Hypoferremia is a common response to systemic infections or generalized inflammatory disorders. In mouse models, the development of hypoferremia during inflammation requires hepcidin, an iron regulatory peptide hormone produced in the liver, but the inflammatory signals that regulate hepcidin are largely unknown. Our studies in human liver cell cultures, mice, and human volunteers indicate that IL-6 is the necessary and sufficient cytokine for the induction of hepcidin during inflammation and that the IL-6-hepcidin axis is responsible for the hypoferremia of inflammation.

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IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin

The gram-positive bacterium Listeria monocytogenes is the causative agent of listeriosis, a highly fatal opportunistic foodborne infection. Pregnant women, neonates, the elderly, and debilitated or immunocompromised patients in general are predominantly affected, although the disease can also develop in normal individuals. Clinical manifestations of invasive listeriosis are usually severe and include abortion, sepsis, and meningoencephalitis. Listeriosis can also manifest as a febrile gastroenteritis syndrome. In addition to humans, L. monocytogenes affects many vertebrate species, including birds. Listeria ivanovii, a second pathogenic species of the genus, is specific for ruminants. Our current view of the pathophysiology of listeriosis derives largely from studies with the mouse infection model. Pathogenic listeriae enter the host primarily through the intestine. The liver is thought to be their first target organ after intestinal translocation. In the liver, listeriae actively multiply until the infection is controlled by a cell-mediated immune response. This initial, subclinical step of listeriosis is thought to be common due to the frequent presence of pathogenic L. monocytogenes in food. In normal indivuals, the continual exposure to listerial antigens probably contributes to the maintenance of anti-Listeria memory T cells. However, in debilitated and immunocompromised patients, the unrestricted proliferation of listeriae in the liver may result in prolonged low-level bacteremia, leading to invasion of the preferred secondary target organs (the brain and the gravid uterus) and to overt clinical disease. L. monocytogenes and L. ivanovii are facultative intracellular parasites able to survive in macrophages and to invade a variety of normally nonphagocytic cells, such as epithelial cells, hepatocytes, and endothelial cells. In all these cell types, pathogenic listeriae go through an intracellular life cycle involving early escape from the phagocytic vacuole, rapid intracytoplasmic multiplication, bacterially induced actin-based motility, and direct spread to neighboring cells, in which they reinitiate the cycle. In this way, listeriae disseminate in host tissues sheltered from the humoral arm of the immune system. Over the last 15 years, a number of virulence factors involved in key steps of this intracellular life cycle have been identified. This review describes in detail the molecular determinants of Listeria virulence and their mechanism of action and summarizes the current knowledge on the pathophysiology of listeriosis and the cell biology and host cell responses to Listeria infection. This article provides an updated perspective of the development of our understanding of Listeria pathogenesis from the first molecular genetic analyses of virulence mechanisms reported in 1985 until the start of the genomic era of Listeria research.

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Listeria pathogenesis and molecular virulence determinants.

Iron has the capacity to accept and donate electrons readily, interconverting between ferric (Fe2+) and ferrous (Fe3+) forms. This capability makes it a useful component of cytochromes, oxygen-bind...

Disorders of iron metabolism.

This report updates and combines earlier versions of guidelines for the prevention and treatment of opportunistic infections (OIs) in HIV-infected adults (i.e., persons aged >/=18 years) and adolescents (i.e., persons aged 13--17 years), last published in 2002 and 2004, respectively. It has been prepared by the Centers for Disease Control and Prevention (CDC), the National Institutes of Health (NIH), and the HIV Medicine Association (HIVMA) of the Infectious Diseases Society of America (IDSA). The guidelines are intended for use by clinicians and other health-care providers, HIV-infected patients, and policy makers in the United States. These guidelines address several OIs that occur in the United States and five OIs that might be acquired during international travel. Topic areas covered for each OI include epidemiology, clinical manifestations, diagnosis, prevention of exposure; prevention of disease by chemoprophylaxis and vaccination; discontinuation of primary prophylaxis after immune reconstitution; treatment of disease; monitoring for adverse effects during treatment; management of treatment failure; prevention of disease recurrence; discontinuation of secondary prophylaxis after immune reconstitution; and special considerations during pregnancy. These guidelines were developed by a panel of specialists from the United States government and academic institutions. For each OI, a small group of specialists with content-matter expertise reviewed the literature for new information since the guidelines were last published; they then proposed revised recommendations at a meeting held at NIH in June 2007. After these presentations and discussion, the revised guidelines were further reviewed by the co-editors; by the Office of AIDS Research, NIH; by specialists at CDC; and by HIVMA of IDSA before final approval and publication. The recommendations are rated by a letter that indicates the strength of the recommendation and a Roman numeral that indicates the quality of evidence supporting the recommendation, so that readers can ascertain how best to apply the recommendations in their practice environments. Major changes in the guidelines include 1) greater emphasis on the importance of antiretroviral therapy for the prevention and treatment of OIs, especially those OIs for which no specific therapy exists; 2) information regarding the diagnosis and management of immune reconstitution inflammatory syndromes; 3) information regarding the use of interferon-gamma release assays for the diagnosis of latent Mycobacterium tuberculosis (TB) infection; 4) updated information concerning drug interactions that affect the use of rifamycin drugs for prevention and treatment of TB; 5) the addition of a section on hepatitis B virus infection; and 6) the addition of malaria to the list of OIs that might be acquired during international travel. This report includes eleven tables pertinent to the prevention and treatment of OIs, a figure that pertains to the diagnois of tuberculosis, a figure that describes immunization recommendations, and an appendix that summarizes recommendations for prevention of exposure to opportunistic pathogens.

Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America.

Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation.

Iron is essential to all microorganisms. To obtain iron from the very low concentrations present in their environment, microorganisms have developed sophisticated mechanisms such as the siderophore system. As a primitive defense mechanism, humans have developed mechanisms to withhold iron from microorganisms. Iron-binding proteins such as transferrin, ferritin, and lactoferrin have a central role in human ferrokinetics. These iron-binding proteins also participate in the process of decreasing iron availability for the microorganisms. They do so by decreasing iron reutilization. Anemia of inflammation (previously called anemia of chronic disease) is seen in the setting of infectious, inflammatory, and neoplastic diseases. It results, in part, from changes in the intracellular metabolism of iron. Alterations of iron physiology seen in many clinical circumstances make excess iron available to microorganisms, thus enhancing their pathogenicity. Understanding the molecular basis of iron withholding by the human host, both in the absence of and during infection, and that of iron acquisition by microorganisms may provide us with new and innovative antimicrobial agents and vaccines.

Iron, infections, and anemia of inflammation

Clinical Utility of Blood Cultures in Adult Patients with Community-Acquired Pneumonia Without Defined Underlying Risks

The incidence, demographics, and clinical outcome of infections due to Listeria monocytogenes in individuals infected with the human immunodeficiency virus (HIV) were evaluated by prospective population-based surveillance. During a 2-year study period, 37 cases of invasive listeriosis occurred in metropolitan Atlanta (annual incidence, 0.8 case per 100,000 population). Seven of these cases occurred in known HIV-infected individuals (19% of all cases); five had an AIDS-defining illness, and the other two had CD4 lymphocyte cell counts of < 200/microL. The estimated incidence of listeriosis among HIV-infected patients in metropolitan Atlanta was 52 cases per 100,000 patients per year, and among patients with AIDS it was 115 cases per 100,000 patients per year, rates 65-145 times higher than those among the general population. HIV-associated cases occurred in adults who were 29-62 years of age and in postnatal infants who were 2 and 6 months of age. Mortality among the HIV-infected group was 29%. L. monocytogenes serotypes 1/2a, 1/2b, and 4b were isolated from the HIV-infected patients. L. monocytogenes is an important opportunistic pathogen in HIV-infected patients.

Increased Risk of Meningitis and Bacteremia Due to Listeria monocytogenes in Patients with Human Immunodeficiency Virus Infection

We present three patients with syphilis in which the prozone phenomenon was present—a very high antibody titer, leading to a false-negative test in undiluted specimens. One of our three patients was positive for human immunodeficiency virus (HIV), another was at risk for HIV infection, and had some clinical findings compatible with HIV infection (this patient was seen before HIV serologic tests were available). We propose that HIV infection, by its B-cell dysregulation, may lead to higher nontreponemal serologic titers, raising the possibility that the prozone phenomenon may be more prevalent in HIV-positive individuals with syphilis than in luetic patients who are negative for HIV. (Arch Intern Med. 1993;153:2496-2498)

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=INTEMED&articleId=618025&pdfFileName=archinte_153_21_014.pdf

Rafael L. Jurado

Papers

Iron, infections, and anemia of inflammation

Clinical Utility of Blood Cultures in Adult Patients with Community-Acquired Pneumonia Without Defined Underlying Risks

Increased Risk of Meningitis and Bacteremia Due to Listeria monocytogenes in Patients with Human Immunodeficiency Virus Infection

Prozone phenomenon in secondary syphilis. Has its time arrived

Tuberculosis of the pancreas: report of two cases and review of the literature