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‣ A Mouse Model for the Evaluation of Pathogenesis and Immunity to Influenza A (H5N1) Viruses Isolated from Humans

Lu, Xiuhua; Tumpey, Terrence M.; Morken, Timothy; Zaki, Sherif R.; Cox, Nancy J.; Katz, Jacqueline M.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /07/1999 Português
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During 1997 in Hong Kong, 18 human cases of respiratory illness, including 6 fatalities, were caused by highly pathogenic avian influenza A (H5N1) viruses. Since H5 viruses had previously been isolated only from avian species, the outbreak raised questions about the ability of these viruses to cause severe disease and death in humans. To better understand the pathogenesis and immunity to these viruses, we have used the BALB/c mouse model. Four H5N1 viruses replicated equally well in the lungs of mice without prior adaptation but differed in lethality for mice. H5N1 viruses that were highly lethal for mice were detected in multiple organs, including the brain. This is the first demonstration of an influenza A virus that replicates systemically in a mammalian species and is neurotropic without prior adaptation. The mouse model was also used to evaluate a strategy of vaccination against the highly pathogenic avian H5N1 viruses, using an inactivated vaccine prepared from nonpathogenic A/Duck/Singapore-Q/F119-3/97 (H5N3) virus that was antigenically related to the human H5N1 viruses. Mice administered vaccine intramuscularly, with or without alum, were completely protected from lethal challenge with H5N1 virus. Protection from infection was also observed in 70% of animals administered vaccine alone and 100% of mice administered vaccine with alum. The protective effect of vaccination correlated with the level of virus-specific serum antibody. These results suggests a strategy of vaccine preparedness for rapid intervention in future influenza pandemics that uses antigenically related nonpathogenic viruses as vaccine candidates.

‣ Susceptibility of Immature and Mature Langerhans Cell-Type Dendritic Cells to Infection and Immunomodulation by Human Cytomegalovirus

Hertel, Laura; Lacaille, Vashti G.; Strobl, Herbert; Mellins, Elizabeth D.; Mocarski, Edward S.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /07/2003 Português
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Human cytomegalovirus (CMV) infection initiates in mucosal epithelia and disseminates via leukocytes throughout the body. Langerhans cells (LCs), the immature dendritic cells (DCs) that reside in epithelial tissues, are among the first cells to encounter virus and may play important roles in the immune response, as well as in pathogenesis as hosts for viral replication and as vehicles for dissemination. Here, we demonstrate that CD34+ progenitor cell-derived LC-type DCs exhibit a differentiation state-dependent susceptibility to CMV infection. In contrast to the small percentage (3 to 4%) of the immature LCs that supported infection, a high percentage (48 to 74%) of mature, LC-derived DCs were susceptible to infection with endotheliotropic strains (TB40/E or VHL/E) of CMV. These cells were much less susceptible to viral strains AD169varATCC, TownevarRIT3, and Toledo. When exposed to endotheliotropic strains, viral gene expression (IE1/IE2 and other viral gene products) and viral replication proceeded efficiently in LC-derived mature DCs (mDCs). Productive infection was associated with downmodulation of cell surface CD83, CD1a, CD80, CD86, ICAM-1, major histocompatibility complex (MHC) class I, and MHC class II on these cells. In addition...

‣ Murine intranasal challenge model for the study of Campylobacter pathogenesis and immunity.

