Abstract
SummaryCryptosporidium is a leading cause of diarrheal disease and an important contributor to early childhood mortality, malnutrition, and growth faltering. Older children in high endemicity regions appear resistant to infection, while previously unexposed adults remain susceptible. Experimental studies in humans and animals support the development of disease resistance, but we do not understand the mechanisms that underlie protective immunity to Cryptosporidium. Here, we derive an in vivo model of Cryptosporidium infection in immunocompetent C57BL/6 mice by isolating parasites from naturally infected wild mice. Similar to human cryptosporidiosis, this infection causes intestinal pathology, and interferon-γ controls early infection while T cells are critical for clearance. Importantly, mice that controlled a live infection were resistant to secondary challenge and vaccination with attenuated parasites provided protection equal to live infection. Both parasite and host are genetically tractable and this in vivo model will facilitate mechanistic investigation and rational vaccine design.
Highlights
Cryptosporidiosis, initially recognized as an opportunistic infection associated with advanced HIV-AIDS, is known as a leading cause of diarrheal disease in immunocompetent individuals around the world (Checkley et al, 2015; Striepen, 2013)
Isolation of Cryptosporidium tyzzeri and De Novo Genome Assembly Mouse fecal pellets were collected from farms in Athens, Georgia in the United States; PCR analyses showed the presence of DNA from mice of the species Mus musculus domesticus (Figures S1A and S1B), and for 30% of the samples, Cryptosporidium DNA
SNP abundance peaks between C. tyzzeri and C parvum correlate with those between C. tyzzeri and C. hominis, and they correlate with such peaks between C. parvum and C. hominis
Summary
Cryptosporidiosis, initially recognized as an opportunistic infection associated with advanced HIV-AIDS, is known as a leading cause of diarrheal disease in immunocompetent individuals around the world (Checkley et al, 2015; Striepen, 2013). In the Global Enteric Multicenter Study, the largest study of its kind to assess the etiology of early childhood diarrheal disease in sub-Saharan Africa and southeast Asia, Cryptosporidium was strongly associated with moderate-to-severe diarrhea and death across all study sites (Kotloff et al, 2013). Children that survive these life-threatening Cryptosporidium infections remain prone to malnutrition and stunted growth, with measurable decreases in height-for-age scores (Checkley et al, 1998; Mølbak et al, 1997; Mondal et al, 2009; Platts-Mills et al, 2015). This massive impact on public health is exacerbated by the lack of tools to manage the disease; the current treatment for Cryptosporidium is of limited efficacy and new more potent medicines are still under development (Huston et al, 2015; Manjunatha et al, 2017) and no vaccine is available to prevent the infection
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