TABLE 3.

Malnutrition-associated susceptibility to specific pathogens^d

Pathogena	Modelb and/or study type	Infection outcome(s)c	Immunological outcome(s)c	Reference(s)
Viral pathogens
Influenza virus	Mouse; 2% protein diet	Increased severity (viral persistence, pulmonary inflammation, mortality)	Decreased virus-specific antibody and CD8+ T cell responses	126
Influenza virus	Mouse; 40% energy restriction	Increased viral burden and lung pathology, decreased survival	Decreased no. and function of natural killer cells; decreased levels of type I interferons	110
Respiratory syncytial virus	Longitudinal study of birth cohort of rural Kenyan children	Stunting (HAZ of ≤−2) associated with higher incidence of RSV LRTI	Not evaluated	339
Respiratory syncytial virus	Longitudinal study of infants in Niger	Increased rate of severe RSV LRTI (hospitalization) in children with WAZ of ≤−2 and lower than median growth between 1st and 3rd vaccination visits	Not evaluated	338
Lymphocytic choriomeningitis virus	Mouse; isocaloric low-protein (0.6%) diet	Increased viral burden in liver	Decrease in no. of LCMV-specific CD8+ memory T cells; decreased homeostatic T cell proliferation; defects rescued by protein supplementation	549
Lymphocytic choriomeningitis virus	Mouse; isocaloric low-protein (0.6%) diet; adoptive transfer of virus-specific CD8+ T cells from normal to malnourished mice	Reduced viral clearance from serum	Reduced no. of total and LCMV-activated splenic CD8+ T cells; reduced frequency of virus-specific IFN-γ-producing T cells; adoptive transfer of virus-specific T cells showed that the malnourished microenvironment was a major determinant of impaired T cell activation	131
Norovirus	Mouse; 2% protein diet	Increased severity	Reduced antiviral antibody responses, loss of protective immunity	349
Rotavirus	Weanling mouse, dams of 3-day-old litters fed multideficient regional basic diet (5% fat, 7% protein, 88% carbohydrate)	Earlier peak intensity of infection and increased early viral shedding	No differences in rotavirus-specific serum IgG and stool IgA levels; higher rotavirus-specific serum IgA levels; rotavirus vaccine equally protective in the malnourished group	69
Bacterial pathogens
Streptococcus pneumoniae	Mouse; protein-free diet for 21 days	Increased bacterial burden in lung and blood	Impaired macrophage and neutrophil responses, proinflammatory cytokines, granulopoiesis	337
Nontyphoidal Salmonella	Prospective hospital-based study of children (median age, 15 mo)	Increased severity of illness and increased mortality in children with severe acute malnutrition (WAZ of <−3)	Not evaluated	550
Shigella spp.	Prospective 1-yr study of children <15 yr of age in Dhaka, Bangladesh	Reduced wt for age associated with increased mortality	Not evaluated	551
Enteroaggregative E. coli	Mouse; 2% protein diet	Increased severity of disease (reduced wt gain); increased EAEC fecal shedding	Not evaluated	345
Enteroaggregative E. coli	Mouse; 7 % protein and reduced fat and micronutrients	Increased EAEC fecal shedding; increased intestinal tissue burden	Increased expression levels of IL-4, IL-12, IL-17, and TNF-α mRNAs in the ileum	346
Mycobacterium tuberculosis	Mouse; leptin-deficient mice	Higher bacterial loads in lungs	Reduced no. of well-shaped granulomas, no. of lung lymphocytes, and IFN-γ levels at the site of infection and delayed-type hypersensitivity	552
Mycobacterium tuberculosis	Population-based, retrospective cohort study of adult and child contacts of active TB cases	Increased incidence of active disease (hazard ratio, 37.5) in malnourished subjects (malnutrition not defined)	Not evaluated	553
Mycobacterium tuberculosis	Prospective study of children <5 yr of age who were household contacts of active adult TB cases	Increased incidence (odds ratio, 3.97) of active disease in children with severe malnutrition (wt <60% of that expected)	Not evaluated	401
BCG	Mouse; dietary restriction to 70% of controls	Increased bacterial dissemination	Dietary restriction blunted spleen cell production of IFN-γ, TNF-α, and IL-10 in an antigen-induced recall assay	406
Protozoal pathogens
Leishmania donovani	Mouse; 3% protein, low Fe and Zn	Increased dissemination following cutaneous inoculation	Impaired LN barrier function; reduced no. of LN myeloid cells; increased LN conduit transit	56, 57
Leishmania chagasi	Mouse; 3% protein, low Fe and Zn	Increased parasite burden in liver and spleen during chronic infection	Reduced spleen IFN-γ levels	554
