The term pathogenicity island has been used to refer to large chromosomal regions in pathogenic bacteria that encode virulence genes. This article reviews the recent history of this term and considers what characteristics define a pathogenicity island. It appears that pathogenicity islands can confer complex virulence phenotypes and were acquired by bacteria from unrelated organisms, leading to interesting hypotheses about how bacterial pathogens evolved. It is likely that mechanisms that generate pathogenicity islands continue to operate and may contribute to the emergence of bacterial pathogens with new virulence properties.
Invasive aspergillosis is a common infection in patients who are immunocompromised, particularly in oncology patients, patients receiving other immunosuppressive therapy, bone marrow transplant patients, and HIV-infected patients. The diagnosis of invasive aspergillosis is difficult in the absence of tissue biopsy and histologic confirmation. Therefore, the need for and progress in recent advances in the development of highly sensitive and specific serodiagnostic tests for the early diagnosis of invasive aspergillosis have been reviewed. Anti-Aspergillus antibody detection lacks the utility to lead to early diagnosis of invasive aspergillosis. However, sensitive methods that detect significant amounts of Aspergillus antigen in body fluids, primarily serum, of high risk patients are currently being evaluated and may provide a noninvasive early diagnostic test that is both sensitive and specific. Our recent results with an inhibition enzyme-linked immunosorbent assay, which detects small but significant amounts of Aspergillus antigen in serum, in 35 patients with invasive aspergillosis are discussed. Also, current antifungal agents with anti-Aspergillus activity that have the potential for use as therapy or prophylaxis are briefly reviewed.
Rickettsiae are bacterial obligate intracellular parasites ranging from harmless endosymbionts to the etiologic agents of some of the most devastating diseases known to mankind. Rickettsiae are primarily associated with arthropod vectors in which they may exist commensally and, in most cases, only accidentally infect humans. These fascinating microbes are the prototypical obligate intracellular parasites. Other than being extremely fastidious in their growth requirements, however, rickettsiae are typical gram-negative bacteria. Only a few intracellular parasites multiply within the cytoplasm of eukaryotic cells. In this environment, rickettsiae are provided with a rich source of biosynthetic precursors not normally encountered by free-living bacteria and have evolved a number of unique mechanisms to transport such metabolites as nucleotides and nucleotide sugars. The physiologic basis for their obligate parasitism, however, has remained elusive for > 90 years. Other than the obvious property of replicating inside eukaryotic cells, the molecular mechanisms of cellular damage are ill defined. The typhus-group rickettsiae multiply within host cells to great numbers without profound damage until lysis occurs. In contrast, the spotted fever-group rickettsiae spread rapidly from cell to cell by an actin-based motility. This property, in itself, is not sufficient to cause cell death, because avirulent spotted fever-group rickettsiae also spread by actin-based movement but do not cause lysis of the host cell. Despite the obvious limitations imposed by their obligate intracellular lifestyle and the current lack of methods for genetic manipulation, there are enough interesting biological properties of rickettsiae to offer an attractive area for research.
Blood-feeding arthropods transmit numerous types of infectious agent and parasite that have a tremendous impact on human health and mortality throughout the world. These vector-borne pathogens display a wide array of evolutionary patterns that allow them to infect and to be successfully transmitted by ticks, mites, and hematophagous insects. The vector's method of feeding, type of development, and host preference are also critical factors for the transfer of zoonotic agents from wild animal reservoirs to susceptible humans. Ticks are obligate blood-feeders in all life stages and biologically transmit many infectious agents. In North America, two ticks that are involved in the maintenance and transmission of pathogenic spirochetes include Ixodes scapularis (family Ixodidae) and Ornithodoros hermsi (family Argasidae). These ticks are the respective vectors of the Lyme disease spirochete Borrelia burgdorferi and a relapsing fever spirochete, Borrelia hermsii. Little is known concerning how these and related species of Borrelia adapt to successfully alternate between warm-blooded vertebrates and ticks; however, the possibility that borrelial surface proteins are differentially expressed in their different hosts is an exciting area of current research.
