claudi

    Phenotypic variation of Salmonella in host tissues delays eradication by antimicrobial chemotherapy

    Cell

    (2014)
  • J.V. Price et al.

    The macrophage paradox

    Immunity

    (2014)
  • J. Van den Bossche

    Macrophage immunometabolism: where are we (going)?

    Trends Immunol.

    (2017)
  • J. Behnsen

    Exploiting host immunity: the Salmonella paradigm

    Trends Immunol.

    (2015)
  • P. Mastroeni et al.

    Dynamics of spread of Salmonella enterica in the systemic compartment

    Microbes Infect.

    (2013)
  • M. Ackermann

    A functional perspective on phenotypic heterogeneity in microorganisms

    Nat. Rev. Microbiol.

    (2015)
  • S. Castanheira et al.

    Salmonella populations inside host cells

    Front. Cell. Infect. Microbiol.

    (2017)
  • K.M. Davis et al.

    One for all, but not all for one: social behavior during bacterial diseases

    Trends Microbiol.

    (2018)
  • P. Branchu

    Genome variation and molecular epidemiology of Salmonell aenterica serovar Typhimurium pathovariants

    Infect. Immun.

    (2018)
  • D.M. Monack

    Persistent bacterial infections: the interface of the pathogen and the host immune system

    Nat. Rev. Microbiol.

    (2004)
  • M.T. Sorbara et al.

    Interbacterial mechanisms of colonization resistance and the strategies pathogens use to overcome them

    Mucosal Immunol.

    (2018)
  • P. Kaiser

    The streptomycin mouse model for Salmonella diarrhea: functional analysis of the microbiota, the pathogen’s virulence factors, and the host’s mucosal immune response

    Immunol. Rev.

    (2011)
  • D.M. Monack

    Salmonella Typhimurium persists within macrophages in the mesenteric lymph nodes of chronically infected Nramp1+/+ mice and can be reactivated by IFNγ neutralization

    J. Exp. Med.

    (2004)
  • B. Ilyas

    Evolution of Salmonella-host cell interactions through a dynamic bacterial genome

    Front. Cell. Infect. Microbiol.

    (2017)
  • A. Haraga

    Salmonellae interplay with host cells

    Nat. Rev. Microbiol.

    (2008)
  • J.E. Galán

    Molecular genetic bases of Salmonella entry into host cells

    Mol. Microbiol.

    (1996)
  • M. Barthel

    Pretreatment of mice with streptomycin provides a Salmonella enterica serovar Typhimurium colitis model that allows analysis of both pathogen and host

    Infect. Immun.

    (2003)
  • S. Patel et al.

    Mucosal inflammatory response to Salmonella Typhimurium infection

    Front. Immunol.

    (2014)
  • I. Hautefort

    Single-copy green fluorescent protein gene fusions allow accurate measurement of Salmonella gene expression in vitro and during infection of mammalian cells

    Appl. Environ. Microbiol.

    (2003)
  • M.C. Schlumberger

    Real-time imaging of type III secretion: Salmonella SipA injection into host cells

    Proc. Natl. Acad. Sci. U. S. A.

    (2005)
  • M. Ackermann

    Self-destructive cooperation mediated by phenotypic noise

    Nature

    (2008)
  • A. Sturm

    The cost of virulence: retarded growth of Salmonella Typhimurium cells expressing type III secretion system 1

    PLoS Pathog.

    (2011)
  • M. Diard

    Stabilization of cooperative virulence by the expression of an avirulent phenotype

    Nature

    (2013)
  • S. Saini

    The role of coupled positive feedback in the expression of the SPI1 type three secretion system in Salmonella

    PLoS Pathog.

    (2010)
  • B. Stecher

    Salmonella enterica serovar Typhimurium exploits inflammation to compete with the intestinal microbiota

    PLoS Biol.

    (2007)
  • M. Arnoldini

    Bistable expression of virulence genes in Salmonella leads to the formation of an antibiotic-tolerant subpopulation

    PLoS Biol.

    (2014)
  • D. Dubnau et al.

    Bistability in bacteria

    Mol. Microbiol.

    (2006)
  • Y.A. Golubeva

    Integrating global regulatory input into the Salmonella pathogenicity island 1 type III secretion system

    Genetics

    (2012)
  • S.W. Dickey

    Different drugs for bad bugs: antivirulence strategies in the age of antibiotic resistance

    Nat. Rev. Drug Discov.

    (2017)
  • L.A. Knodler

    Quantitative assessment of cytosolic Salmonella in epithelial cells

    PLoS One

    (2014)
  • L.A. Knodler

    Dissemination of invasive Salmonella via bacterial-induced extrusion of mucosal epithelia

    Proc. Natl. Acad. Sci. U. S. A.

    (2010)
  • Cited by (0)

    View full text