Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0085110 (SCID)
 11,041 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Studies on HIV-1 mucosal transmission to evaluate early events in pathogenesis and the development of effective preventive/prophylactic methods have thus far been hampered by the lack of a suitable animal model susceptible to HIV-1 infection by either vaginal and/or rectal routes. In this regard, while primate-SIV/SHIV and cat-FIV models provided useful surrogate platforms to derive comparative data, these viruses are distinct and different from that of HIV-1. Therefore an optimal model that permits direct study of HIV-1 transmission via mucosal routes is highly desirable. The new generation of humanized NOD/SCID BLT, NOD/SCIDgammac(-/-), and Rag2(-/-)gammac(-/-) mouse models show great promise to achieve this goal. Here, we show that humanized Rag2(-/-)gammac(-/-) mice (RAG-hu) engrafted with CD34 hematopoietic progenitor cells harbor HIV-1-susceptible human cells in the rectal and vaginal mucosa and are susceptible to HIV-1 infection when exposed to cell-free HIV-1 either via vagina or rectum. Infection could be established without any prior hormonal conditioning or mucosal abrasion. Both R5 and X4 tropic viruses were capable of mucosal infection resulting in viremia and associated helper T cell depletion. There was systemic spread of the virus with infected cells detected in different organs including the intestinal mucosa. R5 virus was highly efficient in mucosal transmission by both routes whereas X4 virus was relatively less efficient in causing infection. HIV-1 infection of RAG-hu mice by vaginal and rectal routes as shown here represents the first in vivo model of HIV-1 transmission across intact mucosal barriers and as such may prove very useful for studying early events in HIV-1 pathogenesis in vivo, as well as the testing of microbicides, anti-HIV vaccines/therapeutics, and other novel strategies to prevent HIV-1 transmission.
 ...
PMID:Mucosal transmission of R5 and X4 tropic HIV-1 via vaginal and rectal routes in humanized Rag2-/- gammac -/- (RAG-hu) mice. 1820 84

The economically important effects of Tritrichomonas foetus infection in cattle are abortion and infertility, yet there has not been an animal model to examine the parasite-host interactions during gestation. In this study, 5- and 7- to 8-week-old BALB/cAnNCr, BALB/cJ, and SCID/NCr mice on a BALB/c background were intravaginally infected with T. foetus. All BALB/cAnNCr and BALB/cJ mice, and 89% of SCID/NCr mice sustained infections for 13 weeks, if inoculated before 5 weeks of age. Infection rates were lower in all mouse strains inoculated at 7 weeks of age, although BALB/cAnNCr mice were significantly more susceptible than BALB/cJ or SCID/NCr mice. Vaginal bacterial flora did not account for the variation in mouse-strain susceptibility, although coagulase-negative staphylococci in vaginal flora were associated with failure of T. foetus to infect. As with infected cattle, T. foetus-specific vaginal immunoglobulin (Ig) G and IgA antibodies were elevated after infection. The number and viability of day-10 fetuses were reduced in mice infected at 5 weeks of age and bred 12 weeks after infection. Lesions in pregnant and nonpregnant infected mice, including suppurative and eosinophilic vaginitis; cervicitis; endometritis with distension of the uterine lumen; endometrial ulceration; and glandular ectasia, with neutrophils in the glandular lumen and loss of gland epithelium, were similar to those in cattle. The decidua and placenta were multifocally necrotic. Immunohistochemistry demonstrated trichomonads in vaginal folds and uterine glands, and adjacent to fetal tissues. In summary, experimentally infected BALB/cAnNCr mice showed many pathologic similarities to cattle and may serve as a model to study host-trichomonad interactions.
 ...
PMID:A pregnant mouse model for bovine Tritrichomonas foetus infection. 1898 88

