Dual Transcriptomics To Determine Gamma Interferon-Independent Host Response to Intestinal Cryptosporidium parvum Infection

Gina M Gallego-Lopez,Andrew L Garfoot,Carolina Mendoza Cavazos,Andrés M Tibabuzo Perdomo,Laura J Knoll,Roberta M O’Connor,Andreas J Bãumler

doi:10.1128/iai.00638-21

Gina M Gallego-Lopez, Andrew L Garfoot + Show 5 more

Open Access

https://doi.org/10.1128/iai.00638-21

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Abstract

ABSTRACTAnimals with a chronic infection of the parasite Toxoplasma gondii are protected against lethal secondary infection with other pathogens. Our group previously determined that soluble T. gondii antigens (STAg) can mimic this protection and be used as a treatment against several lethal pathogens. Because treatments are limited for the parasite Cryptosporidium parvum, we tested STAg as a C. parvum therapeutic. We determined that STAg treatment reduced C. parvum Iowa II oocyst shedding in gamma interferon knockout (IFN-γ-KO) mice. Murine intestinal sections were then sequenced to define the IFN-γ-independent transcriptomic response to C. parvum infection. Gene Ontology and transcript abundance comparisons showed host immune response and metabolism changes. Transcripts for type I interferon-responsive genes were more abundant in C. parvum-infected mice treated with STAg. Comparisons between phosphate-buffered saline (PBS) and STAg treatments showed no significant differences in C. parvum gene expression. C. parvum transcript abundance was highest in the ileum and mucin-like glycoproteins and the GDP-fucose transporter were among the most abundant. These results will assist the field in determining both host- and parasite-directed future therapeutic targets.

Highlights

Cryptosporidium is an enteric, protozoan parasite of global distribution that causes the diarrheal disease, cryptosporidiosis
We observed that soluble T. gondii antigen (STAg) treatment significantly reduced oocyst shedding compared with the phosphate-buffered saline (PBS) treated group (p=0.030), indicating that STAg has a therapeutic or immunomodulatory effect against C. parvum infection (Fig 1A)
Our results show that STAg treatment reduces the oocyst shedding in C. parvum infected IFNγ-deleted mice

Summary

Introduction

Cryptosporidium is an enteric, protozoan parasite of global distribution that causes the diarrheal disease, cryptosporidiosis. C. parvum, the most studied species of the 31 species of Cryptosporidium reported until now, can cause severe diarrhea in many species, including calves and humans [1]. In human immunodeficiency virus (HIV) infected patients and other immunocompromised individuals, Cryptosporidium causes a chronic, debilitating, and sometimes lethal diarrheal disease [2]. The oocyst releases sporozoites which invade epithelial cells of the gastrointestinal tract. The parasite is intracellular it remains extra-cytoplasmic, forming a feeder organelle by which it extracts nutrients from the host cell. Because of its very reduced metabolism, Cryptosporidium relies on the host cell for nucleotides [17,18], fatty acids [8,9], and glutaminolysis [21]

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