Baqar, S; Bourgeois, A L; Applebee, L A; Mourad, A S; Kleinosky, M T; Mohran, Z; Murphy, J R
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /12/1996 Português
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Campylobacter jejuni infection of mice initiated by intranasal administration was investigated as a potential model for studies of pathogenesis and immunity. By using a standard challenge (5 x 10(9) CFU), C. jejuni 81-176 was more virulent for BALB/c (72% mortality) than for C3H/Hej (50%), CBA/CAJ (30%), or C58/J (0%). Intranasal challenge of BALB/c was used to compare the relative virulence of three reference strains; C.jejuni 81-176 was more virulent (killing 83% of challenged mice) than C. jejuni HC (0%) or C. coli VC-167 (0%). The course of intranasally initiated C. jejuni 81-176 infection in BALB/c was determined. C. jejuni was recovered from the lungs, intestinal tract, liver, and spleen at 4 h after challenge, the first interval evaluated. After this initial interval, three distinct patterns of infection were recognized: (i) a progressive decline in number of C. jejuni CFU (stomach, blood, lungs), (ii) decline followed by a second peak in the number of organisms recovered at 2 or 3 days postchallenge (intestine, liver, mesenteric lymph nodes), and (iii) persistence of approximately the same number of C.jejuni CFU during the course of the experiment (spleen). Intranasally induced infection initiated with a sublethal number of bacteria or intranasal immunization with killed Campylobacter preparations resulted in both the generation of Campylobacter antigen-specific immune responses and an acquired resistance to homologous rechallenge. The model was used to evaluate the relative virulence of nine low-in vitro-passage (no more than five passages) isolates of C. jejuni species from patients with diarrhea. The patient isolates were differentially virulent for mice; one killed all exposed mice...

‣ Astrovirus Induces Diarrhea in the Absence of Inflammation and Cell Death

Koci, Matthew D.; Moser, Lindsey A.; Kelley, Laura A.; Larsen, Diane; Brown, Corrie C.; Schultz-Cherry, Stacey
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /11/2003 Português
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Astroviruses are a leading cause of infantile viral gastroenteritis worldwide. Very little is known about the mechanisms of astrovirus-induced diarrhea. One reason for this is the lack of a small-animal model. Recently, we isolated a novel strain of astrovirus (TAstV-2) from turkeys with the emerging infectious disease poult enteritis mortality syndrome. In the present studies, we demonstrate that TAstV-2 causes growth depression, decreased thymus size, and enteric infection in infected turkeys. Infectious TAstV-2 can be recovered from multiple tissues, including the blood, suggesting that there is a viremic stage during infection. In spite of the severe diarrhea, histopathologic changes in the intestine were mild and there was a surprising lack of inflammation. This may be due to the increased activation of the potent immunosuppressive cytokine transforming growth factor beta during astrovirus infection. These studies suggest that the turkey will be a useful small-animal model with which to study astrovirus pathogenesis and immunity.

‣ Systematic Pathogenesis and Replication of Avian Hepatitis E Virus in Specific-Pathogen-Free Adult Chickens

Billam, P.; Huang, F. F.; Sun, Z. F.; Pierson, F. W.; Duncan, R. B.; Elvinger, F.; Guenette, D. K.; Toth, T. E.; Meng, X. J.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /03/2005 Português
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Hepatitis E virus (HEV) is an important human pathogen. Due to the lack of a cell culture system and a practical animal model for HEV, little is known about its pathogenesis and replication. The discovery of a strain of HEV in chickens, designated avian HEV, prompted us to evaluate chickens as a model for the study of HEV. Eighty-five 60-week-old specific-pathogen-free chickens were randomly divided into three groups. Group 1 chickens (n = 28) were each inoculated with 5 × 104.5 50% chicken infectious doses of avian HEV by the oronasal route, group 2 chickens (n = 29) were each inoculated with the same dose by the intravenous (i.v.) route, and group 3 chickens (n = 28) were not inoculated and were used as controls. Two chickens from each group were necropsied at 1, 3, 5, 7, 10, 13, 16, 20, 24, 28, 35, and 42 days postinoculation (dpi), and the remaining chickens were necropsied at 56 dpi. Serum, fecal, and various tissue samples, including liver and spleen samples, were collected at each necropsy for pathological and virological testing. By 21 dpi, all oronasally and i.v. inoculated chickens had seroconverted. Fecal virus shedding was detected variably from 1 to 20 dpi for the i.v. group and from 10 to 56 dpi for the oronasal group. Avian HEV RNA was detected in serum...