Infection of humans with Ehrlichia chaffeensis, the etiologic agent of human monocytic ehrlichiosis, can cause hepatitis of various levels of severity. When the three human isolates of E. chaffeensis, each belonging to a different genogroup, are inoculated into severe combined immunodeficiency mice, the order of severity of clinical signs and bacterial burden detected in the liver is as follows (from greatest to least severity and highest to lowest burden): strain Wakulla, followed by strain Liberty, followed by strain Arkansas. In this article, we used microarray analysis to define transcriptional profiles characteristic of the histopathological features in the mouse liver. Cytokine and chemokine profiles and their receptor profiles were strikingly different among the three strains of E. chaffeensis: gamma interferon, CCL5, CXCL1, CXCL2, CXCL7, CXCL9, interleukin 2 receptor gamma (IL2Rgamma), IL21R, CCR2, and CXCR6 were highly upregulated with strain Arkansas; and tumor necrosis factor (TNF), CCL2, CCL3, CCL5, CCL6, CCL12, CCL20, CXCL2, CXCL7, CXCL9, CXCL13, TNF receptor superfamily 9 (TNFRSF9), TNFRSF13beta, IL1R2, IL2Rgamma, IL20Rbeta, IL21R, CCR1, CCR2, and CXCR4 were highly upregulated with strain Wakulla. With strain Liberty, only CXCL13 was highly upregulated, and IL13Ralpha2 was downregulated. In livers infected with the Arkansas strain, monocytes/macrophages and NK cells were enriched in the granulomas and an increase in NK cell marker mRNAs was detected. Livers infected with the Wakulla strain displayed infiltration of significantly more neutrophils and an increase in neutrophil marker mRNAs. Genes commonly upregulated in liver tissue infected with the three strains are other host innate immune and inflammatory response genes, including those encoding several acute-phase proteins. Genes downregulated commonly are related to host physiologic functions. The results suggest that marked modulation of host cytokine and chemokine profiles by E. chaffeensis strains underlies the distinct host liver disease.
 ...
PMID:Liver transcriptome profiles associated with strain-specific Ehrlichia chaffeensis-induced hepatitis in SCID mice. 1900 Oct 77

Hepatitis C virus (HCV) is a blood-borne pathogen and a major cause of liver disease worldwide. Gene expression profiling was used to characterize the transcriptional response to HCV H77c infection. Evidence is presented for activation of innate antiviral signaling pathways as well as induction of lipid metabolism genes, which may contribute to oxidative stress. We also found that infection of chimeric SCID/Alb-uPA mice by HCV led to signs of hepatocyte damage and apoptosis, which in patients plays a role in activation of stellate cells, recruitment of macrophages, and the subsequent development of fibrosis. Infection of chimeric mice with HCV H77c also led an inflammatory response characterized by infiltration of monocytes and macrophages. There was increased apoptosis in HCV-infected human hepatocytes in H77c-infected mice but not in mice inoculated with a replication incompetent H77c mutant. Moreover, TUNEL reactivity was restricted to HCV-infected hepatocytes, but an increase in FAS expression was not. To gain insight into the factors contributing specific apoptosis of HCV infected cells, immunohistological and confocal microscopy using antibodies for key apoptotic mediators was done. We found that the ER chaperone BiP/GRP78 was increased in HCV-infected cells as was activated BAX, but the activator of ER stress-mediated apoptosis CHOP was not. We found that overall levels of NF-kappaB and BCL-xL were increased by infection; however, within an infected liver, comparison of infected cells to uninfected cells indicated both NF-kappaB and BCL-xL were decreased in HCV-infected cells. We conclude that HCV contributes to hepatocyte damage and apoptosis by inducing stress and pro-apoptotic BAX while preventing the induction of anti-apoptotic NF-kappaB and BCL-xL, thus sensitizing hepatocytes to apoptosis.
 ...
PMID:HCV induces oxidative and ER stress, and sensitizes infected cells to apoptosis in SCID/Alb-uPA mice. 1924 62

The lack of a mouse model has hampered an understanding of the pathogenesis and immunity of Marburg hemorrhagic fever (MHF), the disease caused by marburgvirus (MARV), and has created a bottleneck in the development of antiviral therapeutics. Primary isolates of the filoviruses, i.e., ebolavirus (EBOV) and MARV, are not lethal to immunocompetent adult mice. Previously, pathological, virologic, and immunologic evaluation of a mouse-adapted EBOV, developed by sequential passages in suckling mice, identified many similarities between this model and EBOV infections in nonhuman primates. We recently demonstrated that serially passaging virus recovered from the liver homogenates of MARV-infected immunodeficient (SCID) mice was highly successful in reducing the time to death in these mice from 50 to 70 days to 7 to 10 days after challenge with the isolate MARV-Ci67, -Musoke, or -Ravn. In this study, we extended our findings to show that further sequential passages of MARV-Ravn in immunocompetent mice caused the MARV to kill BALB/c mice. Serial sampling studies to characterize the pathology of mouse-adapted MARV-Ravn revealed that this model is similar to the guinea pig and nonhuman primate MHF models. Infection of BALB/c mice with mouse-adapted MARV-Ravn caused uncontrolled viremia and high viral titers in the liver, spleen, lymph node, and other organs; profound lymphopenia; destruction of lymphocytes within the spleen and lymph nodes; and marked liver damage and thrombocytopenia. Sequencing the mouse-adapted MARV-Ravn strain revealed differences in 16 predicted amino acids from the progenitor virus, although the exact changes required for adaptation are unclear at this time. This mouse-adapted MARV strain can now be used to develop and evaluate novel vaccines and therapeutics and may also help to provide a better understanding of the virulence factors associated with MARV.
 ...
PMID:Development and characterization of a mouse model for Marburg hemorrhagic fever. 1936 50

