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Intracellular Lifestyles and Their Impact on Host-to-Host Transmission

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  • Authors: M. Graciela Pucciarelli1,2, Francisco García-Del Portillo3
  • Editors: Fernando Baquero4, Emilio Bouza5, J.A. Gutiérrez-Fuentes6, Teresa M. Coque7
    Affiliations: 1: Laboratory of Intracellular Bacterial Pathogens, Departamento de Biotecnología Microbiana, Centro Nacional de Biotecnología-Consejo Superior de Investigaciones Científicas (CNB-CSIC), Madrid, Spain; 2: Centro de Biología Molecular Severo Ochoa (CBMSO-CSIC), Departamento de Biología Molecular, Universidad Autónoma de Madrid, Madrid, Spain; 3: Laboratory of Intracellular Bacterial Pathogens, Departamento de Biotecnología Microbiana, Centro Nacional de Biotecnología-Consejo Superior de Investigaciones Científicas (CNB-CSIC), Madrid, Spain; 4: Hospital Ramón y Cajal (IRYCIS), Madrid, Spain; 5: Hospital Ramón y Cajal (IRYCIS), Madrid, Spain; 6: Complutensis University, Madrid, Spain; 7: Hospital Ramón y Cajal (IRYCIS), Madrid, Spain
  • Source: microbiolspec July 2017 vol. 5 no. 4 doi:10.1128/microbiolspec.MTBP-0009-2016
  • Received 14 February 2017 Accepted 03 March 2017 Published 21 July 2017
  • M. Graciela Pucciarelli, [email protected]
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  • Abstract:

    More than a century ago, infections by were already associated with foodborne enteric diseases with high morbidity in humans and cattle. Intestinal inflammation and diarrhea are hallmarks of infections caused by nontyphoidal serovars, and these pathologies facilitate pathogen transmission to the environment. In those early times, physicians and microbiologists also realized that typhoid and paratyphoid fever caused by some serovars could be transmitted by “carriers,” individuals outwardly healthy or at most suffering from some minor chronic complaint. In his pioneering study of the nontyphoidal serovar Typhimurium in 1967, Takeuchi published the first images of intracellular bacteria enclosed by membrane-bound vacuoles in the initial stages of the intestinal epithelium penetration. These compartments, called -containing vacuoles, are highly dynamic phagosomes with differing biogenesis depending on the host cell type. Single-cell studies involving real-time imaging and gene expression profiling, together with new approaches based on genetic reporters sensitive to growth rate, have uncovered unprecedented heterogeneous responses in intracellular bacteria. Subpopulations of intracellular bacteria displaying fast, reduced, or no growth, as well as cytosolic and intravacuolar bacteria, have been reported in both and infection models. Recent investigations, most of them focused on the serovar Typhimurium, point to the selection of persisting bacteria inside macrophages or following an autophagy attack in fibroblasts. Here, we discuss these heterogeneous intracellular lifestyles and speculate on how these disparate behaviors may impact host-to-host transmissibility of serovars.

  • Keywords: carrier state; transmission; cytosolic bacteria; persistence; Salmonella-containing vacuole; intracellular lifestyle; autophagy; extracellular

  • Citation: Pucciarelli M, García-Del Portillo F. 2017. Intracellular Lifestyles and Their Impact on Host-to-Host Transmission. Microbiol Spectrum 5(4):MTBP-0009-2016. doi:10.1128/microbiolspec.MTBP-0009-2016.


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More than a century ago, infections by were already associated with foodborne enteric diseases with high morbidity in humans and cattle. Intestinal inflammation and diarrhea are hallmarks of infections caused by nontyphoidal serovars, and these pathologies facilitate pathogen transmission to the environment. In those early times, physicians and microbiologists also realized that typhoid and paratyphoid fever caused by some serovars could be transmitted by “carriers,” individuals outwardly healthy or at most suffering from some minor chronic complaint. In his pioneering study of the nontyphoidal serovar Typhimurium in 1967, Takeuchi published the first images of intracellular bacteria enclosed by membrane-bound vacuoles in the initial stages of the intestinal epithelium penetration. These compartments, called -containing vacuoles, are highly dynamic phagosomes with differing biogenesis depending on the host cell type. Single-cell studies involving real-time imaging and gene expression profiling, together with new approaches based on genetic reporters sensitive to growth rate, have uncovered unprecedented heterogeneous responses in intracellular bacteria. Subpopulations of intracellular bacteria displaying fast, reduced, or no growth, as well as cytosolic and intravacuolar bacteria, have been reported in both and infection models. Recent investigations, most of them focused on the serovar Typhimurium, point to the selection of persisting bacteria inside macrophages or following an autophagy attack in fibroblasts. Here, we discuss these heterogeneous intracellular lifestyles and speculate on how these disparate behaviors may impact host-to-host transmissibility of serovars.

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(1) Limited proliferation of serovar Typhimurium in intestinal epithelial cells (IECs) during penetration of the intestinal barrier. The pathogen proliferates actively in a few IECs, which are rapidly extruded by a mechanism that depends on the inflammasome proteins NAIP/NLRC4. This proliferation was reported to occur within phagosomes and in the cytosol. Bacteria have also been observed in phagocytic (neutrophils, macrophages) and nonphagocytic cells (fibroblasts) in the underlying lamina propria. (2) Extrusion of heavily infected epithelial cells observed in the epithelium lining the gallbladder. As in the IECs, there is also evidence for replication of intracellular cytosolic serovar Typhimurium cells. (3) Serovar Typhimurium targets mainly macrophages in the liver. The most-accepted models support an increase in infection foci due to subsequent episodes of macrophage infection, a few rounds of intracellular replication of the pathogen, and reinfection of nearby macrophages. The intracellular lifestyle in these macrophages is entirely intraphagosomal. (4) Serovar Typhimurium colonizes distinct types of phagocytes in the red pulp of the spleen. The infection is highly contained by inflammatory monocytes and neutrophils, although some bacteria colonize and persist in resident macrophages. Note that the proliferation detected in the few epithelial cells that extrude in the intestinal epithelium and gallbladder ultimately favors shedding of the pathogen outside the host. Although not shown, serovar Typhimurium has also been shown to persist in macrophages present in mesenteric lymph nodes.

Source: microbiolspec July 2017 vol. 5 no. 4 doi:10.1128/microbiolspec.MTBP-0009-2016
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These examples include (A) the production by intracellular serovar Typhi of defined type III effector proteins targeting Rab proteins (see text for details); (B) inflammasome intervention in IECs to exclude cells heavily infected with serovar Typhimurium; and (C) attenuation of intracellular growth in fibroblasts linked to changes in yet undefined functions of intracellular serovar Typhimurium regulated by the two-component regulatory system PhoP-PhoQ or other regulators (SlyA, RpoS). This process could be either followed by or occur concomitantly with selective autophagy attack (aggrephagy). Formation of small-colony serovar Typhimurium variants has also been shown to occur in fibroblasts at long postinfection times. (D) The actions of toxins encoded in TA loci contribute to the selection of serovar Typhimurium persisters following ingestion by macrophages.

Source: microbiolspec July 2017 vol. 5 no. 4 doi:10.1128/microbiolspec.MTBP-0009-2016
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and host responses discussed in this chapter with probable impact on host-to-host transmission of the pathogen

Source: microbiolspec July 2017 vol. 5 no. 4 doi:10.1128/microbiolspec.MTBP-0009-2016

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