Biomedical subjects

Cynthia L Chappell

Publications and source records attributed to Cynthia L Chappell.

8 recordsLinked to original sources

PubMed2003

Substance P expression correlates with severity of diarrhea in cryptosporidiosis.

Cryptosporidiosis, caused by Cryptosporidium parvum, is self-limited in immunocompetent hosts but may cause chronic diarrhea in patients with acquired immunodeficiency syndrome (AIDS). Substance P (SP), a neuropeptide belonging to the tachykinin family, is expressed in gastrointestinal tract and can cause electrogenic chloride anion secretion. Therefore, we studied SP mRNA and protein expression in jejunal tissue samples of patients with AIDS with naturally occurring chronic cryptosporidiosis and healthy volunteers with mild cryptosporidiosis or asymptomatic infection after experimental C. parvum challenge. SP mRNA was associated with symptoms in cryptosporidiosis. SP protein levels were greater in symptomatic than asymptomatic volunteers. Similarly, greater expression of SP mRNA and protein were noted in patients with AIDS with chronic cryptosporidiosis versus immunocompetent volunteers with self-limited infection. This study demonstrates a direct correlation between SP levels and disease severity and may imply that SP plays a role in diarrhea mediation.

AIDS-Related Opportunistic Infections↗

PubMed2003

Interleukin-8, tumor necrosis factor-alpha, and lactoferrin in immunocompetent hosts with experimental and Brazilian children with acquired cryptosporidiosis.

To examine the importance of intestinal inflammation in the diagnosis and pathogenesis of human cryptosporidiosis, stools of healthy adult volunteers before and after experimental infection were tested for fecal lactoferrin, interleukin-8 (IL-8), and tumor necrosis factor-alpha (TNF-alpha). Stool samples of Brazilian children with well-defined Cryptosporidium infection, with or without diarrhea, were also tested for IL-8 and TNF-alpha. Only one of the 14 volunteers challenged with Cryptosporidium had increased fecal lactoferrin. However, of 17 stool specimens from children with only Cryptosporidium infection from a previous study, 12 had mild to moderately elevated lactoferrin despite negative work-up for inflammatory enteritides. One of 10 adult volunteers who developed diarrhea with experimental cryptosporidiosis and three of 11 children with cryptosporidiosis and diarrhea had detectable fecal IL-8. The level of TNF-alpha was increased only in one of 14 volunteers and in none of the children. Although considered relatively non-inflammatory. cryptosporidiosis is often associated with mild inflammation, especially in children in an endemic area.

Adult↗

PubMed2002

Infectivity of a Cryptosporidium parvum isolate of cervine origin for healthy adults and interferon-gamma knockout mice.

The infectivity of a Cryptosporidium parvum isolate of cervine origin (type 2, Moredun) propagated in calves was investigated simultaneously in healthy adult human volunteers and in interferon-gamma knockout (GKO) mice. After exposure to 100-3000 oocysts, 16 volunteers recorded, for a duration of 6 weeks, the number and form of stools that they passed and any symptoms that they experienced. Oocyst excretion was assessed by enzyme-linked immunosorbent assay and direct immunofluorescence assay. Eleven subjects (69%) became ill, and 8 subjects (50%) shed oocysts in stool. The median duration of illness was 169 h, and the median number of unformed stools passed was 24. The duration and intensity of symptoms were more severe than were those associated with previously studied isolates. The median infectious dose was estimated to be 300 oocysts for humans and 1 oocyst for the GKO mouse model. The Moredun isolate was more pathogenic than the reference GCH-1 isolate. The GKO mouse model of cryptosporidiosis is useful for discerning isolate-specific differences in pathogenicity.

Adult↗

PubMed2002

Molecular cloning and analysis of the Cryptosporidium parvum aminopeptidase N gene.

Cryptosporidium parvum proteases have been associated with release of infective sporozoites from oocysts, and their specific inhibition blocks parasite excystation in vitro. Additionally, proteases have been implicated in the processing of parasite adhesion molecules found on the surface of sporozoites and merozoites. In this study, we cloned and expressed the C. parvum aminopeptidase N gene by screening a large insert, P1 artificial chromosome library with a probe identified from a Cryptosporidium genome survey-sequencing project. Analysis of the predicted protein encoded by the 2.3 kb gene demonstrated a high degree of homology with prokaryotic and eukaryotic aminopeptidases. The 783 amino acid sequence predicted a M(r) of approximately 89,000. The active site sequence was found to be highly conserved when compared with other Apicomplexan aminopeptidases. Motifs commonly found in aminopeptidases of this class and a unique single Arg-Gly-Asp (RGD) tripeptide motif predictive of cell adhesion were identified. The aminopeptidase N mRNA was expressed in infective sporozoites and during the infection of human HCT-8 enterocytes as revealed by reverse transcription PCR.