Human herpesvirus (HHV)-6 strains segregate into two variants (HHV-6A and HHV-6B), closely related to each other but clearly and easily distinguishable. These two HHV-6 variants differ in their ability to grow in T-cell lines, have distinctive patterns of DNA restriction fragments, and show specific reactivities with some monoclonal antibodies. The degree of DNA homology between variants ranges from 97% in the most conserved region to 75% in the immediate early region 1. HHV-6B is the etiologic agent of exanthema subitum but HHV-6A has not yet been clearly associated with any human pathology. HHV-6 sequences are frequently detected by the polymerase chain reaction (PCR) in healthy and pathological tissues. HHV-6B is more prevalent in peripheral blood mononuclear cells and in lymphatic tissue. The prevalence of HHV-6A may be greater in some pathological conditions such as Kaposi's sarcoma, and in skin biopsies. Results so far available support the hypothesis that HHV-6 variants may have different epidemiologies.
Perhaps the most challenging event of the malaria parasite's lifecycle is the sporozoite's journey to the hepatocyte. Because few parasites are injected by the mosquito, they must be efficiently and rapidly targeted to hepatocytes, where they will invade and develop into merozoites, the form of the parasite infective for red blood cells. Little is known about how sporozoites make their way to the liver and subsequently invade hepatocytes. Some evidence suggests that they are initially trapped by Kupffer cells and then transported to hepatocytes. Other findings support the hypothesis that sporozoites home to hepatocytes directly. We have found that the major surface protein of malaria sporozoites, the CS protein, binds to the basolateral domain of hepatocytes and, when injected intravenously into mice, is rapidly cleared from the circulation by the liver. Whether sporozoites are arrested in the liver by the same mechanisms as CS protein is not known, although preliminary data suggests this may be the case. Other sporozoite proteins are also likely to be involved in hepatocyte invasion. TRAP or SSP2, found on the parasite surface and in micronemes, binds to hepatocytes in a similar pattern as CS protein. There is evidence demonstrating its involvement in invasion, although it is not known whether it functions in the initial sequestration of the parasites by the liver or in subsequent invasion events.
Cytomegaloviral (CMV) seronegative women who acquire a primary CMV infection during pregnancy are at the greatest risk for delivering infants who may be deaf or intellectually handicapped because of congenital CMV infection. Maternal immunization before pregnancy may protect newborns from congenital disease because mothers who are naturally seropositive are protected against secondary infection and because newborns who acquire CMV either via transfusion or transplacentally are protected if their mothers had antibodies to CMV prior to pregnancy. Further evidence for the feasibility of immunization for CMV comes from studies of patients immunocompromised following solid organ transplantation protection. These patients are protected against severe cytomegaloviral disease by immunity acquired either by wild-type infection prior to transplantation or by passive or active immunization. In three randomized placebo-controlled studies, live attenuated CMV Towne vaccine has successfully protected seronegative recipients of seropositive kidneys from severe CMV disease by inducing humoral and cellular immunity. Subunit vaccines comprised of glycoprotein gB, the viral component containing the majority of viral neutralizing epitopes, are in the early phases of study, as are studies with highly immunogenic preparations of Towne vaccine. Given all of these facts, safe and effective CMV immunoprophylaxis against CMV disease is possible.
Epidemiologic studies have long suggested that Kaposi's sarcoma (KS) is caused by a sexually transmissible infectious agent. A new, and presumably human, herpesvirus, Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8), has been detected in KS lesions from AIDS patients by sequence-based detection techniques. KSHV is present in almost all KS lesions from all forms of KS. The virus is a Rhadinovirus or gamma-2 herpesvirus most closely related to Herpesvirus saimiri (HVS), and possesses several genes that may allow it to modify its host cell environment. KSHV has been isolated in vitro with immortalized B cell lines derived from a second malignancy associated with KSHV, body cavity-based lymphomas (BCBL). Epidemiologic studies performed to date indicate that KSHV, unlike other human herpesviruses (HHV), is not ubiquitous. The growing body of evidence indicates that KSHV is a potent oncogenic herpesvirus and the likely infectious cause of KS and BCBL.
