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Review
. 2017 Oct;30(4):919-971.
doi: 10.1128/CMR.00119-16.

Impact of Childhood Malnutrition on Host Defense and Infection

Affiliations
Review

Impact of Childhood Malnutrition on Host Defense and Infection

Marwa K Ibrahim et al. Clin Microbiol Rev. 2017 Oct.

Abstract

The global impact of childhood malnutrition is staggering. The synergism between malnutrition and infection contributes substantially to childhood morbidity and mortality. Anthropometric indicators of malnutrition are associated with the increased risk and severity of infections caused by many pathogens, including viruses, bacteria, protozoa, and helminths. Since childhood malnutrition commonly involves the inadequate intake of protein and calories, with superimposed micronutrient deficiencies, the causal factors involved in impaired host defense are usually not defined. This review focuses on literature related to impaired host defense and the risk of infection in primary childhood malnutrition. Particular attention is given to longitudinal and prospective cohort human studies and studies of experimental animal models that address causal, mechanistic relationships between malnutrition and host defense. Protein and micronutrient deficiencies impact the hematopoietic and lymphoid organs and compromise both innate and adaptive immune functions. Malnutrition-related changes in intestinal microbiota contribute to growth faltering and dysregulated inflammation and immune function. Although substantial progress has been made in understanding the malnutrition-infection synergism, critical gaps in our understanding remain. We highlight the need for mechanistic studies that can lead to targeted interventions to improve host defense and reduce the morbidity and mortality of infectious diseases in this vulnerable population.

Keywords: Mycobacterium tuberculosis; host defense; immunology; infectious disease; malaria; malnutrition; micronutrients; pneumonia; sepsis.

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Figures

FIG 1
FIG 1
Interplay of malnutrition with environmental enteric dysfunction and systemic inflammation. Exposure to intestinal pathogens and intestinal dysbiosis, as a consequence of poor sanitation and possibly specific nutrient deficiencies (e.g., zinc, vitamin A, and protein), lead to intestinal inflammation and disruption of intestinal barrier function. Impaired barrier function allows the translocation of bacteria and bacterial products from the intestine, which activate innate immune cells in the mesenteric lymph nodes, liver, and systemic circulation to generate proinflammatory cytokines. The increased systemic inflammation carries a metabolic cost and leads to impaired host defense. Collectively, these vicious cycles lead to growth faltering and increased mortality.
FIG 2
FIG 2
Effects of acute malnutrition on lymphoid and hematopoietic organs. The effects of acute malnutrition on the thymus, lymph nodes, spleen, and bone marrow are shown. Note that observations for the spleen and lymph node are based largely on data from animal studies. The effect of malnutrition on the immune and hematopoietic functions of the liver has not been investigated.
FIG 3
FIG 3
Vitamin A metabolism and effect on immune cells in mucosa- and gut-associated lymphoid tissues. The fat-soluble vitamin A is acquired in the diet in the form of all-trans-retinol, retinyl esters, or β-carotene. These forms are solubilized in products of fat digestion and absorbed in micelles through the enterocyte membrane. Retinol circulates in the blood, complexed with retinol binding protein (RBP) and transthyretin (TTR). Retinol is oxidized to all-trans-retinal, which is then oxidized to all-trans-retinoic acid (RA) by retinal dehydrogenases, which are found in intestinal epithelial cells and gut-associated dendritic cells. Retinoic acid is exported from the cell and exerts autocrine and paracrine effects on immune cells by binding to nuclear receptors of the retinoic acid receptor (RAR) family, which heterodimerize with receptors of the retinoic X receptor (RXR) family. Together, these forms bind to retinoic acid response elements within promoters of retinoic acid response genes. In the presence of inflammatory stimuli, RA enhances dendritic cell maturation and antigen-presenting capacity. Dendritic cells also store and release RA to act on other immune cells. RA acts on naive T cells to upregulate the expression of gut-homing receptors. It reduces Th1 differentiation by blocking the expression of IL-12 by dendritic cells and T cell expression of the transcription factor Tbet and Th1 cytokines. It also blocks the induction of the transcription factor retinoic acid receptor-related orphan receptor γt (RORγt) and the differentiation of Th17 cells. In contrast, RA induces GATA3 and IL-4 expression, leading to enhanced Th2 differentiation, and promotes the differentiation of naive T cells to FoxP3+ regulatory T cells in intestinal tissue. B cells in mucosa- and gut-associated lymphoid tissues activated in the presence of RA differentiate into IgA+ antibody-secreting cells (ASC) (211).
FIG 4
FIG 4
Vitamin D metabolism and cells of the immune system. Vitamin D3 (VD3) (cholecalciferol) is primarily acquired preformed in the diet or synthesized in the skin through the action of UVB radiation in sunlight from 7-dehydrocholesterol. VD3 is metabolized first in the liver to 25-hydroxyvitamin D3 [25(OH)VD3] and then in the kidney to the most physiologically active metabolite, 1,25-dihydroxyvitamin D3 [1,25(OH)2VD3]. VD3 can also be metabolized by cells of the immune system (e.g., dendritic cells and macrophages) to 25(OH)VD3 and 1,25(OH)2VD3 through the action of the enzymes CYP27A and CYP27B1, respectively. 1,25(OH)2VD3 acts on immune cells in an autocrine or paracrine manner through binding to the nuclear vitamin D receptor (VDR). Upon binding with 1,25(OH)2VD3, VDR heterodimerizes with nuclear receptors of the retinoic X receptor (RXR) family, and the complex binds to VD3 response elements in the promoters of VD3 response genes. CYP27B1 and VDR are upregulated in cells activated through TLR2, TLR4/NF-κB, and IFN-γ/STAT1. VD3 has a largely suppressive effect on the adaptive immune system. Markers of dendritic cell maturation, activation, and antigen presentation are downregulated by exposure to 1,25(OH)2VD3. In particular, IL-12 production is diminished, leading to reduced Th1 differentiation, and suppressive cytokines such as IL-10 are upregulated. T lymphocytes show evidence of reduced proliferation, cytotoxic activity, and effector cytokine expression and increased regulatory function through increased regulatory T cell (Treg) and Th2 differentiation and IL-4 and IL-10 production. It is unclear if B cells express VDR or if their function is modulated indirectly through the reduced activity of antigen-presenting cells or reduced T cell help. B cells show reduced proliferation, differentiation to plasma cells, and immunoglobulin secretion. In contrast, monocytes and macrophages exposed to 1,25(OH)2VD3 have increased proinflammatory properties and produce antimicrobial peptides that are important for the innate immune response (211).
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