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PubMed2003

Abnormal mucosal extracellular matrix deposition is associated with increased TGF-beta receptor-expressing mesenchymal cells in a mouse model of colitis.

Transforming growth factor-beta (TGF-beta) depresses mucosal inflammation and upregulates extracellular matrix (ECM) deposition. We analyzed TGF-beta receptors RI and RII as well as ECM components using the CD4(+) T-cell-transplanted SCID mouse model of colitis. The principal change in colitis was an increased proportion of TGF-beta RII(+) mucosal mesenchymal cells, predominantly alpha-smooth muscle actin (SMA)(+) myofibroblasts, co-expressing vimentin and basement membrane proteins, but not type I collagen. TGF-beta RII(+) SMA(-) fibroblasts producing type I collagen were also increased, particularly in areas of infiltration and in ulcers. Type IV collagen and laminin were distributed throughout the gut lamina propria in disease but were restricted to the basement membrane in controls. In areas of severe epithelial damage, type IV collagen was lost and increased type I collagen was observed. To examine ECM production by these cells, mucosal mesenchymal cells were isolated. Cultured cells exhibited a similar phenotype and matrix profile to those of in vivo cells. The data suggested that there were at least two populations of mesenchymal cells responsible for ECM synthesis in the mucosa and that ligation of TGF-beta receptors on these cells resulted in the disordered and increased ECM production observed in colitic mucosa.

Activin Receptors, Type I↗

PubMed2005

Assessment of human islet viability using various mouse models.

To date no in vitro viability test is known to accurately predict in vivo human islet function, making transplantation into various nonimmune animal models mandatory. The diabetic mouse model has been proposed as a standard method for human islet viability assessment. However, the use of streptozotocin for diabetes induction is associated with inconsistency with respect to induction protocols and the significant mortality rate. The purpose of this study was to compare a nondiabetic NOD-scid mouse model to its diabetic counterpart in terms of predicting islet viability. Diabetes was induced in NOD-scid mice using intraperitoneal injection of streptozotocin at concentrations ranging from 100 to 200 mg/kg. Blood glucose levels were monitored for 7 to 10 days, and mice that had levels of >300 mg/dL were used in the experiment. For nondiabetic mice, blood glucose and baseline human C-peptide levels were checked after an overnight fast. Transplantation of 2000 human islet equivalent was done in both models using the same technique. Islet function was determined in the diabetic mice by return to normoglycemia for 2 consecutive days and measurement of fasting human C-peptide on days 7 and 14 posttransplant. Viability was tested in nondiabetic mice after intraperitoneal injection of glucose (2 g/kg) and the measurement of human C-peptide levels using radioimmunoassay. Titration of the streptozotocin dose from 200 to 100 mg/kg showed a significant reduction in mice mortality (40% to 10%) and an increase of diabetes induction (55% to 81%). The 23 human islet isolations tested in both models showed complete consistency of the viability results.

Animals↗

PubMed1998

Salivary gland changes in the NOD mouse model for Sjögren's syndrome: is there a non-immune genetic trigger?

Sjögren's syndrome is a systemic autoimmune disease characterized by patient complaints of oral and ocular dryness accompanied by clinical observations of a progressive loss of salivary and lacrimal function, related to the presence of a focal, periductal leukocyte infiltrate. Progress in understanding the mechanisms involved in the development of autoimmune diseases in general, and Sjögren's syndrome specifically, has been generated as a result of renewed interest in animal models, such as the NOD mouse, which mimics autoimmune sialoadenitis. Biochemical analyses have indicated that the salivary glands have reduced beta-adrenergic, muscarinic, and neuropeptide signal transduction responses that correlate to reduced receptor density and the appearance of autoantibodies directed against these and other cell surface proteins. Using the NOD-scid mouse (lacking functional B- and T-lymphocytes) it has been determined that salivary flow rates are normal; however, these animals show abnormal changes in protein biosynthesis with increasing age. Histological evaluation of the submandibular gland from older NOD-scid mice revealed a loss of acinar cells accompanied by a potential increase in the ductal cell component of the tissue. Consistent with this finding, we recently have observed increased levels of cell death-associated cysteine proteases in the submandibular glands of 20 week NOD and NOD-scid mice but not in BALB/c and young NOD controls. Other novel protease activity was detected in the parotid and submandibular glands from NOD mice, which were able to generate the aberrantly processed PSP from purified BALB/c protein. Taken together, these data paint a complex picture of the development of Sjögren's syndrome-like disease in the NOD mouse model. The presence of activated lymphocytes appears to be necessary for the ultimate loss of exocrine gland function, potentially through the loss of tolerance to glandular proteins. However, the findings of high levels of apoptosis and aberrant protein expression in the submandibular gland in the absence of an immune response (NOD-scid) suggests that genetic alterations in glandular homeostasis involving the death program contribute to disease progression or even the initial trigger of autoimmunity.