Leishmania chagasi	Mouse; 4% protein	Modest increase in parasite load in spleen but not liver	Decreased thymic and splenic cellularity; reduced no. of lymphoid follicles in spleen; increased no. of thymic CD4+ T cells and decreased no. of thymic CD4+ CD8+ T cells; decreased IL-12 production by thymus and spleen cells	55
Plasmodium spp.	Prospective longitudinal cohort study of young children in Uganda	Stunting (HAZ of ≤−1) associated with increased incidence of clinical malaria	Not evaluated	415
Plasmodium berghei	Pregnant mice; low protein	Early mortality; increased fetal loss	Lower plasma nitric oxide levels	555
Trypanosoma cruzi	Rats; 6% protein diet	Increased inflammatory process of Chagas disease; increased parasitemia	Reduced levels of cardiac CX3CL1, endothelin-1, and CD68 and CD163 macrophages	556
Cryptosporidium parvum	Mouse; 2% protein diet	Higher-level fecal C. parvum shedding; increased intestinal pathology (reduction in the villous ht/crypt depth ratio in the ileum)	Depressed TLR2 and -4 signaling and Th1 cytokine response	361
Cryptosporidium parvum	Mouse; 2% protein diet	Higher intensity of C. parvum infection (fecal oocyst counts)	Not evaluated	360
Cryptosporidium parvum	Mouse; undernutrition induced by daily separation of pups from lactating dams	Increased fecal oocyst shedding; increased ileal and colonic tissue infection; hyperplastic crypts and increased inflammation in the ileum	Increased TNF-α and IFN-γ levels in infected ileal tissues	351
Cryptosporidium parvum	Mouse; undernutrition induced by daily separation of pups from lactating dams	Increased fecal oocyst shedding; increased ileal and colonic tissue infection; hyperplastic crypts and increased inflammation in the ileum (all of which were improved by administration of l-arginine)	l-Arginine supplementation enhanced ileal nitric oxide production and decreased arginase 1 expression	362
Giardia lamblia	Mouse; 3 wk old; 2% protein diet	No difference in intensities of infection but enhanced infection-induced growth impairment; absence of infection-induced crypt hyperplasia; blunted villus architecture	Blunted increase in no. of B220+ cells in lamina propria; blunted mucosal eosinophil infiltration and expression of IL-4 and IL-5 mRNAs	358
Giardia lamblia	Gerbil; 4–6 wk old; 5% protein	No difference in intensities of infection; reduced villus ht	Not evaluated	359
Entamoeba histolytica	Prospective longitudinal study of children 2–5 yr of age	Not evaluated	Lower-level IFN-γ and higher-level IL-5 production by PBMCs in response to soluble amebic extract	355
Entamoeba histolytica	Prospective longitudinal study of children 2–5 yr of age	Increased incidence of amebiasis in malnourished children (WAZ of <2)	Not evaluated	344
Helminth pathogens
Schistosoma japonicum	Cross-sectional study of people aged 7–30 yr	Intensity of infection inversely correlated with HAZ in children <12 yr of age	Not evaluated	557
Schistosoma mansoni	Mouse; neonatal malnutrition induced in pups by low-protein (8%) or calorie-restricted diet of lactating dams; mice infected as adults	Increased intensity of intestinal infection and increased liver pathology in low-protein group; smaller granulomas and increased liver regeneration in calorie-restricted group	Not evaluated	373
Heligmosomoides polygyrus	Mouse; low selenium and/or vitamin E	Delayed adult worm expulsion and increased fecundity during secondary infection	Blunted IL-4 response in selenium/vitamin E-deficient mice	558
Heligmosomoides bakeri	Mouse; 6% protein diet; refeeding with a protein-sufficient diet	Increased fecal egg output and worm burdens in protein-deficient animals; restored parasite clearance in protein-refed animals	Reduced IL-4 and IL-13 levels	559, 560
Heligmosomoides polygyrus	Mouse; 3% protein diet	Higher intestinal worm burdens	Decreased gut-associated IL-4 and increased IFN-γ levels; decreased serum IgE response; reduced intestinal eosinophilia and mucosal mast cell proliferation and activation	372
Heligmosomoides polygyrus	Mouse; low protein (3% or 7%) or low zinc	Higher intestinal worm burdens	Decreased eosinophilia in protein- and zinc-deficient mice	561

^aOnly studies that identified a specific pathogen were included.

^bHuman studies included prospective longitudinal studies unless noted otherwise.

^cImmunological outcomes related to malnutrition.

^dLN, lymph node; PBMCs, peripheral blood mononuclear cells.