Amino Acid Sequence↗

PubMed2002

Cryptosporidium virulence determinants--are we there yet?

Exposure to Cryptosporidium parvum in healthy individuals results in transient infection that may be asymptomatic or can result in self-limited diarrhoea. In contrast, acquired immune deficiency syndrome patients with cryptosporidiosis can experience severe manifestations of disease. Volunteer studies have demonstrated that as few as 10 oocysts can cause infection in otherwise healthy adults and that isolates from geographically diverse regions differ in infectivity and, perhaps, virulence. Variability in isolate pathogenicity and infectivity has also been seen in bovine and murine models, respectively. Furthermore, isolate specific differences in protein composition and in host immunoreactivity have been observed. The molecular basis for differences in pathogenicity is not understood. Determining which factors are responsible for host selectivity and for the initiation, establishment, and perpetuation of infection with Cryptosporidium is key to rational drug design and vaccine development. To date, no specific virulence factors have been unequivocally shown to individually cause direct or indirect damage to host tissues nor have mutant strains been produced that could prove that particular deletions result in less virulent strains. Nevertheless, a number of candidate molecules have been identified by immunological and molecular methods. Here, we review the salient characteristics of some of these putative virulence determinants, including molecules that are involved in adhesion, protein degradation and the modulation of the host responses.

Adult↗

PubMed2002

Cryptosporidiosis.

PURPOSE OF REVIEW: Cryptosporidiosis is a self-limited diarrheal disease that occurs in the community setting but can be chronic and potentially serious in immunocompromised patients. Community outbreaks are often associated with water-borne transmission. Cryptosporidium research has increased dramatically since the human disease was first recognized in 1976. The present review summarizes recent work in three of the several areas of active Cryptosporidium investigation. RECENT FINDINGS: Molecular techniques have revealed that current taxonomic designations need re-evaluation and that humans are host to several Cryptosporidium spp. that were once believed to be limited to the veterinary realm. These findings have important public health implications for water quality standards in the USA and other developed countries. Second, techniques for detecting the parasite in infected individuals (or environmental samples) have progressed from acid-fast staining of fecal smears to the currently used antibody-based systems (enzyme immunoassays and immunofluorescent assays). New molecular methodologies, based on polymerase chain reaction amplification of gene loci, are being developed to improve the sensitivity and specificity for diagnostic and epidemiologic purposes. Third, curative therapy is attained only by an effective immune response or the reconstitution of a failing immune system in the compromised host. However, several drugs are in development, and compounds such as nitazoxanide appear to hold some promise. SUMMARY: Cryptosporidiosis continues to be a serious problem in immunocompromised patients and on a worldwide scale in undernourished infants and children. The lack of an effective treatment, and the propensity of the parasite to survive in and be transmitted through source waters make this an important public health threat.

Animals↗

PubMed2002

Cryptosporidium dose response studies: variation between isolates.

The infectivity of three different isolates of the waterborne protozoan parasite Cryptosporidium parvum has been tested in human feeding studies. These three isolates (Iowa, TAMU, and UCP) have different ID50s, indicating substantial variation in their infectivity for humans. This finding is of great importance for quantitative risk assessment as it provides strong evidence for heterogeneity in infectivity among isolates of the same species.

Animals↗

PubMed2002

Cryptosporidium dose-response studies: variation between hosts.

The issue of variation is highly important in dose-response analysis: variation among genetically related pathogens infecting the same host, but also variation among hosts, in susceptibility to infection by the same pathogen. This latter issue is addressed here for the protozoan parasite Cryptosporidium parvum, the causative agent for many outbreaks of water-borne gastrointestinal illness. In human feeding studies, infectivity has been shown to be low in subjects with high preexisting anti-Cryptosporidium IgG-levels. Here we adapt the hit theory model of microbial infection to incorporate covariables, characterizing the immune status of the susceptible host. The probability of any single oocyst in the inoculum to cause infection appears to depend on preexisting IgG-levels. This does not necessarily imply direct protection by the humoral immune system; high IgG-levels may reflect a recent episode of infection/illness, and be an epi-phenomenon associated with other protective responses. The IgG-dependence of the dose-response relation can be easily applied in quantitative risk analysis. The distribution of anti-Cryptosporidium IgG levels in the general population is accessible by analyzing serum banks, which are maintained in many Western countries. Using such an approach provides first insights into the variation of susceptibility to infection in the general population.

Animals↗