Animals↗

PubMed2005

Virulent variants emerging in mice infected with the apathogenic prototype strain of the parvovirus minute virus of mice exhibit a capsid with low avidity for a primary receptor.

The mechanisms involved in the emergence of virulent mammalian viruses were investigated in the adult immunodeficient SCID mouse infected by the attenuated prototype strain of the parvovirus Minute Virus of Mice (MVMp). Cloned MVMp intravenously inoculated in mice consistently evolved during weeks of subclinical infection to variants showing altered plaque phenotypes. All the isolated large-plaque variants spread systemically from the oronasal cavity and replicated in major organs (brain, kidney, liver), in sharp contrast to the absolute inability of the MVMp and small-plaque variants to productively invade SCID organs by this natural route of infection. The virulent variants retained the MVMp capacity to infect mouse fibroblasts, consistent with the lack of genetic changes across the 220-to-335 amino acid sequence of VP2, a capsid domain containing main determinants of MVM tropism. However, the capsid of the virulent variants shared a lower affinity than the wild type for a primary receptor used in the cytotoxic infection. The capsid gene of a virulent variant engineered in the MVMp background endowed the recombinant virus with a large-plaque phenotype, lower affinity for the receptor, and productive invasiveness by the oronasal route in SCID mice, eventually leading to 100% mortality. In the analysis of virulence in mice, both MVMp and the recombinant virus similarly gained the bloodstream 1 to 2 days postoronasal inoculation and remained infectious when adsorbed to blood cells in vitro. However, the wild-type MVMp was cleared from circulation a few days afterwards, in contrast to the viremia of the recombinant virus, which was sustained for life. Significantly, attachment to an abundant receptor of primary mouse kidney epithelial cells by both viruses could be quantitatively competed by wild-type MVMp capsids, indicating that virulence is not due to an extended receptor usage in target tissues. We conclude that the selection of capsid-receptor interactions of low affinity, which favors systemic infection, is a major evolutionary process in the adaptation of parvoviruses to new hosts and in the cause of disease.

Animals↗

PubMed2002

Characterization of the murine cytomegalovirus 38 kDa m137 gene product.

Murine cytomegalovirus (MCMV) m137 null mutants, Deltam137A and Deltam137B, were generated by inserting a gpt cassette into a deleted region of the open reading frame. A polyclonal antiserum produced to an Escherichia coli expressed gst-m137 fusion protein was used to show that a 38 kDa polypeptide corresponding to the predicted m137 gene product was present in NIH 3T3 fibroblasts infected with wild-type MCMV but was not detected in Deltam137 infected cells. The protein did not fractionate with infected cell membranes and was not detectable in purified wild-type virions. Plaque size, plaque morphology, and viral yield did not differ significantly between Deltam137 and wild-type MCMV infected 3T3 fibroblasts. The results showed that deletion of the 38 kDa protein did not negatively effect viral growth in 3T3 fibroblasts indicating that the m137 gene product is not essential for replication in these cells. In vivo analysis revealed that two independently isolated m137 mutants showed a significant delay in time until death but ultimately killed 100% of the mice in a SCID mouse model of virulence.

3T3 Cells↗

PubMed2001

CD8+ T cells induce medullary thymic epithelium and CD4+CD8+CD25+ TCRbeta- thymocytes in SCID mice.

During T-cell development the transition in the thymus of CD4-CD8- double negative (DN) progenitor T cells into CD4+CD8+ double positive (DP) cells is dependent on the expression of a T-cell receptor (TCR)-beta-chain protein. In this study purified peripheral CD4+ and CD8+ T lymphocytes from the C.B-17 strain of mice were adoptively transferred into syngeneic, neonatal SCID mice, where donor cells resided at constant numbers in thymus from 2 weeks until 10 weeks post cell transfer. In the recipient thymus the CD8+ donor cells outnumbered the CD4+ cells by a factor of three to five and both subsets contained a large fraction of activated cells. During the late phase of treatment, CD8+ T cells induced high numbers of DP thymocytes in the SCID mice, a process accompanied by the maturation of medullary epithelial cells. Such thymic development in the SCID mouse was inhibited by coresiding CD4+ donor T cells. These results indicate a regulatory role by mature peripheral T cells on medullary epithelial growth and thymocyte development in the treated SCID mice.

