Date Published: May 1, 2007
Publisher: Public Library of Science
Author(s): Ulrich E Schaible, Stefan H. E Kaufmann
Abstract: The authors discuss current concepts and controversies surrounding the complex influences of malnutrition on infection and immunity, and point to practical consequences of countermeasures in acute malnutrition.
Partial Text: Activation and sustenance of immune responses during infection requires increased energy consumption. Protein energy malnutrition (PEM) is a critical, yet underestimated factor in susceptibility to infection, including the “big three” infectious diseases: HIV/AIDS, tuberculosis, and malaria. In this article, we discuss current concepts and controversies surrounding the complex influences of malnutrition on infection and immunity, and point to practical consequences of countermeasures in acute malnutrition. We call for new strategies to overcome worldwide morbidity and mortality caused by chronic malnutrition in impoverished countries and by the newly emerging public health threat of overnutrition in industrialized societies.
In response to infection, the immune system first executes innate and then subsequently acquired host defense functions of high diversity. Both processes involve activation and propagation of immune cells and synthesis of an array of molecules requiring DNA replication, RNA expression, and protein synthesis and secretion, and therefore consume additional anabolic energy. Mediators of inflammation further increase the catabolic response. Studies in a simple system, involving measurement of the survival of malnourished bumblebee workers, showed that the energy cost of immunity further impairs fitness . Consequently, the nutritive status of the host critically determines the outcome of infection.
Severe protein malnutrition in newborns and small children causes atrophy of the thymus with reduced cell numbers and subsequently ill-developed peripheral lymphoid organs, i.e., lymph nodes and spleen . This causal chain leads to long-lasting immune defects characterized by leucopenia, decreased CD4 to CD8 ratio and increased numbers of CD4/CD8 double-negative T cells, and, therefore, the appearance of immature T cells in the periphery. Malnourished children suffer in greater proportion from respiratory infections, infectious diarrhea, measles, and malaria, characterized by a protracted course and exacerbated disease. These malnourished children present with diminished functional T cell counts, increased undifferentiated lymphocyte numbers, and depressed serum complement activity (Table 1).
Malnutrition is generally appreciated as a major risk factor in the onset of active tuberculosis . This notion is largely based on historical reports but also on more recent experimental animal studies.
Leptin is a central mediator connecting nutrition and immunity. Levels of the pleiotropic hormone leptin, which regulates satiety, are reduced in patients with PEM. Leptin concentrations correlate with body fat mass and are quickly reduced by fasting . Leptin is a 16 kDa α-helix type protein similar to the cytokines IL-6 and IL-12, and is mainly secreted by adipose tissue. At least six receptors representing different splice forms encoded by one gene are broadly distributed on different cell types. The isoform is not only full-length ObRb expressed in the hypothalamus, but is also prevalent on lymphocytes and macrophages [36,37]. Leptin binding activates immune cells via the to ObRb JAK-2/STAT-3 and the MAPK pathway and induces TNF-α, IL-6, and IL-12 secretion in macrophages. Leptin stimulates naïve T cells (CD45RA+) but blocks proliferation of memory T cells (CD45RO+). Concomitantly, leptin promotes IFN-γ secretion by memory T cells, inhibits Th2 responses [38,39], and induces activation markers (CD69, CD25, and CD71) . Apart from inducing lymphopoiesis, leptin seems to deliver survival signals to T cells by upregulating anti-apoptotic proteins T-bet and Bcl-xL .
The hormonal connection between immunity and nutrition becomes equally evident in nutritional dysregulatory eating disorders such as obesity, which is becoming alarmingly common in high-income countries, notably in the United States and United Kingdom, and is also spreading to transitional societies at an unexpectedly high speed.
Extrapolating the studies discussed, malnutrition can be considered a major risk factor for morbidity and mortality worldwide due to infections with bacterial, viral, and protozoal agents [2,8,9]. This causal relationship was suggested in the US Surgeon General’s Report in 1988 . With more than 842 million chronically malnourished people worldwide , we agree with the notion that “…malnutrition may account for a greater population-attributable risk of tuberculosis than HIV infection, and certainly a much more correctable one” .