The cell biology of cryptosporidium infection

Abstract

Cryptosporidiosis remains a significant cause of enteric disease worldwide. Basic investigations of host: pathogen interactions have revealed the intricate processes mediating infection. The following summarizes the interactions that mediate infection and the host responses that both permit and ultimately clear the infection.

Fig. 1

Overview of the infection process and life cycle. A. Cryptosporidiosis is initiated through the ingestion of viable oocysts, each of which contains four sporozoites. The excystation process is enhanced at 37°C, and likely involves parasite derived enzymes. Zoite motility requires discharge of adhesive molecules from the apical complex and is temperature, Ca++, and parasite cytoskeleton dependent. Ultimately, the apical end of the parasite attaches to the epithelial cell and initiates the internalization process. The end result of excystation, attachment, and internalization is a fully encapsulated parasite or trophozoite that develops into a Type I meront. B. Members of the genus Cryptosporidium complete all developmental stages, both sexual and asexual, in a single host. The trophozoite undergoes cell divisions resulting in 8 merozoites within a type I meront. These merozoites can re-infect the epithelium and form either a type I meront, effectively escalating the infection, or a type II meront, destined for sexual reproduction. The merozoites derived form type II meronts re-infect the epithelium and differentiate into either a micro- or macrogamont. The microgametes are released and fertilize a marogamont resulting in the only diploid stage of development, the zygote. The diploid zygote undergoes a process similar to meiosis and forms either a thin or thick walled oocyst. The former excysts in the gut lumen and re-infects the host, while the latter exits the host.

Fig. 2

Typical zoite cellular organization. Cryptosporidium zoites share a similar body plan to other Apicomplexans including: a crescent shaped cell body; apically localized rhoptry and micronemes; and numerous dense granules throughout. The parasite pellicle consists of an outer plasma membrane and an inner membrane complex composed of 2 distinct membranes with an underlying array of subpellicular microtubules. Zoite gliding motility requires the secretion of adhesive molecules from the apical pole of the parasites (e.g. TRAP) that adhere to substrate receptors; posterior translocation of the adhesive molecules in an actomyosin-dependent manner; and iii) proteolytic cleavage and release of the parasite molecule in motility trails. Zoite stylized from [58].

Fig. 3

Epithelial cellular processes initiated by Cryptosporidium infection. The infection process induces epithelial responses including, activation of anti- and pro-apoptotic pathways, chemokine/cytokine secretion, modulated expression of miRNAs, and alterations of the cytoskeleton. Numerous studies have demonstrated an essential role for NF-κB in the host cell response to cryptosporidium infection. This transcription factor, which can be activated by Toll-like receptors, has been implicated in anti- and pro-apoptotic signaling cascades, as well as the modulated expression of proinflammatory chemokines, and miRNAs. Additionally, the infection process induces host membrane alterations including remodeling of the host actin cytoskeleton. Multiple signaling cascades have been implicated in infection-induced actin reorganization including cortactin/c-src; PI3K/Cdc42/ARP2/3; and Ca⁺⁺/PKCα/β. The host cell responses both foster early parasite development and initiate processes for parasite clearance.