Adoptive Transfer↗

PubMed1996

Circulating immunoglobulin G can play a critical role in clearance of intestinal reovirus infection.

Reoviruses are encapsidated double-stranded RNA viruses that cause systemic disease in mice after peroral (p.o.) inoculation and primary replication in the intestine. In this study, we define components of the immune system involved in the clearing of reovirus from the proximal small intestine. The intestines of immunocompetent adult CB17, 129, and C57BL/6 mice were cleared of reovirus serotype 3 clone 9 (T3C9) within 7 days of p.o. inoculation. Antigen-specific lymphocytes were important for the clearance of intestinal infection, since severe combined immunodeficient (SCID) mice failed to clear T3C9 infection. To define specific immune components required for intestinal clearance, reovirus infection of mice with null mutations in the immunoglobulin M (IgM) transmembrane exon (MuMT; B cell and antibody deficient) or beta 2 microglobulin gene (beta 2-/-; CD8 deficient) was evaluated. beta 2-/- mice cleared reovirus infection with normal kinetics, while MuMT mice showed delayed clearance of T3C9 7 to 11 days after p.o. inoculation. Adoptive transfer of splenic lymphocytes from reovirus-immune CB17 mice inhibited growth of T3C9 in CB17 SCID mouse intestine 11 days after p.o. inoculation. The efficiency of viral clearance by adoptively transferred cells was significantly diminished by depletion of B cells prior to adoptive transfer. Results in SCID and MuMT mice demonstrate an important role for B cells or IgG in clearance of reovirus from the intestines. Polyclonal reovirus-immune rabbit serum, protein A-purified immune IgG, and murine monoclonal IgG2a antibody specific for reovirus outer capsid protein sigma 3 administered intraperitoneally all normalized clearance of reovirus from intestinal tissue in MuMT mice. This result demonstrates an IgA-independent role for IgG in the clearance of intestinal virus infection. Polyclonal reovirus-immune serum also significantly decreased reovirus titers in the intestines of SCID mice, demonstrating a T-cell-independent role for antibody in the clearance of intestinal reovirus infection. B cells and circulating IgG play an important role in the clearance of reovirus from intestines, suggesting that IgG may play a more prominent functional role at mucosal sites of primary viral replication than was previously supposed.

Animals↗

PubMed1984

Functional status of cells from lymphoid and myeloid tissues in mice with severe combined immunodeficiency disease.

Cells from mice with severe combined immunodeficiency disease (SCID) were tested in assays that measure myeloid and lymphoid function. Results showed that C.B-17 scid and their normal counterparts (C.B-17) have similar levels of spleen colony-forming units. The frequency of in vitro myeloid colony-forming units in C.B-17 scid spleen is elevated, but the absolute number of colony-forming units in C.B-17 scid and C.B-17 spleen is similar. The absolute number of bone marrow colony-forming units in C.B-17 scid and C.B-17 mice is comparable. Cells from C.B-17 scid spleen are consistently negative in all tests of B and T cell function. C.B-17 scid splenocytes fail to proliferate in response to T and B cell mitogens or to allogeneic lymphocytes in a one-way MLR; C.B-17 scid cells do serve as stimulators in MLR. B lymphocyte colony-forming units are absent, as are cytotoxic lymphocyte precursors and cells that can generate T cell colonies with cytotoxic progenitors. The microenvironment of the C.B-17 scid mouse is conducive to lymphocyte differentiation, because functional B and T cells are easily detectable in mice reconstituted with normal bone marrow cells. The results of this study indicate that scid specifically impairs the differentiation of stem cells into mature lymphocytes; myeloid cell differentiation is not affected.

Animals↗

PubMed2005

The SCID-hu myeloma model.

The severe combined immune deficient human (SCID-hu) myeloma model is the only available model in which primary myeloma cells grow in vivo in a human bone marrow micro environment. A SCID mouse receives an implanted human fetal bone into which myeloma cells are directly injected. Through interaction with the human bone marrow microenvironment, the myeloma cells induce typical myeloma manifestations in the SCID host, such as the appearance of M protein in the serum, and changes in the implanted human bone, which often result in osteolysis of the human bone. The model provides the only platform for in vivo investigation of the biology and therapy of primary human myeloma in a human microenvironment. This chapter describes in detail all the steps necessary to establish this model and evaluate its success.