Infection with human T-cell leukemia virus type 1 (HTLV-1) leads sometimes to the development of adult T-cell lymphoma/leukemia (ATL), which is invariably fatal and often associated with humoral hypercalcemia of malignancy. The transformation of infected CD4 T cells and the pathogenesis of leukemia have been studied with great limitation in tissue culture and patients. To better understand the pathogenesis and perform preclinical drug studies, animal models of ATL are urgently needed. In mice, inoculation of HTLV-1 cell lines mostly leads to development of localized lymphomas. To develop an ATL animal model with leukemic spread of ATL cells, mouse strains with different well-defined immune deficiencies were inoculated intraperitoneally with different HTLV-1-infected cell lines (ACH.2, C8166, MT-2, MET-1). Inoculation of MET-1 cells into NOD/SCID mice provided the best model system for slowly developing T-cell leukemia with multiple organ involvement. In leukemic mice, an increase in serum calcium levels correlated with expression of receptor activator of nuclear factor kappa-light-chain-enhancer of activated B cells ligand on leukemic cells and secretion of parathyroid hormone-related protein and interleukin-6. In contrast to the other cell lines that did not spread systemically, MET-1 expressed both the adhesion molecules CD11a (LFA-1alpha) and CD49d (VLA-4alpha) and produced or induced expression of matrix metalloproteinases 1, 2, 3, and 9, thus underlining the importance of these molecules in the spread of adult T-cell leukemia cells. The MET-1/NOD/SCID model will be useful for developing interventions against invasion and spread of leukemic cells and subsequent humoral hypercalcemia of malignancy.
 ...
PMID:Expression of tumor invasion factors determines systemic engraftment and induction of humoral hypercalcemia in a mouse model of adult T-cell leukemia. 1942 77

The pe and ppe genes are unique to mycobacteria and are widely speculated to play a role in tuberculosis pathogenesis. However, little is known about how expression of these genes is controlled. Elucidating the regulatory control of genes found exclusively in mycobacteria, such as the pe and ppe gene families, may be key to understanding the success of this pathogen. In this study, we used a transposon mutagenesis approach to elucidate pe and ppe regulation. This resulted in the identification of Rv0485, a previously uncharacterized transcriptional regulator. Microarray and quantitative real-time PCR analysis confirmed that disruption of Rv0485 reduced the expression of the pe13 and ppe18 gene pair (Rv1195 and Rv1196), defined the Rv0485 regulon, and emphasized the lack of global regulation of pe and ppe genes. The in vivo phenotype of the Rv0485 transposon mutant strain (Rv0485::Tn) was investigated in the mouse model, where it was demonstrated that the mutation has minimal effect on bacterial organ burden. Despite this, disruption of Rv0485 allowed mice to survive for significantly longer, with substantially reduced lung pathology in comparison with mice infected with wild-type Mycobacterium tuberculosis. Infection of immune-deficient SCID mice with the Rv0485::Tn strain also resulted in extended survival times, suggesting that Rv0485 plays a role in modulation of innate immune responses. This is further supported by the finding that disruption of Rv0485 resulted in reduced secretion of proinflammatory cytokines by infected murine macrophages. In summary, we have demonstrated that disruption of a previously uncharacterized transcriptional regulator, Rv0485, results in reduced expression of pe13 and ppe18 and attenuation of M. tuberculosis virulence.
 ...
PMID:The transcriptional regulator Rv0485 modulates the expression of a pe and ppe gene pair and is required for Mycobacterium tuberculosis virulence. 1965 61

