Protein Malnutrition Alters Tryptophan and Angiotensin-Converting Enzyme 2 Homeostasis and Adaptive Immune Responses in Human Rotavirus-Infected Gnotobiotic Pigs with Human Infant Fecal Microbiota Transplant

Abstract

Malnutrition leads to increased morbidity and is evident in almost half of all deaths in children under the age of 5 years. Mortality due to rotavirus diarrhea is common in developing countries where malnutrition is prevalent; however, the relationship between malnutrition and rotavirus infection remains unclear. In this study, gnotobiotic pigs transplanted with the fecal microbiota of a healthy 2-monthold infant were fed protein-sufficient or -deficient diets and infected with virulent human rotavirus (HRV). After human rotavirus infection, protein-deficient pigs had decreased human rotavirus antibody titers and total IgA concentrations, systemic T helper (CD3 ϩ CD4 ϩ ) and cytotoxic T (CD3 ϩ CD8 ϩ ) lymphocyte frequencies, and serum tryptophan and angiotensin I-converting enzyme 2. Additionally, deficientdiet pigs had impaired tryptophan catabolism postinfection compared with sufficient-diet pigs. Tryptophan supplementation was tested as an intervention in additional groups of fecal microbiota-transplanted, rotavirus-infected, sufficientand deficient-diet pigs. Tryptophan supplementation increased the frequencies of regulatory (CD4 ϩ or CD8 ϩ CD25 ϩ FoxP3 ϩ ) T cells in pigs on both the sufficient and the deficient diets. These results suggest that a protein-deficient diet impairs activation of the adaptive immune response following HRV infection and alters tryptophan homeostasis.

Assessing ACE2 expression patterns in lung tissues in the pathogenesis of COVID-19

“…4). Moreover, ACE2 is also related to adaptive immune responses [17]. In this current study, GSEA analysis showed that the high expression of ACE2 was related to innate immune responses, adaptive immune responses, B cell regulation and cytokine secretion, as well as an enhanced inflammatory response induced by IL-1, IL-10, IL-6, IL-8.…”

Malnutrition Decreases Antibody Secreting Cell Numbers Induced by an Oral Attenuated Human Rotavirus Vaccine in a Human Infant Fecal Microbiota Transplanted Gnotobiotic Pig Model

“…With parental consent, sequential fecal samples were collected from a healthy, 2-monthold, exclusively breastfed, vaginally delivered infant. Samples were pooled and diluted to 1:20 (wt/vol) in PBS containing 0.05% (vol/vol) cysteine and 30% glycerol and stored at −80 • C as described previously (11,12).…”

“…The cell-culture adapted attenuated HRV (AttHRV) Wa G1P [8] strain passaged in African green monkey kidney cells (MA-104) was used as a vaccine at a dose of 1 × 10 7 fluorescent foci-forming units (FFU) (25). The Gn pig passaged virulent HRV (VirHRV) Wa strain at pig passage 26 was used as challenge virus at a dose of 1 × 10 6 FFU as described previously (11,12).…”

“…Some clinical studies have reported decreased protection rates against RV diarrhea following RV vaccination of malnourished children (9,10). A number of field and animal studies have shown that malnutrition induces immune dysfunction, including altered innate and adaptive immune responses, impairment of epithelial cell barriers and dysfunction of intestinal epithelial stem cells (11)(12)(13)(14)(15)(16). However, studies to elucidate the effect of malnutrition on B cell responses following oral HRV vaccine are lacking.…”

“…Previously we have established a protein deficient HIFMtransplanted neonatal Gn pig model that recapitulates major aspects of protein malnutrition in children (11,12). Because malnutrition is prevalent in African and South Asian countries with low HRV vaccine efficacy, we hypothesized that malnutrition will affect the B cell immune responses to oral AttHRV vaccination and subsequent VirHRV challenge.…”