Helicobacter pylori is a recently recognized bacterial pathogen associated with diverse pathologies of varying severity, such as chronic gastritis, peptic ulceration, mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric carcinoma. We here present a review of our current knowledge on the properties of H. Pylori that adapt it to its particular niche by allowing it to survive in the stomach and to colonize the gastric mucosa, as well as those that underlie its persistence and pathogenicity. While the bacterial determinants that preclude the persistent colonization of the gastric mucosa are better understood, those associated with pathogenicity appear to result from the possibility for some of the bacteria of the species to synthesize products that directly or indirectly damage the gastric mucosa, cause a persistent inflammatory reaction, and/or perturb the regulation of acid secretion.
During the last 10 years, studies of the immune response to M. tuberculosis in humans and animal models have increased our understanding of the complex roles of T-cell subsets in protection against tuberculosis. Although CD4+ T cells remain the dominant and critical T-cell subset, others, such as gamma delta and CD8+ T cells, probably have important complementary roles. Since all three subsets are sources of IFN-gamma and competent cytotoxic effector cells, in vivo kinetics and differences in antigen processing/recognition likely will define how each T-cell subset functions in different phases of the immune response to M. tuberculosis. In addition, individuals may differ in terms of the dominance of CD8+ and gamma delta T cells as accessory T-cell populations. In some, gamma delta T cells; in others, CD8+ T cells; or both T-cell subsets may complement CD4+ T-cell function. Future studies in animal models (with human cells obtained from sites of infection such as lung or lymph node), characterizations of the antigen repertoire, and longitudinal immunoepidemiological studies should define more clearly how different T-cell subsets contribute to protection against M. tuberculosis. Such studies may determine how failure of T-cell subset function results in reactivation or progressive primary tuberculosis. Enhanced understanding of the function of, and antigen recognition by, T-cell subsets in M. tuberculosis infection also is necessary for the development of improved diagnostic tests and vaccines for tuberculosis.
Synovial lymphocytes, from the site of disease, by their response to microbiological antigen stimulation as measured by the [3H]thymidine uptake method, indicate the microbiological causes of reactive arthritis and also oligoarthritis unassociated with enteric or genital symptoms. In the study of the etiology and pathogenesis of rheumatoid arthritis, the application of the same procedures gives an indication that the disease is an immune response to a variety of common infective agents, both viral and bacterial. The demonstration of antigens or nucleic acid of an infective agent at the site of disease, in association with a specific local immune response suggests the pathogenetic importance of the agent. Recent studies of relationships between epitopes of infective agents and MHC gene products suggest several ways in which infective agents can directly cause a disease such as rheumatoid arthritis without any requirement for autoimmune contributions. Because the infective agent may be the primary determining factor and the one most amenable to correction or eradication, the term "infective-immune" is suggested in preference to "autoimmune" for these immune-mediated diseases.
Women of childbearing age are a logical target for a vaccine aimed at prevention of congenital cytomegalovirus (CMV) infections. However, the impact of a CMV vaccine could likely be enhanced by considering the sources of maternal infection and characteristics of mothers of infected newborns. Contact with preschool-age children and sexual activity are important sources of CMV infection for young women. Approximately half of infants with congenital CMV infection in the U.S. are born to unmarried, adolescent mothers. To prevent CMV infection in those who are the sources of maternal infection as well as in young, unmarried mothers, universal immunization of toddlers and preteen children should be considered.
The emergence of severe group A streptococcal (GAS) infection since the 1980s has now been reported from most parts of the world. Many of these cases have been associated with deep-seated infection associated with shock and multiple-organ failure and are defined as streptococcal toxic shock syndrome (StrepTSS). Strains of GAS isolated from patients with invasive disease have been predominantly of M types 1 and 3, which produce either pyrogenic exotoxin A or B or both. In this article, the clinical and demographic features of streptococcal bacteremia, myositis, and necrotizing fasciitis are presented and compared with those of StrepTSS. Current concepts about the pathogenesis of invasive streptococcal infection are also discussed, in terms of the interaction between GAS virulence factors and host-defense mechanisms. Finally, the efficacy of clindamycin, the failure of penicillin, and new ideas for future treatment of serious streptococcal infections are outlined.