‣ The Cotton Rat (Sigmodon hispidus) Is a Permissive Small Animal Model of Human Metapneumovirus Infection, Pathogenesis, and Protective Immunity

Williams, John V.; Tollefson, Sharon J.; Johnson, Joyce E.; Crowe, James E.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /09/2005 Português
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Human metapneumovirus (hMPV) is a newly described paramyxovirus that is an important cause of acute respiratory tract disease. We undertook to develop a small animal model of hMPV infection, pathogenesis, and protection. Hamsters, guinea pigs, cotton rats, and nine inbred strains of mice were inoculated intranasally with hMPV. The animals were sacrificed, and nasal and lung tissue virus yields were determined by plaque titration. None of the animals exhibited respiratory symptoms. The quantity of virus present in the nasal tissue ranged from 4.6 × 102 PFU/gram tissue (C3H mice) to greater than 105 PFU/gram (hamster). The amount of virus in the lungs was considerably less than in nasal tissue in each species tested, ranging from undetectable (<5 PFU/g; guinea pigs) to 1.8 × 105 PFU/gram (cotton rat). The peak virus titer in cotton rat lungs occurred on day 4 postinfection. hMPV-infected cotton rat lungs examined on day 4 postinfection exhibited histopathological changes consisting of peribronchial inflammatory infiltrates. Immunohistochemical staining detected virus only at the luminal surfaces of respiratory epithelial cells throughout the respiratory tract. hMPV-infected cotton rats mounted virus-neutralizing antibody responses and were partially protected against virus shedding and lung pathology on subsequent rechallenge with hMPV. Viral antigen was undetectable in the lungs on challenge of previously infected animals. This study demonstrates that the cotton rat is a permissive small animal model of hMPV infection that exhibits lung histopathology associated with infection and that primary infection protected animals against subsequent infection. This model will allow further in vivo studies of hMPV pathogenesis and evaluation of vaccine candidates.

‣ The S Segment of Punta Toro Virus (Bunyaviridae, Phlebovirus) Is a Major Determinant of Lethality in the Syrian Hamster and Codes for a Type I Interferon Antagonist▿

Perrone, Lucy A.; Narayanan, Krishna; Worthy, Melissa; Peters, C. J.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Português
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Two strains of Punta Toro virus (PTV), isolated from febrile humans in Panama, cause a differential pathogenesis in Syrian hamsters, which could be a useful model for understanding the virulence characteristics and differential outcomes in other phleboviral infections such as Rift Valley fever virus. Genetic reassortants produced between the lethal Adames (A/A/A) and nonlethal Balliet (B/B/B) strains were used in this study to investigate viral genetic determinants for pathogenesis and lethality in the hamster model. The S segment was revealed to be a critical genome segment, determining lethality with log10 50% lethal doses for each PTV genotype as follows (L/M/S convention): A/A/A, <0.7; B/A/A, <0.7; A/B/A, 1.5; B/B/A, 2.2; B/A/B, 4.7; A/B/B, >4.7; A/A/B, >4.7; B/B/B, >4.7. In addition, the Adames strain inhibits the induction of alpha/beta interferon (IFN-α/β) in vivo and in vitro and inhibits the activation of the IFN-β promoter. Expression of the PTV Adames NSs protein, encoded by the S RNA segment, inhibited the virus-mediated induction of an IFN-β promoter-driven reporter gene, suggesting that PTV NSs functions as a type I IFN antagonist. Taken together, these data indicate a mechanism of pathogenesis in which the suppression of the type I IFN response early during PTV infection leads to early and uncontrolled viral replication and...

