Chapter 6 : Intracellular Lifestyles and Their Impact on Host-to-Host Transmission

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The bacterial species comprises Gram-negative pathogenic microorganisms that cause infections in humans and livestock. is subdivided into six subspecies, with subspecies I responsible for infections in warm-blooded vertebrates, including mammals and birds ( ). To date, >2,500 serovars have been reported in subspecies I. Some of these serovars are host adapted, whereas others infect a broad range of hosts. Host-adapted serovars cause systemic infections that result in typhoid (paratyphoid) fever and bacteremia. Among these serovars are Typhi, Paratyphi A, Paratyphi C (humans), Cholerasuis (swine), Dublin (cow), and Gallinarum (fowl). Nontyphoidal serovars normally cause self-limiting gastroenteritis, although the severity of the infection varies depending on the immune defense status of the host and/or a unique genetic makeup that may render the clone highly invasive. An example is the recently characterized invasive serovar Typhimurium isolates that cause systemic disease in HIV-infected individuals of sub-Saharan African countries ( ) and Latin America ( ). Importantly, high transmissibility has been reported for all serovars, especially in those areas in which hygiene conditions in water and food are poor. The ability of all serovars to cause persistent asymptomatic infections, especially following infection by host-adapted serovars, imposes more difficulties on control of transmission ( ). This capacity to persist in the host without causing pathology has attracted physicians and microbiologists for more than a century, given its undoubtable negative impact on pathogen eradication. The reader is directed to the pioneering book by Ledingham and Arkwright, which in 1912 exhaustively compiled all existing information about cases of asymptomatic carriers and their impact on pathogen transmission ( ). These authors focused on six diseases known at that time to have high transmission rates, including typhoid and paratyphoid fever, diphtheria, epidemic cerebrospinal meningitis, dysentery, and cholera ( ). Studies performed in mouse asymptomatic chronic infection models using the serovar Typhimurium have identified pathogen genes required to persist in the animal for long periods of time (weeks to a few months) ( ). These studies also showed that serovar Typhimurium evolves during a chronic infection in the host and that this condition selects for adaptive mutations ( ). This is an intense and fascinating area of research that will certainly aid to combat transmissibility among individuals. We also refer to the chapter in this book by Wolf-Dietrich Hardt and colleagues, which addresses within-host evolution in and the transmission of the virulent genotype in populations differentially affected by antibiotic treatments.

Citation: Pucciarelli M, García-del Portillo F. 2019. Intracellular Lifestyles and Their Impact on Host-to-Host Transmission, p 95-116. In Baquero F, Bouza E, Gutiérrez-Fuentes J, Coque T (ed), Microbial Transmission. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MTBP-0009-2016
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Figure 1

Distinct intracellular lifestyles of serovar Typhimurium reported in various host locations during local inflammation of the intestine or acute systemic disease. (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.

Citation: Pucciarelli M, García-del Portillo F. 2019. Intracellular Lifestyles and Their Impact on Host-to-Host Transmission, p 95-116. In Baquero F, Bouza E, Gutiérrez-Fuentes J, Coque T (ed), Microbial Transmission. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MTBP-0009-2016
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Figure 2

Representative conditions reported to control intracellular growth of serovars Typhimurium and Typhi favoring persistence inside the infected cell. 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.

Citation: Pucciarelli M, García-del Portillo F. 2019. Intracellular Lifestyles and Their Impact on Host-to-Host Transmission, p 95-116. In Baquero F, Bouza E, Gutiérrez-Fuentes J, Coque T (ed), Microbial Transmission. ASM Press, Washington, DC. 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

Citation: Pucciarelli M, García-del Portillo F. 2019. Intracellular Lifestyles and Their Impact on Host-to-Host Transmission, p 95-116. In Baquero F, Bouza E, Gutiérrez-Fuentes J, Coque T (ed), Microbial Transmission. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MTBP-0009-2016

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