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Adv Parasitol

Natural history and biology of Cryptosporidium parvum.

Year 1998
Tzipori S. Griffiths JK.
Division of Infectious Diseases, Tufts University School of Veterinary Medicine, North Grafton, MA 01536, USA.
The taxonomy of the genus Cryptosporidium remains ambiguous, because the current criteria for speciation are insufficient to validate the 6-8 named species. Cross-transmission experiments have shown varying and conflicting results, and the limited genetic data available do not necessarily support currently proposed species designations. The reasons for this ambiguity lie with the ubiquitous nature of Cryptosporidium, probably infecting all vertebrates and variety of tissues therein, and the absence of reference strains with defined virulence attributes that can be linked to genetic markers for comparative analysis. The inability to classify oocysts or confidently to identify their origin, implicate oocysts from all sources as hazardous to humans. Another major issue is the unusual degree of resistance that Cryptosporidium has shown to antiprotozoan and antimicrobial agents. The intracellular but extracytoplasmic domain the parasite occupies is in itself a significant barrier to drug entry. In support of this we outline how the intracellular niche of this parasite differs from the related Apicomplexans, Plasmodium and Toxoplasma, and delineate why the feeder organelle membrane, rather than, or in addition to, the parasitophorous membrane, is the major portal of nutrient entry for Cryptosporidium. The broad conclusion is that anticryptosporidial agents will have to enter the parasite via the multiple apical membranes that camouflage the parasite, or via the host cell, possibly transported by vesicles to the feeder organelle membrane. This may have major implications for rational drug discovery and design.

Human cryptosporidiosis: epidemiology, transmission, clinical disease, treatment, and diagnosis.

Year 1998
Griffiths JK.
Department of Family Medicine and Community Health, Tufts University School of Medicine, Boston, MA 02111, USA.
Cryptosporidiosis is now recognized as one of the most common human enteric infections. In this critical review, relatively unexplored details of transmission, the interaction with malnutrition and the development of chronic diarrhea, and the need for effective treatment are highlighted. Our inability to detect small numbers of foodborne oocysts limits our understanding of this transmission route, and the possibility of respiratory transmission is yet to be rigorously studied. The toll this disease imposes on children, especially the malnourished, has not been fully appreciated. Indeed, the dynamics of the progression from acute cryptosporidiosis to chronic diarrhea and death of malnourished children is still enigmatic. Our knowledge of the intestinal pathophysiology, while limited, is increasing. The lack of effective drug therapy is both remarkable and sobering. Overall, these unknown areas demonstrate how little we truly know about this parasite.

Innate and cell-mediated immune responses to Cryptosporidium parvum.

Year 1998
Theodos CM.
Division of Infectious Diseases, Tufts University School of Veterinary Medicine, North Grafton, MA 01536, USA.
Cryptosporidium parvum has gained much attention as a major cause of diarrhea in the world. Knowledge of the host immune mechanisms responsible for the clearance of this parasite from the gastrointestinal tract may prove to be vital for successful therapeutic treatment of cryptosporidiosis, particularly in the immunodeficient host. This chapter focuses on the innate and cell-mediated immune mechanisms associated with resistance to and resolution of a C. parvum infection. Much of the work in these areas is still in its infancy. Despite this, general consensus supports a role for interferon-gamma (IFN gamma) in mediating the initial resistance to C. parvum, although the mechanism by which this cytokine imparts resistance is unclear. It is also generally agreed that CD4+ T lymphocytes are required for the resolution of both acute and chronic cryptosporidiosis. However, the effector mechanism is again unclear. Several studies suggest that IFN gamma may also be involved in the resolution of cryptosporidiosis. However, the extent to which this cytokine is involved in the actual resolution of infection has been debated. Less extensive studies investigating the participation of other cells and cytokines in the innate and cell-mediated immune responses to C. parvum are also discussed.

Antibody-based immunotherapy of cryptosporidiosis.