Animals↗

PubMedDate not supplied

Improved engraftment of human tumours in SCID mice pretreated with radiation and anti-asialo GM1.

The effects of sublethal radiation (3 Gy) and anti-asialo GM1 (anti-ASGM1) on engraftment of human tumour cell lines and fresh tumour were evaluated in the severe combined immunodeficient (SCID) mouse. Four tumour cell lines (colonic adenocarcinoma LS174T, malignant melanoma MEWO, lung adenocarcinoma H125, chronic myelogenous leukemia K562) and a fresh colon cancer metastasis were injected subcutaneously, intraperitoneally or intravenously into SCID mice. Tumour volume and metastatic spread of implanted tumours were evaluated 3-8 weeks following inoculation. Pretreatment with radiation and anti-ASGM1 resulted in more rapid and extensive uptake of subcutaneous and intraperitoneal tumours. Tail vein injection into pretreated animals also resulted in a greater number of lung metastases of H125, MEWO and K562 cell lines. This study demonstrates that sublethal radiation and the elimination of murine NK cell activity with anti-ASGM1 improves tumour take rates. These findings should prove useful for investigations of human cancer immunotherapy using SCID mice engrafted with human lymphocytes and human tumours.

Animals↗

PubMed1994

Cryptosporidium muris in adult mice: adoptive transfer of immunity and protective roles of CD4 versus CD8 cells.

The aim of this study was to investigate the role of the CD4 and CD8 T cells in immunity to cryptosporidia by using Cryptosporidium muris and a mouse model of infection. Two approaches were used, each involving the use of rat anti-T-cell surface marker monoclonal antibodies (MAbs). In the first, the adoptive transfer of immunity was studied by using the CB.17 SCID mouse (which lacks T and B cells) as the host; in the second, the effect on susceptibility of BALB/c mice to infection was examined following depletion of T cells or subsets of T cells. In adoptive immunity experiments, the conditions which differentiated between resistance associated with reconstitution of SCID mice with naive BALB/c lymphocytes and the transfer of immunity with primed lymphocytes from infected animals were determined. Primed spleen or mesenteric lymph node cells conferred better protection to recipients than naive cells when obtained from donors which had developed resistance to infection. Adoptive immunity was abrogated when Thy.1 cells or CD4 cells were depleted from primed cells, while depletion of CD8 cells could reduce the level of protection. In the study of C. muris in BALB/c mice, treatment with either anti-Thy.1 plus anti-Lyt.1 or anti-CD4 MAbs increased susceptibility to a primary infection as determined by the size and duration of oocyst production, but an anti-CD8 MAb produced an increase only in oocyst shedding. Thus, both CD4 and, to a lesser extent, CD8 cells appeared to be involved in resistance to primary and secondary C. muris infection.

Animals↗

PubMed1998

Apoptosis induced by X-rays and chemical agents in murine fibroblastic cell lines with a defect in repair of DNA double-strand breaks.

PURPOSE: To investigate apoptosis in murine fibroblasts that are deficient in DNA double-stand breaks (dsb) repair. MATERIALS AND METHODS: BALB/c 3T3 cells and cells from a severe combined immunodeficient (scid) mouse were exposed to X-rays, UV light, bleomycin, etoposide or cisplatin. After exposure, the rate of apoptosis was assayed by propidium iodide staining based on characteristic morphological change. RESULTS: The scid cells, defective in dsb repair, were extremely sensitive to apoptosis induced by X-rays and bleomycin compared with BALB/c 3T3 cells. The scid cells were slightly sensitive to apoptosis induced by etoposide, an agent producing protein-associated dsb, and to apoptosis induced by agents not causing dsb. CONCLUSIONS: These studies show that sensitivity of cells to apoptosis induced by X-rays or bleomycin is enhanced by the scid mutation and that apoptosis induced by etoposide, which causes protein-associated dsb, is not greatly affected. There may be different processes involved in the induction of apoptosis by X-rays or bleomycin and etoposide.

3T3 Cells↗

PubMed1993

High frequency of normal DJH joints in B cell progenitors in severe combined immunodeficiency mice.

