The Journal of immunology : official journal of the American Association of Immunologists
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C-reactive protein (CRP) is an acute-phase protein that plays an important defensive role in innate immunity against bacterial infection, but it is also upregulated in many noninfectious diseases. The generic function of this highly conserved molecule in diseases that range from infection, inflammation, trauma, and malignancy is not well understood. In this article, we demonstrate that CRP defends the human body against the toxicity of histones released into the circulation after extensive cell death. ⋯ CRP is able to compete with phospholipid-containing liposomes for the binding to histones. This explains how CRP prevents histones from integrating into cell membranes, which would otherwise induce calcium influx as the major mechanism of cytotoxicity caused by extracellular histones. Because histone elevation occurs in the acute phase of numerous critical illnesses associated with extensive cell death, CRP detoxification of circulating histones would be a generic host defense mechanism in humans.
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During the 2009 pandemic H1N1 influenza A virus (pH1N1) outbreak, obese individuals were at greater risk for morbidity and mortality from pandemic infection. However, the mechanisms contributing to greater infection severity in obese individuals remain unclear. Although most individuals lacked pre-existing, neutralizing Ab protection to the novel pH1N1 virus, heterologous defenses conferred from exposure to circulating strains or vaccination have been shown to impart protection against pH1N1 infection in humans and mice. ⋯ Further, obese mice had elevated viral titers, greater lung inflammation and lung damage, and more cytotoxic memory CD8(+) T cells in the lung airways. Although obese mice had more regulatory T cells (Tregs) in the lung airways than did lean controls during the pH1N1 challenge, Tregs isolated from obese mice were 40% less suppressive than Tregs isolated from lean mice. In sum, excessive inflammatory responses to pH1N1 infection, potentially owing to greater viral burden and impaired Treg function, may be a novel mechanism by which obesity contributes to greater pH1N1 severity.
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Influenza infection predisposes patients to secondary bacterial pneumonia that contributes significantly to morbidity and mortality. Although this association is well documented, the mechanisms that govern this synergism are poorly understood. A window of hyporesponsiveness following influenza infection has been associated with a substantial increase in local and systemic IFN-γ concentrations. ⋯ To determine whether these effects were due to suppression of IFN-γ, linezolid-treated animals were given intranasal instillations of rIFN-γ before challenge with S. pneumoniae. This partially reversed the protective effects observed in the linezolid-treated mice, suggesting that the modulatory effects of linezolid are mediated partially by its ability to blunt IFN-γ production. These results suggest that IFN-γ, and potentially TNF-α, may be useful drug targets for prophylaxis against secondary bacterial pneumonia following influenza infection.
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Tuberculosis, caused by Mycobacterium tuberculosis, remains a leading cause of mortality and morbidity worldwide, causing ≈ 1.4 million deaths per year. Key immune components for host protection during tuberculosis include the cytokines IL-12, IL-1, and TNF-α, as well as IFN-γ and CD4(+) Th1 cells. However, immune factors determining whether individuals control infection or progress to active tuberculosis are incompletely understood. ⋯ The TPL-2-ERK1/2 signaling pathway regulated production by macrophages of several cytokines important in the immune response to M. tuberculosis as well as regulating induction of a large number of additional genes, many in a type I IFN-dependent manner. In the absence of TPL-2 in vivo, excess type I IFN promoted IL-10 production and exacerbated disease. These findings describe an important regulatory mechanism for controlling tuberculosis and reveal mechanisms by which type I IFN may promote susceptibility to this important disease.
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Iron is a trace element important for the proper folding and function of various proteins. Physiological regulation of iron stores is of critical importance for RBC production and antimicrobial defense. Hepcidin is a key regulator of iron levels within the body. ⋯ This response was independent of IL-6 and was attenuated in the absence of the IL-22R-associated signaling kinase, Tyk2. Ab-mediated blockade of hepcidin partially reversed the effects on iron biology caused by IL-22R stimulation. Taken together, these data suggest that exogenous IL-22 regulates hepcidin production to physiologically influence iron usage.