Year 1998
Crabb JH.
ImmuCell Corporation, Portland, ME 04103, USA.
Passive antibody immunotherapy (PAI) for cryptosporidiosis is a treatment strategy that has been actively pursued in laboratory studies and early-stage clinical studies for the last decade. Several experimental approaches have been initiated, including use of bovine colostrum and colostral antibodies (hyperimmune and natural), monoclonal antibodies, chicken egg yolk antibodies, and even orally administered human plasma antibodies. Most studies have employed oral administration to treat or prevent this intestinal infection. The interest in this treatment strategy has been sparked by the lack of an effective or approved therapy, increased awareness of the widespread nature of this parasite, epidemiological evidence that humoral immunity plays an important role in host resistance, and several early case reports of antibody therapy in which remarkable resolution of the disease was observed. Most studies using a variety of preparations of antibodies administered to animals and humans have shown some degree of efficacy, though the responses have been, for the most part, partial rather than complete resolution of the disease. This chapter examines critically the scientific rationale and the evidence for PAI for cryptosporidiosis, including practical considerations and future approaches.

Cryptosporidiosis: laboratory investigations and chemotherapy.

Year 1998
Tzipori S.
Division of Infectious Diseases, Tufts University School of Veterinary Medicine, North Grafton, MA 01536, USA.
Much progress has been achieved in the last decade in terms of development of laboratory techniques, reagents and in vivo models. They have undoubtedly contributed to better and more accurate investigations. Despite a concerted effort by many investigators, however, breakthroughs have been minimal. The development of adequate in vitro and in vivo techniques for drug screening, and the intensified and systematic screening, has so far not resulted in the discovery of an effective therapy. The reason for the failure may well be due to the unique biological niche the parasite occupies (discussed at length in the first chapter in this volume). Its location beneath the cell membrane, but outside the cell cytoplasm, may prove a crucial element that needs to be considered when designing new therapeutic approaches. Laboratory investigations on two drugs currently used against chronic Cryptosporidium parvum in acquired immune deficiency syndrome (AIDS) are discussed. This chapter also provides information and the rationale for work in progress in our laboratory that relates to the development of novel approaches for control of the disease. This includes the identification of molecular targets of parasite origin for drug design, and studies on the structure-activity relationships of partially effective drugs with a view to synthesize more effective derivatives. Other investigations attempt to establish the role of secretory antibody, and the merit of repeated mucosal immunizations as a means of providing protection to individuals with AIDS who are at risk of developing chronic C. parvum infection.

Genetic heterogeneity and PCR detection of Cryptosporidium parvum.

Year 1998
Widmer G.
Tufts University School of Veterinary Medicine, North Grafton, MA 01536, USA.
A variety of methods have been applied to the study of genotypic and phenotypic polymorphism in Cryptosporidium parvum. Results from these studies have consistently shown the existence of different genotypes and phenotypes within the species. A long-term goal of this work is the identification of markers for virulence in humans and animals and the elucidation of transmission cycles of C. parvum. Achievement of these goals will depend on the identification of highly polymorphic loci. Of particular interest are polymorphisms amenable to typing by polymerase chain reaction (PCR), as C. parvum cannot be expanded in vitro. Fingerprinting of isolates by restriction of PCR fragments or allele-specific PCR has given promising results. As originally observed by isoenzyme analysis, genetic fingerprinting has confirmed the occurrence in humans of unique C. parvum genotypes which are not found among calf isolates. This observation remains to be reconciled with the cross-infectivity of C. parvum to ruminant and nonruminant hosts and the important role that bovines play in the epidemiology of C. parvum and human cryptosporidiosis. Although PCR detection of C. parvum DNA from individual oocysts has been reported, the sensitivity of PCR detection when working with environmental or fecal samples is significantly reduced. Therefore, PCR is currently not used for routine diagnosis or environmental monitoring for C. parvum. Inhibitors present in environmental samples, mainly in water and soil, which can negatively affect PCR recoveries, have been identified, and several methods have been proposed to circumvent these problems. The further refinement of detection and genetic fingerprinting protocols will provide essential tools for indentifying environmental sources of oocysts and elucidating transmission cycles.

Water-borne cryptosporidiosis: detection methods and treatment options.