Infection of mice with the gastrointestinal nematode Trichuris muris represents a valuable tool to investigate and dissect intestinal immune responses. Resistant mouse strains respond to T. muris infection by mounting a T helper type 2 response. Previous results have shown that CD4(+) T cells play a critical role in protective immunity, and that CD4(+) T cells localize to the infected large intestinal mucosa to confer protection. Further, transfer of CD4(+) T cells from immune mice to immunodeficient SCID mice can prevent the development of a chronic infection. In the current study, we characterize the protective CD4(+) T cells, describe their chemokine receptor expression and explore the functional significance of these receptors in recruitment to the large intestinal mucosa post-T. muris infection. We show that the ability to mediate expulsion resides within a subpopulation of CD4(+) T cells marked by down-regulation of CD62L. These cells can be isolated from intestine-draining mesenteric lymph nodes (MLN) from day 14 post-infection, but are rare or absent in MLN before this and in spleen at all times post-infection. Among CD4(+) CD62L(low) MLN cells, the two most abundantly expressed chemokine receptors were CCR6 and CXCR3. We demonstrate for the first time that CD4(+) CD62L(low) T-cell migration to the large intestinal mucosa is dependent on the family of G alpha(i)-coupled receptors, to which chemokine receptors belong. CCR6 and CXCR3 were however dispensable for this process because neutralization of CCR6 and CXCR3 did not prevent CD4(+) CD62L(low) cell migration to the large intestinal mucosa during T. muris infection.
 ...
PMID:CD4+ T-cell localization to the large intestinal mucosa during Trichuris muris infection is mediated by G alpha i-coupled receptors but is CCR6- and CXCR3-independent. 1982 22

The effectiveness of a new first-in-class antibiotic, tigecycline (glycylcycline), was evaluated during the early dissemination (1 week), early immune (3 weeks), or late persistent (4 months) phases of Borrelia burgdorferi infection in C3H mice. Mice were treated with high or low doses of tigecycline, saline (negative-effect controls), or a previously published regimen of ceftriaxone (positive-effect controls). Infection status was assessed at 3 months after treatment by culture, quantitative ospA real-time PCR, and subcutaneous transplantation of joint and heart tissue into SCID mice. Tissues from all saline-treated mice were culture and ospA PCR positive, tissues from all antibiotic-treated mice were culture negative, and some of the tissues from most of the mice treated with antibiotics were ospA PCR positive, although the DNA marker load was markedly decreased compared to that in saline-treated mice. Antibiotic treatment during the early stage of infection appeared to be more effective than treatment that began during later stages of infection. The viability of noncultivable spirochetes in antibiotic-treated mice (demonstrable by PCR) was confirmed by transplantation of tissue allografts from treated mice into SCID mice, with dissemination of spirochetal DNA to multiple recipient tissues, and by xenodiagnosis, including acquisition by ticks, transmission by ticks to SCID mice, and survival through molting into nymphs and then into adults. Furthermore, PCR-positive heart base tissue from antibiotic-treated mice revealed RNA transcription of several B. burgdorferi genes. These results extended previous studies with ceftriaxone, indicating that antibiotic treatment is unable to clear persisting spirochetes, which remain viable and infectious, but are nondividing or slowly dividing.
 ...
PMID:Ineffectiveness of tigecycline against persistent Borrelia burgdorferi. 1999 19

Cryptosporidium parvum is an enteric coccidian parasite that is recognised as a frequent cause of water-borne disease in humans. We report for the first time on use of the in vitro HCT-8 cell culture-quantitative PCR (qPCR) assay and the in vivo SCID-mouse bioassay for evaluating critical factors that reduce or eliminate infectivity of C. parvum after irradiating oocysts in saline solution under varying operational conditions with pulsed UV light. Infections post UV treatments were detected by immunofluorescence (IF) microscopy and by quantitative PCR in cell culture, and by IF staining of faeces and by hematoxylin and eosin staining of intestinal villi in mice. There was a good agreement between using cell culture-qPCR and the mouse assay for determining reduction or elimination of C. parvum infectivity as a consequence of varying UV operating conditions. Reduction in infectivity depended on the intensity of lamp discharge energy applied, amount of pulsing and population size of oocysts (P < or = 0.05). Conventional radiometer was unable to measure fluence or UV dose in saline samples due to the ultra-short non-continuous nature of the high-energy light pulses. Incorporation of humic acid at a concentration above that found in surface water (i.e., < or =10 ppm) did not significantly affect PUV disinfection capability irrespective of parameters tested (P < or = 0.05). These observations show that use of this HCT-8 cell culture assay is equivalent to using the 'gold standard' mouse-based infectivity assay for determining disinfection performances of PUV for treating C. parvum in saline solution.
 ...
PMID:Investigations of the relationship between use of in vitro cell culture-quantitative PCR and a mouse-based bioassay for evaluating critical factors affecting the disinfection performance of pulsed UV light for treating Cryptosporidium parvum oocysts in saline. 2009 10


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>