CD11c- and CD11b-expressing mouse leukocytes transport single Toxoplasma gondii tachyzoites to the brain

Abstract

The protozoan parasite Toxoplasma gondii enters hosts through the intestinal mucosa and colonizes distant tissues such as the brain, where its progeny persists for a lifetime. We investigated the role of CD11c-and CD11b-expressing leukocytes in T gondii transport during the early step of parasitism from the mouse small intestine and during subsequent parasite localization in the brain. Following intragastric inoculation of cystcontaining parasites in mice, CD11c ؉ dendritic cells from the intestinal lamina propria, the Peyer patches, and the mesenteric lymph nodes were parasitized while in the blood, parasites were associated with the CD11c ؊ CD11b ؉ monocytes. Using adoptive transfer experiments, we demonstrated that these parasitized cells triggered a parasitic process in the brain of naive recipient mice. Ex vivo analysis of parasitized leukocytes showed that single tachyzoites remained at the cell periphery, often surrounded by the host cell plasma membrane, but did not divide. Using either a dye that labels circulating leukocytes or an antibody known to prevent CD11b ؉ circulating leukocytes from leaving the microvascular bed lumen, and chimeric mice in which the hematopoietic cells expressed the green fluorescent protein, we established that T gondii zoites hijacked CD11b ؉ leukocytes to reach the brain extravascular space. IntroductionMany microorganisms initiate interactions with vertebrate hosts through digestive mucosa. Some will develop only in these peripheral host tissues, whereas others, including the protozoan parasite Toxoplasma gondii, disseminate throughout the host organism and colonize distant nonmucosal tissues. When hosts, including humans, ingest T gondii-containing cysts or oocysts, free T gondii zoites are released in the gut lumen. They subsequently enter enterocytes, where they multiply and initiate the parasitic process per se. [1][2][3] Enterocytes loaded with zoites secrete chemokines such as monocyte chemotactic protein 1 (MCP-1/CCL-2), macrophage inflammatory protein 1␣, and ␤ (MIP-1␣ and ␤/CCL3 and CCL4), as well as MIP-2/CXCL2, 4,5 which recruit leukocytes in the lamina propria (LP) extravascular space. Parasites then disseminate to several distant tissues, including the brain, a major site supporting T gondii progeny latency. 6,7 Such features have important clinical implications since T gondii can remain, for a lifetime, cryptic as bradyzoite, a slowly replicative intracellular stage under the control of unique host-dependent immune signals. However, upon rupture of this equilibrium, such as the one occurring in HIV-loaded individuals or following tissue transplantation and cancer therapy, bradyzoites can differentiate into tachyzoites, which massively replicate. This process of parasite reactivation is assessed by pathology, especially severe to fatal cerebral toxoplasmosis. 8,9 To date, whether they are acting at the cell lineage or tissue levels, the mechanisms underlying T gondii dissemination and entry into the brain remain largely unknown.T gondii zoites display unique ...

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

“…Surprisingly little is known about how T. gondii behaves in the small intestine of orally infected hosts. There are isolated reports of dividing parasites in intestinal tissue 1 d after infection (dpi), and the parasite increases in number in the small intestine between 3 and 7 dpi (2,(4)(5)(6)9). However, we lack basic information concerning the distribution of parasites in the small intestine during the first week of infection and how this distribution…”

“…between tissues. For example, dendritic cells (DCs) have been implicated in spread between tissues, transporting T. gondii from the intestine to the draining mesenteric lymph node early after infection (4). We speculated that immune cells also may be involved in spread within the intestine by facilitating exit of the parasite into the intestinal lumen and the reinfection of new villi.…”

“…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)(5)(6)(7)(8)(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).…”

“…Consequently, recent studies have focused on the role of immune cells in transporting parasites between tissues (4,(16)(17)(18)(19)(20)(21)(22)(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, it is thought that the initial invasion or traversal of intestinal epithelial cells by ingested parasites is followed by parasite replication in tissue and the transport by host cells to other tissues.…”

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

“…The active penetration model was defined largely by using nonphagocytic host cells and hypervirulent strains of the parasite. Unlike their virulent counterparts, the interaction of avirulent Toxoplasma strains with macrophage and dendritic cell results in heightened innate cytokine and chemokine production (9) and the development of a "hypermotile" host cellular phenotype (10), which promotes the control of acute infection and mediates dissemination into sites of parasite latency (11,12). Here, we investigated whether avirulent parasites interact with phagocytic host cells in a fundamentally different way from the outset.…”