Abstract
Infection caused by more than 1500 serotypes of Salmonella enterica subsp. enterica is one of the most common food-borne diseases, prevalent worldwide. Concerning public health, Salmonella latent carrier animals represent an important source of transmission of the disease. They are responsible for silent introduction of the bacteria into the food chain and the environment. Most pathogenesis studies of salmonellosis are focused on events that lead to clinical disease. Researchers have been unable to clearly discern the interaction between intracellular microorganisms and their resistant hosts in latency. However, understanding this interaction is essential for the proper employment of the control and eradication strategies. Thus, the objective of this article is to present an overview of some important events that occur during the infection cycle of S. enterica in latent carriers.
Keywords
- Salmonella asymptomatic carrier animals
- pathogen-host interaction
- pathogenisis
- public health
- intracellular bacteria
1. Introduction
The genus
Most outbreaks of salmonellosis in humans and in domestic animals are caused by a few serotypes, which are grouped according to their adaptation to the host. The first group consists of a few
Epidemiologically, infections caused by
Certain animal species may develop asymptomatic persistent infection with intermittent shedding of
Latent carrier animals are therefore natural reservoirs of
2. Pathogenesis of Salmonella enterica : the role of Salmonella pathogenicity islands (SPIs)
The pathogenesis of salmonellosis depends on a combination of several factors, including the components of bacterial virulence, the infective dose, route of infection, the genetic makeup and the immune status of the host [11]. All of these variables can influence the immunological responses of the host, resulting in different degrees of inflammation that confer an acute, moderate, chronic or even asymptomatic nature to the disease [12].
Infection by
Studies of SPIs help in understanding the mechanisms of bacterial virulence, and they may also be useful to clarify the phylogenetic relationships among species [21, 22]. Phylogenetic studies indicated that the gene sequences present in SPI-1 were acquired by lateral gene transfer before the diversification between
The virulence mechanisms of
According to the animal model, the virulence genes required for systemic infection differ from those genes responsible for the enteritis caused by
2.1. SPI-1-mediated invasion of host cells
After oral infection, a proportion of the
Once in contact with the intestinal epithelium, the effector proteins SopE, SopE2 and SopB (encoded by genes outside of SPI-1) are translocated to the interiors of enterocytes and M cells via the SPI-1 T3SS. These proteins activate certain GTPases within the host cell, such as Cdc42, Rac-1 and Rho, causing a rearrangement of the actin cytoskeleton called membrane ruffling [28], which is stabilized by the SipA and SipC effector proteins. Furthermore, they also activate the MAP kinase (mitogen-activated protein kinase) pathway, thereby destabilizing tight junctions. Consequently, bacteria can penetrate into the host cell through the apical membrane in a process called macropinocytosis or cross the intercellular space until reaching the lamina propria. This destabilization of tight junctions also allows for the transmigration of polymorphonuclear cells (PMNs) from the basolateral space to the apical surface. However, this transmigration can occur independently from the destabilization of tight junctions when mediated by the bacterial protein SopA [29]. Once inside the cell, the effector protein SptP modulates the inactivation of the GTPases Cdc42 and Rac-1, thus resulting in the end of the membrane ruffling [30].
Signaling via MAP kinase, in addition to promoting the destabilization of tight junctions, also activates the transcription factors AP-1 (activator protein-1) and NF-κB (nuclear factor- κB), which leads to the synthesis of pro-inflammatory interleukin (IL)-8 by PMN leukocytes, thus acting as a chemotactic factor for neutrophils [29].
During the invasion of macrophages, the bacterium injects the effector protein SipB, which is encoded by SPI-1, inducing the intracellular activation of caspase-1 by resident macrophages. Caspase-1 induces apoptosis of infected macrophages resulting in
There is an alternative SPI-1-independent invasion mechanism in which
2.2. SPI-2-mediated intracellular multiplication
The ability of
Soon after entry by means of macropinocytosis,
3. Natural resistance mechanism to infection by S. enterica : the role of Nramp1 glycoprotein
The resistance mechanisms of host to infection by
Nramp1 is a transmembrane glycoprotein and divalent metal ion symporter that deprives intracellular pathogens of these metals by removing mainly Fe++ and Mn++ from the luminal space of the phagosomal and lysosomal vesicles. Because iron and other divalent cations are cofactors for vital enzymes,
The interaction between the surface receptors of macrophages and microbial ligands results in the internalization of the microorganism into a phagosome. However, this young phagosome is not able to digest its contents, thus requiring a maturation process involving fusion and fission events with endosomes and lysosomes. During the maturation process, phagosomes containing
4. Infection cycle of S. enterica in latent carriers
In asymptomatic carrier animals, the study of the infection cycle of
In pigs, by applying a Markov statistical model, Ivanek et al. [44] were able to distinguish different stages during the dynamic shedding of
Thus, independent of the animal model, in latent carriers, there is a period during which
The site of bacterial colonization in persistent infections varies according to serotype and host species. In humans, serotype Typhi expresses proteins encoded by SPI-7 that inhibit the detection of pathogens by the innate immune system of the host. Thus, the bacteria can spread systemically, colonizing macrophages in the liver, spleen and bone marrow. In the liver,
In asymptomatic animals, the cecum plays an important role as a reservoir for longer periods of shedding [48–51]. Research using resistant mice orally challenged with high doses of
In chickens, the cecum is also a site for long-lasting carriage of
The mechanism of persistence of
5. Role of IFNγ in controlling of S. enterica growth
During intestinal infection,
IFNγ plays a crucial role in resistance to systemic infection by
IFNγ is produced specifically in response to systemic infection and correlates with bacteremia and pathogen invasion of the cells of the mononuclear phagocyte system, such as the lymphoid tissue associated with the intestine (mesenteric lymph nodes and Peyer’s patches), spleen and liver. Its production is essential to restrict bacterial intracellular multiplication, thereby contributing to the establishment of a plateau phase during the growth cycle of
When antigen-specific acquired immunity is triggered, the IFNγ titer in serum begins to decrease [11]. However, even in the presence of high titers of specific circulating antibodies, some
6. Gene expression in latent Salmonella
Zoonotic intracellular pathogens that can cause latent carriers pose a unique public health problem. The ability of such carrier animals to shed pathogens without showing any clinical signs of infection can make outbreak control challenging and the potential of transmission to humans a serious public health concern. Before identifying these carriers, we need to understand the mechanism of bacterial invasion of the host cells and follow the process of establishing a persistent state of infection. SPI 1 encodes for genes
7. Conclusions
Despite host’s activation of anti-inflammatory and antimicrobial responses,
Acknowledgments
The authors thank Universidade Estadual de Santa Cruz-UESC (Bahia State, Brazil) and Fundação de Amparo à Pesquisa do Estado da Bahia-FAPESB (Bahia State, Brazil).
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