Transition metal ions are essential micronutrients for all living organisms. In mammals, these ions are often protein-bound and sequestered within cells, limiting their availability to microbes. Moreover, in response to infection, mammalian hosts further reduce the availability of metal nutrients by activating epithelial cells and recruiting neutrophils, both of which release metal-binding proteins with antimicrobial function. Microorganisms, in turn, have evolved sophisticated systems to overcome these limitations and acquire the metal ions essential for their growth. Here we review some of the mechanisms employed by the host and by pathogenic microorganisms to compete for transition metal ions, with a discussion of how evading "nutritional immunity" benefits pathogens. Furthermore, we provide new insights on the mechanisms of host-microbe competition for metal ions in the mucosa, particularly in the inflamed gut.

Epstein-Barr virus-induced gene 3 (EBI3) associates with p28 and p35 to form the immunomodulatory cytokines IL-27 and IL-35, respectively. Infection of EBI3-/- mice with the neuroadapted JHM strain of mouse hepatitis virus (JHMV) resulted in increased mortality that was not associated with impaired ability to control viral replication but enhanced T cell and macrophage infiltration into the CNS. IFN-γ secretion from virus-specific CD4+ and CD8+ T cells isolated from infected EBI3-/- mice was augmented while IL-10 expression muted in comparison to infected WT mice. These data demonstrate a regulatory role for EBI3-associated cytokines in controlling host responses following CNS viral infection.

Objectives

Hypertrophic cardiomyopathy (HCM) is a life-threatening genetic cardiovascular disease that often goes undetected in young athletes. Neither history nor physical examination are reliable to identify those at risk. The objective of this study is to determine whether minimally trained medical student volunteers can use ultrasound to screen for HCM.

Methods

This was a prospective enrollment of young athletes performed at 12 area high schools and three area colleges, between May 2012 and August 2013. All participants underwent point-of-care ultrasound performed screening for HCM by trained medical students and reviewed by a pediatric cardiologist. An interventricular septum to left ventricular posterior wall ratio greater than 1.25 was considered to be abnormal (positive screen).

Results

A total of 2332 participants were enrolled. There were 137 (5.8%) with a positive screening for HCM, of which 7 (5.1%) were confirmed to have HCM by a pediatric cardiologist. In a small cohort with positive screen for HCM, there was a 100% sensitivity (95% confidence interval, 59.04 to 100%) and 4.86% (95% confidence interval, 1.98 to 9.76%) positive predictive value of for having HCM.

Conclusions

Volunteer medical students, using point-of-care ultrasound, were able to effectively screen for HCM in young athletes.

Impaired T cell immunity with aging increases mortality from infectious disease. The branching of Asparagine-linked glycans is a critical negative regulator of T cell immunity. Here we show that branching increases with age in females more than males, in naïve more than memory T cells, and in CD4⁺ more than CD8⁺ T cells. Female sex hormones and thymic output of naïve T cells (T_N) decrease with age, however neither thymectomy nor ovariectomy altered branching. Interleukin-7 (IL-7) signaling was increased in old female more than male mouse T_N cells, and triggered increased branching. N-acetylglucosamine, a rate-limiting metabolite for branching, increased with age in humans and synergized with IL-7 to raise branching. Reversing elevated branching rejuvenated T cell function and reduced severity of Salmonella infection in old female mice. These data suggest sex-dimorphic antagonistic pleiotropy, where IL-7 initially benefits immunity through T_N maintenance but inhibits T_N function by raising branching synergistically with age-dependent increases in N-acetylglucosamine.

Neutrophils hinder bacterial growth by a variety of antimicrobial mechanisms, including the production of reactive oxygen species and the secretion of proteins that sequester nutrients essential to microbes. A major player in this process is calprotectin, a host protein that exerts antimicrobial activity by chelating zinc and manganese. Here we show that the intestinal pathogen Salmonella enterica serovar Typhimurium uses specialized metal transporters to evade calprotectin sequestration of manganese, allowing the bacteria to outcompete commensals and thrive in the inflamed gut. The pathogen's ability to acquire manganese in turn promotes function of SodA and KatN, enzymes that use the metal as a cofactor to detoxify reactive oxygen species. This manganese-dependent SodA activity allows the bacteria to evade neutrophil killing mediated by calprotectin and reactive oxygen species. Thus, manganese acquisition enables S. Typhimurium to overcome host antimicrobial defenses and support its competitive growth in the intestine.