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Advances in understanding Giardia: determinants and mechanisms of chronic sequelae.

Bartelt LA, Sartor RB - F1000Prime Rep (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Division of Infectious Diseases and International Health, University of Virginia Box 801340, Charlottesville, VA 22908 USA.

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.

No MeSH data available.


Related in: MedlinePlus

Proposed determinants and mechanisms of Giardia infection outcomesComplex 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.
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fig-002: Proposed determinants and mechanisms of Giardia infection outcomesComplex 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.

Mentions: In light of the incompletely understood pathology attributable to Giardia infection, recent advances in parasite and gastrointestinal biology hope to clarify how and when Giardia causes disease. These advances address fundamental questions regarding how Giardia interacts within the complex ecology of microbial, nutritional, and host factors within the small intestine, the determinants of host susceptibility, and whether and how host inflammation contributes to pathogenesis (Figure 2).


Advances in understanding Giardia: determinants and mechanisms of chronic sequelae.

Bartelt LA, Sartor RB - F1000Prime Rep (2015)

Proposed determinants and mechanisms of Giardia infection outcomesComplex 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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4447054&req=5

fig-002: Proposed determinants and mechanisms of Giardia infection outcomesComplex 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.
Mentions: In light of the incompletely understood pathology attributable to Giardia infection, recent advances in parasite and gastrointestinal biology hope to clarify how and when Giardia causes disease. These advances address fundamental questions regarding how Giardia interacts within the complex ecology of microbial, nutritional, and host factors within the small intestine, the determinants of host susceptibility, and whether and how host inflammation contributes to pathogenesis (Figure 2).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Division of Infectious Diseases and International Health, University of Virginia Box 801340, Charlottesville, VA 22908 USA.

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.

No MeSH data available.


Related in: MedlinePlus