The severe combined immunodeficiency (scid) mouse has a defective V(D)J recombinase activity that results in arrested lymphoid development at the pro-B cell stage in the B lineage. The defect is not absolute and scid mice do attempt gene rearrangement. Indeed, approximately 15% of all scid mice develop detectable levels of oligoclonal serum immunoglobulin and T cell activity. To gain more insight into the scid defect and its effect on V(D)J rearrangement, we analyzed DJH recombination in scid bone marrow. We determined that DJH structures are present in scid bone marrow and occur at a frequency only 10-100 times less than C.B-17+/+. The scid DJH repertoire is limited and resembles fetal liver DJH junctions, with few N insertions and predominant usage of reading frame 1. Moreover, 70% of the DJH structures were potentially productive, indicating that normal V(D)J recombinants should be arising continually.

Animals↗

PubMed1999

Transfer of human CD4(+) T lymphocytes producing beta interferon in Hu-PBL-SCID mice controls human immunodeficiency virus infection.

Beta interferon (IFN-beta) exerts pleiotropic antiretroviral activities and affects many different stages of the human immunodeficiency virus (HIV) infectious cycle in IFN-treated cells. To explore whether transfer of genetically engineered human CD4(+) T cells producing constitutively low amounts of IFN-beta can eradicate HIV in vivo, we developed a new Hu-PBL-SCID mouse model supporting a persistent, replicative HIV infection maintained by periodic reinoculations of activated human CD4(+) T cells. Transferring human CD4(+) T cells containing the IFN-beta retroviral vector drastically reduced the preexisting HIV infection and enhanced CD4(+) T-cell survival and Th1 cytokine expression. Furthermore, in 40% of the Hu-PBL-SCID mice engrafted with IFN-beta-transduced CD4(+) T cells, HIV-1 was undetectable in vivo as well as after cocultivation of mouse tissues with human phytohemagglutinin-stimulated lymphoblasts. These results indicate that a therapeutic strategy based upon IFN-beta transduction of CD4(+) T cells may be an approach to controlling a preexisting HIV infection and allowing immune restoration.

Animals↗

PubMed1995

Clearance of Theileria sergenti-infected bovine red blood cells in severe combined immune deficiency mice.

Clearance of Theileria sergenti-infected bovine red blood cells (Bo-RBCs) from the blood circulation of severe combined immune deficiency (SCID) mice was studied to help understand the mechanisms of anemia developing in cattle infected with T. sergenti. For the clearance test, Bo-RBC samples having 2%, 58%, and 76% parasitemia and, as a control, parasite-free Bo-RBCs were prepared in the Bo-RBC-SCID mouse model. The T. sergenti-infected Bo-RBCs and the uninfected control Bo-RBCs were separately labeled with two, green and red, fluorescent dyes, mixed together, and injected intravenously into SCID mice. The blood samples collected at various time points were observed under a fluorescent microscope, and the numbers of green and red fluorescing RBCs were counted differentially to determine the clearance rates of T. sergenti-infected and uninfected Bo-RBCs. This test clearly demonstrated that the Bo-RBC samples having higher parasitemias were cleared faster from the blood circulation of SCID mice. The results suggest that the intravascular clearance system in SCID mice may have a mechanism by which T. sergenti-parasitized and non-parasitized Bo-RBCs are recognized and cleared differentially.

Animals↗

PubMed1992

Growth of MCF-7 human breast carcinoma in severe combined immunodeficient mice: growth suppression by recombinant interleukin-2 treatment and role of lymphokine-activated killer cells.

