Edward J. Wing

Listeria monocytogenes: Clinical and Experimental Update

Listeria monocytogenes, a small gram-positive bacillus, causes sepsis and meningitis in immunocompromised patients and a devastating maternal/fetal infection in pregnant women. Recent outbreaks demonstrated that L. monocytogenes can cause gastroenteritis in otherwise healthy individuals and more severe invasive disease in immunocompromised patients. Centralized processing in the food industry may be the cause of these large-scale listeriosis outbreaks. The mouse model of listeriosis, which was developed in the 1960s, has been extraordinarily useful for studying T cell-mediated immunity. Contrary to the original concept that macrophages are the principal effector cells in listeriosis, we found that immigrating neutrophils play the predominant role in early liver defenses. At later time points, CD8(+) T cells lyse infected hepatocytes by both perforin- and Fas-L/Fas--dependent mechanisms. Of interest, nonclassical major histocompatibility complex (MHC) class Ib--restricted cytolytic activity is expressed early during primary infection, whereas MHC class Ia--restricted activity is predominant through late primary and secondary infections.

Neutrophil-Kupffer cell interaction: a critical component of host defenses to systemic bacterial infections

Most bacteria that enter the bloodstream are taken up and eliminated within the liver. The specific mechanisms that underlie the role of the liver in the resolution of systemic bacterial infections remain to be determined. The vast majority of studies undertaken to date have focused on the function of resident tissue macrophages (Kupffer cells) that line the liver sinusoids. Indeed, it is often reported that Kupffer cells ingest and kill the bulk of organisms taken up by the liver. Recent studies indicate, however, that phagocytosis by Kupffer cells is not the principal mechanism by which organisms are eliminated. Rather, elimination depends on the complex interaction of Kupffer cells and bactericidal neutrophils that immigrate rapidly to the liver in response to infection. We discuss the critical role of neutrophil‐Kupffer cell interaction in innate host defenses and, conceivably, the development and expression of adaptive immunity in the liver.

It Is Time to Implement Routine, Not Risk-Based, HIV Testing

Approximately one-quarter of a million persons in the United States who are infected with human immunodeficiency virus (HIV) do not know it. To decrease the number of such persons, primary care providers should make HIV testing a routine component of health care. HIV testing should also be offered routinely in other settings, such as emergency departments, jails, and substance abuse treatment centers. Currently, the Centers for Disease Control and Prevention and the Infectious Diseases Society of America recommend routine HIV testing only in settings where the prevalence of HIV infection is > or =1%; in settings where the prevalence of HIV infection is <1%, testing should be based on risk assessment. Because of the impracticality of strategies for testing that are based on estimates of prevalence, and because of the inaccuracy of risk assessment, we propose that HIV testing be routinely offered to any person who is sexually active. As an adjunct to the implementation of routine testing programs, counseling practices need to be streamlined, and rapid HIV testing needs to be implemented in the appropriate settings.

Innate defenses in the liver during Listeria infection

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Effector function of hepatocytes and Kupffer cells in the resolution of systemic bacterial infections

It has been suggested that mononuclear phagocytes serve as the principal site of replication for a number of intracellular pathogens including Listeria monocytogenes. To determine the role of the tissue macrophages (Kupffer cells) in the proliferation of Listeria taken up in the liver, the hepatic cell populations were purified and the associated bacteria were quantified at periodic intervals postinfection. Here we report that the bulk of Listeria injected intravenously into nonimmune mice replicated within hepatocytes rather than Kupffer cells. Whereas a 200‐fold increase in the number of hepatocyte‐associated Listeria occurred during the first 3 days following infection, a relatively small (less than 2‐fold) increase in number of Kupffer cell‐associated Listeria was observed. The Listeria injected intravenously into immune animals, on the other hand, were eliminated rapidly from the hepatocyte as well as the Kupffer cell population. The latter findings suggest that uptake and elimination of pathogenic organisms by “nonprofessional phagocytes” in the liver (i.e., hepatocytes) may be an important effector mechanism in host defenses.

