Advances in understanding Giardia: determinants and mechanisms of chronic sequelae

Abstract

Giardia lamblia is a flagellated protozoan that is the most common cause of intestinal parasitic infection in children living in resource-limited settings. The pathogenicity of Giardia has been debated since the parasite was first identified, and clinical outcomes vary across studies. Among recent perplexing findings are diametrically opposed associations between Giardia and acute versus persistent diarrhea and a poorly understood potential for long-term sequelae, including impaired child growth and cognitive development. The mechanisms driving these protean clinical outcomes remain elusive, but recent advances suggest that variability in Giardia strains, host nutritional status, the composition of microbiota, co-infecting enteropathogens, host genetically determined mucosal immune responses, and immune modulation by Giardia are all relevant factors influencing disease manifestations after Giardia infection.

Figure 1.. The clinical spectrum of Giardia infection

The majority of individuals infected with Giardia are asymptomatic. Within the diarrhea spectrum of disease, Giardia paradoxically associates with both protection against acute diarrhea and persistent diarrhea with or without malabsorption and enteropathy. Hypothesized determinants of how disease will manifest on this spectrum include the virulence of the infecting strain(s) of Giardia, host nutritional intake, co-infecting enteropathogens, the composition and function of resident microbiota, immune modulation by Giardia, and host genetics and immunity. Changes in these dynamic variables may further skew disease manifestation. Histological changes vary from normal histopathology (bottom left) to villus shortening and chronic inflammatory infiltrate (enteropathy) (bottom right). Chronic sequelae associated with giardiasis include irritable bowel syndrome, chronic fatigue, childhood growth faltering, failure to thrive, cognitive impairment, and extra-intestinal manifestations presumed to be related to immunologic phenomena (reactive arthritis, inflammatory ocular manifestations, and urticaria) that are not necessarily dependent on severity of diarrheal manifestations and may persist even beyond detection of the parasite. Giardia trophozoite image courtesy of Joel Mancuso and Scott Dawson. Images of small-bowel biopsies from patients with giardiasis showing normal (left) and abnormal (right) histopathology courtesy of Leana Guerin (left) and Jörg-Dieter Schulzke (right).

Figure 2.. Proposed determinants and mechanisms of Giardia infection outcomes

Complex interactions between microbiota, nutrients, Giardia strain, co-enteropathogens, and host molecular responses in the luminal and mucosal environment likely influence Giardia infectivity and disease outcomes. (Left) Resident microbiota maintain resiliency to colonization. Giardia uses, and potentially sequesters, nutrients such as bile, arginine, and zinc in order to survive, replicate, and evade microbiota and host defenses. Flagella and the ventral disc are structures of trophozoites that aid attachment and adherence to intestinal epithelial cells (IECs). Giardia uses functional virulence factors to evade host inflammatory responses through antioxidant production, cleavage of interleukin-8 (IL-8), arginine depletion via arginine deiminase (ADI), and shifts in variant surface protein (VSP) expression. Effects of Giardia on epithelial cells (that is cell-cycle arrest, impaired proliferation, tight-junction disruption, and apoptosis) may be strain dependent and either direct or indirect. Subsequent changes in nutrient availability, microbiota composition, inflammatory defenses, and epithelial cell pathogen attachment sites may secondarily alter disease manifestations of co-infecting enteropathogens. (Right) Redundant mucosal immune responses promote Giardia clearance early (epithelial cell nutrient uptake for host fitness, barrier function maintenance, and pro-inflammatory molecules; IL-6 derived from dendritic cells and mast cells; and CD4⁺ and CD8⁺ T cells) and late in disease (CD4⁺ T-cell memory and B cells). CD4⁺ T cells induce memory responses but also contribute to chronic inflammation and may promote disaccharidase deficiency. CD8⁺ T cells mediate apoptosis, microvillus shortening, and disaccharidase deficiency. Epithelial cell damage may persist beyond parasite clearance, allowing sustained translocation of microbiota and microbial products. The altered mucosal homeostasis and inflammation (enteropathy) and microbiota composition may further impede nutrient uptake and contribute to prolonged sequelae, including impaired growth and cognitive development.