Whooping cough, an infectious disease caused by the gram-negative bacterium Bordetella pertussis, is a life-threatening disease that cannot be controlled by antibiotic treatment or other procedures of modern medicine. Immunization, using a vaccine made of heat-killed bacteria, has been the only way to prevent the disease and keep the infection under control. However, the high reactogenicity of the whole-cell vaccine available so far has made vaccination very controversial, and vaccine use has been restricted to the minimum doses strictly necessary to protect infants during the first few years of life, when the disease is most dangerous. This policy left unsolved the problem of controlling the circulation of the pathogens that are still spreading undisturbed in the population, even after decades of vaccine use. Today, the introduction of acellular vaccines that are efficacious and virtually free of side effects suggests that the new vaccines can be used safely to immunize not only infants, toddlers, and preschool children, but also adolescents and adults, making possible the complete control of the disease and infection, so that policies addressing the eradication of the disease become feasible. The absence of constraints for the use of pertussis vaccine will allow the rational design of the optimal combinations of vaccines for each age.
The progression of human immunodeficiency virus (HIV) infection toward its more advanced stages is accompanied by increasing body iron stores. Iron accumulates in macrophages, microglia, endothelial cells, and myocytes. The iron burden is especially heavy in bone marrow, brain white matter, muscle, and liver. Excess iron potentially enhances oxidative stress, impairs several already compromised immune defense mechanisms, and directly promotes the growth of microbial cells. Thus, we hypothesize that the prevention (or at least, reduction) of iron loading might slow the progression of the infectious complications of HIV infection, and perhaps indirectly, the HIV infection itself. A twofold strategy is proposed, consisting of (a) limitation of iron intake through the alimentary, parenteral, and respiratory routes, and (b) possibly the use of iron chelator drugs that could decrease the iron burden, redistribute the metal to the erythroblasts, and suppress the growth of microorganisms. This approach is still to be considered as hypothetical. However, the available data suggest that there is an urgent need for careful clinical studies to clarify the role of iron status on the course of HIV infection.
Epidemiological surveillance programs have shown that before the introduction of effective vaccines, Haemophilus influenzae type b (Hib) was the primary pathogen associated with bacterial meningitis in children. Vaccines composed of the bacterium's polysaccharide conjugated onto protein carriers began to be introduced into routine health care practices for infants as early as 1989 in some European countries. Continued introduction in industrialized nations, including the United States in late 1990, has resulted in the rapid decline in the incidence of reported invasive Hib disease. Follow-up surveillance studies show that (a) the decline in the incidence of Hib disease is temporally related to the introduction of effective vaccines, (b) the decline in Hib epiglottitis preceded the decline in meningitis in the United States, (c) the incidence of disease declined in children under the age of 5 years but remained constant in older children and adults, (d) other bacterial pathogens are now the primary causative agents of infant meningitis and epiglottitis even though the incidence of disease caused by these other pathogens has not changed, and (e) the pharyngeal carriage rate of Hib in children has declined without any evidence of an increase in the carriage of non-type b strains or other pathogens. The introduction of effective conjugate vaccines appears to protect at-risk children from invasive Hib disease as well as reduce the opportunities for interpersonal transmission of this bacterium. In addition, Hib conjugate vaccine utilization has benefited society through economic savings.
Direct injection of plasmid DNA in vivo was recently shown to induce both prolonged expression of encoded proteins and strong specific immune responses with particular features. Induction of specific antibodies, of CD8+ T lymphocytes, and of CD4+ T lymphocytes differentiated toward the TH1-like phenotype have been achieved in animal models of diseases for which either no vaccines currently exist, or for which vaccine optimization is yet needed. These promising initial results, along with the specific biological characteristics of DNA vaccines that render them particularly interesting in terms of vaccine production, open new perspectives in terms of immunization at a global level. The potential capacities of DNA vaccines to meet the challenge of inducing protection against specific target diseases or for population target groups currently identified as health priorities are reviewed here together with their possible drawbacks.