‣ T Lymphocytes Contribute to Antiviral Immunity and Pathogenesis in Experimental Human Metapneumovirus Infection▿

Kolli, Deepthi; Bataki, Efthalia L.; Spetch, LeAnne; Guerrero-Plata, Antonieta; Jewell, Alan M.; Piedra, Pedro A.; Milligan, Gregg N.; Garofalo, Roberto P.; Casola, Antonella
Fonte: American Society for Microbiology (ASM) Publicador: American Society for Microbiology (ASM)
Tipo: Artigo de Revista Científica
Português
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Human metapneumovirus (hMPV), a member of the family Paramyxoviridae, is a leading cause of lower respiratory tract infections in children, the elderly, and immunocompromised patients. Virus- and host-specific mechanisms of pathogenesis and immune protection are not fully understood. By an intranasal inoculation model, we show that hMPV-infected BALB/c mice developed clinical disease, including airway obstruction and hyperresponsiveness (AHR), along with histopathologic evidence of lung inflammation and viral replication. hMPV infection protected mice against subsequent viral challenge, as demonstrated by undetectable viral titers, lack of body weight loss, and a significant reduction in the level of lung inflammation. No cross-protection with other paramyxoviruses, such as respiratory syncytial virus, was observed. T-lymphocyte depletion studies showed that CD4+ and CD8+ T cells cooperate synergistically in hMPV eradication during primary infection, but CD4+ more than CD8+ T cells also enhanced clinical disease and lung pathology. Concurrent depletion of CD4+ and CD8+ T cells completely blocked airway obstruction as well as AHR. Despite impaired generation of neutralizing anti-hMPV antibodies in the absence of CD4+ T cells, mice had undetectable viral replication after hMPV challenge and were protected from clinical disease...

‣ Pneumonic Plague Pathogenesis and Immunity in Brown Norway Rats

Anderson, Deborah M.; Ciletti, Nancy A.; Lee-Lewis, Hanni; Elli, Derek; Segal, Joshua; DeBord, Kristin L.; Overheim, Katie A.; Tretiakova, Maria; Brubaker, Robert R.; Schneewind, Olaf
Fonte: American Society for Investigative Pathology Publicador: American Society for Investigative Pathology
Tipo: Artigo de Revista Científica
Publicado em /03/2009 Português
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The Brown Norway rat was recently described as a bubonic plague model that closely mimics human disease. We therefore evaluated the Brown Norway rat as an alternative small animal model for pneumonic plague and characterized both the efficacy and potency of vaccine candidates. When infected by intranasal instillation, these rats rapidly developed fatal pneumonic plague within 2 to 4 days of infection. Plague disease was characterized by severe alveolar edema and vascular hemorrhage in the lung in addition to fulminant necrotizing pneumonia caused by massive bacterial replication and inflammation. Twenty-four hours before death, animals developed systemic disease with an apparent delayed inflammatory response. We evaluated the ability of the protective antigen, LcrV, and a mutant derivative, V10, to protect these rats from pneumonic plague. Both were highly effective vaccines because complete protection was observed at challenge doses of 7500 LD50. Antibody analyses suggested stronger potency of V10 immune sera compared with LcrV in the passive transfer of immunity to bubonic plague, with multiple neutralizing epitopes in LcrV. Taken together, these data demonstrate the effectiveness of inhibiting type III secretion in the prevention of pneumonic plague in rats and reveal critical contributions from both the cellular and humoral immune systems. Thus...

‣ Characterization of Respiratory Syncytial Virus M- and M2-Specific CD4 T Cells in a Murine Model▿

Liu, Jie; Ruckwardt, Tracy J.; Chen, Man; Johnson, Teresa R.; Graham, Barney S.
Fonte: American Society for Microbiology (ASM) Publicador: American Society for Microbiology (ASM)
Tipo: Artigo de Revista Científica
Português
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CD4 T cells have been shown to play an important role in the immunity and immunopathogenesis of respiratory syncytial virus (RSV) infection. We identified two novel CD4 T-cell epitopes in the RSV M and M2 proteins with core sequences M213-223 (FKYIKPQSQFI) and M227-37 (YFEWPPHALLV). Peptides containing the epitopes stimulated RSV-specific CD4 T cells to produce gamma interferon (IFN-γ), interleukin 2 (IL-2), and other Th1- and Th2-type cytokines in an I-Ab-restricted pattern. Construction of fluorochrome-conjugated peptide-I-Ab class II tetramers revealed RSV M- and M2-specific CD4 T-cell responses in RSV-infected mice in a hierarchical pattern. Peptide-activated CD4 T cells from lungs were more activated and differentiated, and had greater IFN-γ expression, than CD4 T cells from the spleen, which, in contrast, produced greater levels of IL-2. In addition, M209-223 peptide-activated CD4 T cells reduced IFN-γ and IL-2 production in M- and M2-specific CD8 T-cell responses to Db-M187-195 and Kd-M282-90 peptides more than M225-39 peptide-stimulated CD4 T cells. This correlated with the fact that I-Ab-M209-223 tetramer-positive cells responding to primary RSV infection had a much higher frequency of FoxP3 expression than I-Ab-M226-39 tetramer-positive CD4 T cells...