Year 1998
Fricker CR. Crabb JH.
Thames Water Utilities, Reading, UK.
Since the infamous outbreak in Milwaukee, WI, USA, of water-borne cryptosporidiosis affecting over 400,000 people, there have been at least 20 smaller outbreaks associated with this parasite in the UK and North America. These events have led to an explosion of interest in and research on the nature of cryptosporidiosis as a dangerous water-borne pathogen, particularly patients with acquired immune deficiency syndrome (AIDS). In addition, several major environmental laws and proposed regulations specifically address the control of this parasite. The possible ramifications of these laws include billions of dollars of modifications to water-treatment facilities in the USA. Unfortunately, the methods used to gather the information on which these laws are based have serious deficiencies that could lead to gross underestimation of the magnitude of this problem. The present review considers gaps in our understanding of water-borne cryptosporidiosis, new methods under investigation that could improve our ability to monitor water for the presence of this organism, and treatment and control strategies to limit the threat to our water supplies.

Clinical syndromes associated with microsporidiosis.

Year 1998
Kotler DP. Orenstein JM.
Department of Medicine, St Luke's-Roosevelt Hospital Center, College of Physicians and Surgeons, New York, NY 10032, USA.
Microsporidia are ubiquitous in nature. Several clinical syndromes have been associated with microsporidiosis, especially in HIV-infected individuals, and include enteropathy, keratoconjunctivitis, sinusitis, tracheobronchitis, encephalitis, interstitial nephritis, hepatitis, cholecystitis, osteomyelitis, and myositis. Diarrhea and malabsorption are the most common clinical problems. Enterocytozoon bieneusi is the most common microsporidial cause of intestinal disease. A second species, Encephalitozoon intestinalis (originally named Septata intestinalis) is associated with disseminated as well as intestinal disease. Microsporidiosis has been seen worldwide, and is recognized as a frequent enteric infection in patients with AIDS. The pathogenesis of intestinal disease is related to excess death of enterocytes as a result of cellular infection. Clinically, microsporidiosis most often presents with diarrhea and weight loss as a result of small intestinal injury and malabsorption. However, microsporidia have been detected in virtually all organs, and may provoke symptoms related to their specific localization. The diagnosis of microsporidiosis is made histologically, either from tissue biopsies or secretions. While transmission electron microscopy was required for diagnosis in the past, special stains and light microscopy, as well as immunohistochemical and molecular techniques are capable of providing a firm diagnosis. Therapeutic options are limited. Enc. intestinalis responds well to albendazole, while no antiparasitic therapy has documented efficacy in Ent. bieneusi infections.

Cyclospora cayetanensis.

Year 1998
Ortega YR. Sterling CR. Gilman RH.
Department of Veterinary Science and Microbiology, University of Arizona, Tucson, AZ 85721, USA.
Cyclospora cayetanensis is a coccidian pathogen in humans. Cyclosporiasis is characterized by mild to severe nausea, anorexia, abdominal cramping, and watery diarrhea. Cyclospora has now been described from patients with protracted diarrheal illness in North, Central and South America, the Caribbean, Africa, Bangladesh, south-east Asia, Australia, England, and eastern Europe, and is characterized by marked seasonality. Routes of transmission are still unknown, although the fecal-oral route, either directly or via water, is probably the major one. A recent outbreak in the USA suggested transmission of Cyclospora by ingestion of contaminated berries. Cyclospora oocysts can be detected by phase contrast microscopy, modified acid-fast staining, autofluorescence, and amplification by the polymerase chain reaction. Oocysts are not sporulated when excreted in the feces, and sporulated oocysts are needed for infection. Each sporulated oocyst contains two sporocysts and each sporocyst contains two sporozoites. Humans seem to be the only host for this parasite. Histopathological examination of jejunal biopsies from infected individuals showed mild to moderate acute inflammation of the lamina propria and surface epithelial disarray. Parasitophorous vacuoles containing sexual and asexual forms of Cycl. cayetanensis were located in the cytoplasm of epithelial cells. Cyclospora infections can be treated successfully with trimethoprim-sulfamethoxazole.

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