Complementary Adhesion Molecules Promote Neutrophil- Kupffer Cell Interaction and the Elimination of Bacteria Taken Up by the Liver

Most bacteria that enter the bloodstream are taken up by the liver. Previously, we reported that such organisms are initially bound extracellularly and subsequently killed by immigrating neutrophils, not Kupffer cells as widely presumed in the literature. Rather, the principal functions of Kupffer cells demonstrated herein are to clear bacteria from the peripheral blood and to promote accumulation of bactericidal neutrophils at the principal site of microbial deposition in the liver, i.e., the Kupffer cell surface. In a mouse model of listeriosis, uptake of bacteria by the liver at 10 min postinfection i.v. was reduced from approximately 60% of the inoculum in normal mice to ∼15% in mice rendered Kupffer cell deficient. Immunocytochemical analysis of liver sections derived from normal animals at 2 h postinfection revealed the massive immigration of neutrophils and their colocalization with Kupffer cells. Photomicrographs of the purified nonparenchymal liver cell population derived from these infected mice demonstrated listeriae inside neutrophils and neutrophils within Kupffer cells. Complementary adhesion molecules promoted the interaction between these two cell populations. Pretreatment of mice with mAbs specific for CD11b/CD18 (type 3 complement receptor) or its counter-receptor, CD54, inhibited the accumulation of neutrophils in the liver and the elimination of listeriae. Complement was not a factor; complement depletion affected neither the clearance of listeriae by Kupffer cells nor the antimicrobial activity expressed by infiltrating neutrophils.

Epidemiology of Legionella Pneumonia and Factors Associated with Legionella-Related Mortality at a Tertiary Care Center

Legionella pneumophila is an important pathogen that may cause nosocomial and community-acquired pneumonia in patients with normal or altered immunity. The epidemiology of 40 cases of legionella pneumonia in patients hospitalized between 1986 and 1994 was studied. Fourteen patients (35%) were solid organ transplant recipients. The calculated annual incidence of L. pneumophila infection was highest among lung transplant recipients (2.07 cases per 1,000 transplant-years). There was a trend toward reduced mortality rates and less severe disease among transplant patients vs. nontransplant patients: mortality rate, 36% vs. 54%; incidence of intubation, 50% vs. 69%; rate of concurrent infections, 29% vs. 38%; and overall rate of complications, 86% vs. 96%; respectively. In a multivariate analysis, factors independently associated with an increased mortality rate were nosocomial acquisition, need for intubation, formation of lung abscess or cavitation, and presence of pleural effusion. Thus, despite differing host immune responses, the most important prognostic factors affecting the outcome of legionellosis are nosocomial acquisition and the development of pulmonary complications.

Neutrophil–Kupffer-cell interaction in host defenses to systemic infections

Most relevant textbooks characterize phagocytosis by Kupffer cells as the principal mechanism for clearing bacterial pathogens from the bloodstream and eliminating them from the liver. Here, Stephen Gregory and Edward Wing discuss recent evidence indicating that the actual mechanism is far more complicated, dependent upon the complex interaction of Kupffer cells with neutrophils that immigrate into the liver following infection.

Fasting-enhanced immune effector mechanisms in obese subjects

Acute nutritional deprivation occurs frequently in clinical practice, yet little data exist on its effect on immune host defenses. To investigate this question, various immune parameters were studied in 15 obese subjects before and after a 14-day fast. Blood monocyte bactericidal activity and natural killer cell cytolytic activity were enhanced by fasting: monocyte killing increased in 12 of 14 subjects (p less than 0.05) and natural killer cell activity increased an average of 24 percent in 13 subjects tested (p less than 0.02). Starvation also enhanced parameters of humoral immunity as evidenced by increases in serum concentrations of IgG, IgA, and IgM (p less than 0.01). By contrast, lymphocyte blastogenic responses to the mitogen phytohemagglutinin were modestly decreased. Peripheral blood leukocyte counts, including neutrophils, T cells, and B cells, did not decrease significantly. These results indicate that fasting has differential influences on immune function rather than a uniformly deleterious effect. Of potential import, this nutritional alteration appears to actually enhance certain effector functions of the host defense system.

Disseminated listeriosis presenting as acute hepatitis: Case reports and review of hepatic involvement in listeriosis

We report three cases of disseminated listeriosis that presented as acute hepatitis characterized by striking increase of liver function test values and fever. Peak serum transaminases (SGOT) for each of three patients were 5,380, 2,350, and 443 mu/ml respectively. The correct diagnosis was not suspected in any of the patients until blood and cerebrospinal fluid cultures obtained routinely in the course of evaluation for fever grew Listeria monocytogenes. When antibiotic therapy was instituted, serum transaminase values plummeted in two patients; these two were eventually cured of their infection. The third patient succumbed to his infection; postmortem examination showed miliary abscesses of the liver which revealed L. monocytogenes. Review of the literature for previous reports of hepatic involvement in adult patients with listeriosis shows that hepatitis is an unusual mode of presentation. However, since we observed these three cases over a one-year period, we suspect this may not be an uncommon occurrence.