Motile invaded neutrophils in the small intestine ofToxoplasma gondii-infected mice reveal a potential mechanism for parasite spread

Abstract

Toxoplasma gondii infection occurs through the oral route, but we lack important information about how the parasite interacts with the host immune system in the intestine. We used two-photon laserscanning microscopy in conjunction with a mouse model of oral T. gondii infection to address this issue. T. gondii established discrete foci of infection in the small intestine, eliciting the recruitment and transepithelial migration of neutrophils and inflammatory monocytes. Neutrophils accounted for a high proportion of actively invaded cells, and we provide evidence for a role for transmigrating neutrophils and other immune cells in the spread of T. gondii infection through the lumen of the intestine. Our data identify neutrophils as motile reservoirs of T. gondii infection and suggest a surprising retrograde pathway for parasite spread in the intestine.neutrophil motility | dynamic imaging | gut | mucosal immunology T oxoplasma gondii infects around a third of humans worldwide and is widely dispersed in other warm-blooded hosts. Although clinical manifestations in the brain, eye, and developing fetus receive the most attention, T. gondii is an oral pathogen and first enters the body and establishes infection in the small intestine. Infection follows consumption of cyst-containing meat or oocyst-contaminated water and produce and is associated with the development of small intestinal pathology in a variety of nonhuman hosts (1). Most notably, experimental infection of C57BL/6 mice by the oral route results in an inflammation of the small intestine that shares immunological features with inflammatory bowel disease (2). This model is useful to further our understanding of host-pathogen interactions in the intestine and of common mechanisms underpinning the development of inflammatory bowel disease (3). Nevertheless, we have limited understanding of how and in which cells infection is established in the intestine, the extent to which the parasite replicates and spreads within the intestine, and how these factors contribute to the development of pathology (2, 4-9). The ability to label living parasites fluorescently and track them in the tissues of infected hosts provides an important tool for investigating these questions (10)(11)(12)(13)(14).Starting in the small intestine, T. gondii must travel long distances and surmount a variety of biological barriers to establish chronic infection in the brain. These barriers include the mucus, the intestinal epithelium, and the blood-brain barrier (7,15). Cells of the immune system are often highly motile and represent attractive transport vessels for pathogens seeking to reach and enter tissues while being protected from the external environment. Consequently, recent studies have focused on the role of immune cells in transporting parasites between tissues (4, 16-23). For example, cluster of differentiation 11b-positive (CD11b + ) cells have been implicated in the dissemination of T. gondii through the blood and across the blood-brain barrier (4, 19). Following oral infection, i...

Toxoplasma gondii disrupts β1 integrin signaling and focal adhesion formation during monocyte hypermotility

“…Several studies have demonstrated that immune cells infected with T. gondii become hypermotile (27)(28)(29)(30)(31)(32)(33)(34)41), an effect that has been proposed to facilitate the dissemination of the intracellular parasite in the infected host. In the present study, we have demonstrated that the hypermotility of T. gondii-infected human monocytes is linked to a dysregulation in integrin-dependent cell adhesion through defects in FAK-regulated focal adhesions.…”

“…In this model, an infected cell can act as a Trojan horse for T. gondii in the bloodstream or tissues (26). Several studies have demonstrated that T. gondii infection of monocytes (27,28), neutrophils (29), NK cells (30), and DCs (31-34) induces a hypermotility phenotype in these cells.…”

Toxoplasma gondiiInfection Promotes Epithelial Barrier Dysfunction of Caco-2 Cells

“…3,4 As a consequence, transepithelial migration of immunological cells, preferentially neutrophils and also inflammatory monocytes, represents an important mechanism for parasite spreading. 5 Moreover, oral T. gondii infection results in intestinal tissue damage associated with necrosis in certain lineages of mice, such as C57BL/6, that die 656349J HCXXX10.1369/0022155416656349Toxoplasma Disrupts Cytoskeleton on Caco-2 CellsBriceño et al…”

Avirulent strains of Toxoplasma gondii infect macrophages by active invasion from the phagosome

“…This interplay could then underlie a more robust innate and adaptive immune activation, leading to effective control of avirulent parasites. Additionally, avirulent T. gondii strains preferentially infect mononuclear cells, including naive resident macrophages (this report), monocytes (29,30) and neutrophils (31), and also differentially induce hypermigratory phenotype in infected macrophages and dendritic cells (10,32). It is tempting to speculate that these maneuvers together represent a constellation of adaptive responses characteristic of avirulent T. gondii.…”