The severe combined immunodeficient (SCID) mouse, lacking functional T and B lymphocytes, has been considered by many groups to be a prime candidate for the reconstitution of a human immune system in a laboratory animal. In addition, this immuno-deficient animal would appear to have excellent potential as a host for transplanted human cancers, thus providing an exceptional opportunity for the study of interactions between the human immune system and human cancer in a laboratory animal. However, because this animal model is very recent, few studies have been reported documenting the capability of these mice to accept human cancers, and whether or not the residual immune cells in these mice (e.g. natural killer, NK, cells; macrophages) possess antitumor activities toward human cancers. Thus, the purpose of this study was (a) to determine whether or not a human breast carcinoma cell line (MCF-7) can be successfully transplanted to SCID mice, (b) to determine whether or not chronic treatment of SCID mice with a potent lymphokine (recombinant interleukin-2, rIL-2) could alter MCF-7 carcinoma growth, and (c) to assess whether or not rIL-2-activated NK cells (LAK cells) are important modulators of growth of MCF-7 cells in SCID mice. To fulfill these objectives, female SCID mice were implanted s.c. with MCF-7 cells (5 x 10(6) cells/mouse) at 6 weeks of age. Six weeks later, some of the mice were injected i.p. twice weekly with rIL-2 (1 x 10(4) U mouse-1 injection-1). Results clearly show that MCF-7 cells can grow progressively in SCID mice; 100% of the SCID mice implanted with MCF-7 cells developed palpable measurable tumors within 5-6 weeks after tumor cell inoculation. In addition, MCF-7 tumor growth was significantly (P less than 0.01) suppressed by rIL-2 treatment. rIL-2 treatment was non-toxic and no effect of treatment on body weight gains was observed. For non-tumor-bearing SCID mice, splenocytes treated in vitro with rIL-2 (lymphokine-activated killer, LAK, cells) or splenocytes derived from rIL-2-treated SCID mice (LAK cells) had significant (P less than 0.01) cytolytic activity toward MCF-7 carcinoma cells in vitro. In contrast, splenocytes (LAK cells) derived from tumor(MCF-7)-bearing rIL-2-treated SCID mice lacked cytolytic activities toward MCF-7 cells in vitro. No significant concentration of LAK cells in MCF-7 human breast carcinomas ws observed nor did rIL-2 treatment significantly alter growth of MCF-7 cells in vitro.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1999

Effects of IL-12 on human ovarian tumors engrafted into SCID mice.

OBJECTIVE: The effects of murine interleuken (IL)-12 on the growth of surgical specimen-derived malignant human ovarian tumors engrafted in severe combined immunodeficient (SCID) mice were assessed. The SCID mouse model facilitated the evaluation IL-12's effect on the host innate immune response against human ovarian cancer xenografts. METHODS: Equal portions of specimen-derived human ovarian carcinoma were engrafted subcutaneously into SCID mice. After 7 days, mice were placed into one of two treatment groups: (1) placebo/control or (2) murine IL-12 (0.33 mcg/day intraperitoneally x 20 days). Anti-asialo GM1 was administered on day 0 to 3 mice from the IL-12-treated group. Serial tumor volumes were measured. On day 21, mice from each group were sacrificed, and tumors and spleens were evaluated. Data analysis included chi2 tests, Student t tests, and analysis of variance when appropriate. The entire experiment was repeated for a total of three times with similar results. A total of 45 mice and two different human tumor specimens were utilized. Representative data were reported. RESULTS: IL-12 resulted in mean tumor growth delay and regression when compared to controls (P = 0. 02). Among the IL-12 group, 22% (2/9) developed complete remissions. When anti-asialo GM1 was added prior to IL-12, no tumor growth delay was noted. Splenic weights were higher among IL-12-treated mice compared to controls (P < 0.01). Spleen sections demonstrated expanded white pulp among IL-12-treated mice compared to controls. Histologic evaluation of tumor sections revealed central necrosis among tumors from mice treated with IL-12. Immunohistochemical stains identified increased numbers of NK cells in clusters within tumors from mice treated with IL-12 whereas NK cells were found to be sparsely scattered in control tumors. CONCLUSIONS: Murine IL-12 treatment resulted in significant tumor growth delay and tumor regression in SCID mice engrafted with human ovarian cancer. The data support an immunologic basis for the observed anti-tumor effects and suggest a role for NK cells as part of the effector pool. The current data support the clinical evaluation of IL-12 in the treatment of epithelial ovarian cancer.

Adjuvants, Immunologic↗

PubMed2005

The carbon starvation-inducible genes Rv2557 and Rv2558 of Mycobacterium tuberculosis are not required for long-term survival under carbon starvation and for virulence in SCID mice.

Mycobacterium tuberculosis genes Rv2557 and Rv2558 have no known function. However, proteome, transcriptome and in situ hybridization studies have shown that these genes are significantly upregulated under carbon-starved conditions and in human granulomas, suggesting that they may play a role in persistence. Single and double deletion mutants of M. tuberculosis H37Rv in Rv2557 and/or Rv2558 were generated to explore their individual and/or collective role(s) in growth and survival. The mutants were assessed for growth and survival in vitro under normal and nutrient-deprived conditions and for virulence in the SCID mouse model. Although highly induced by carbon starvation, loss of Rv2557 and/or Rv2558 affected neither the long-term survival of M. tuberculosis under carbon-starved conditions in vitro, nor its virulence in SCID mice.

Animals↗