‣ Development and Characterization of a Mouse Model for Marburg Hemorrhagic Fever▿

Warfield, Kelly L.; Bradfute, Steven B.; Wells, Jay; Lofts, Loreen; Cooper, Meagan T.; Alves, D. Anthony; Reed, Daniel K.; VanTongeren, Sean A.; Mech, Christine A.; Bavari, Sina
Fonte: American Society for Microbiology (ASM) Publicador: American Society for Microbiology (ASM)
Tipo: Artigo de Revista Científica
Português
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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...

‣ Genetic and Pharmacologic Alteration of Cathepsin Expression Influences Reovirus Pathogenesis▿

Johnson, Elizabeth M.; Doyle, Joshua D.; Wetzel, J. Denise; McClung, R. Paul; Katunuma, Nobuhiko; Chappell, James D.; Washington, M. Kay; Dermody, Terence S.
Fonte: American Society for Microbiology (ASM) Publicador: American Society for Microbiology (ASM)
Tipo: Artigo de Revista Científica
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The cathepsin family of endosomal proteases is required for proteolytic processing of several viruses during entry into host cells. Mammalian reoviruses utilize cathepsins B (Ctsb), L (Ctsl), and S (Ctss) for disassembly of the virus outer capsid and activation of the membrane penetration machinery. To determine whether cathepsins contribute to reovirus tropism, spread, and disease outcome, we infected 3-day-old wild-type (wt), Ctsb−/−, Ctsl−/−, and Ctss−/− mice with the virulent reovirus strain T3SA+. The survival rate of Ctsb−/− mice was enhanced in comparison to that of wt mice, whereas the survival rates of Ctsl−/− and Ctss−/− mice were diminished. Peak titers at sites of secondary replication in all strains of cathepsin-deficient mice were lower than those in wt mice. Clearance of the virus was delayed in Ctsl−/− and Ctss−/− mice in comparison to the levels for wt and Ctsb−/− mice, consistent with a defect in cell-mediated immunity in mice lacking cathepsin L or S. Cathepsin expression was dispensable for establishment of viremia, but cathepsin L was required for maximal reovirus growth in the brain. Treatment of wt mice with an inhibitor of cathepsin L led to amelioration of reovirus infection. Collectively...

‣ Interaction of ICP34.5 with Beclin 1 Modulates Herpes Simplex Virus Type 1 Pathogenesis through Control of CD4+ T-Cell Responses▿

Leib, David A.; Alexander, Diane E.; Cox, Douglas; Yin, Jiyi; Ferguson, Thomas A.
Fonte: American Society for Microbiology (ASM) Publicador: American Society for Microbiology (ASM)
Tipo: Artigo de Revista Científica
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Autophagy is an important component of host innate and adaptive immunity to viruses. It is critical for the degradation of intracellular pathogens and for promoting antigen presentation. Herpes simplex virus type 1 (HSV-1) infection induces an autophagy response, but this response is antagonized by the HSV-1 neurovirulence gene product, ICP34.5. This is due, in part, to its interaction with the essential autophagy protein Beclin 1 (Atg6) via the Beclin-binding domain (BBD) of ICP34.5. Using a recombinant virus lacking the BBD, we examined pathogenesis and immune responses using mouse models of infection. The BBD-deficient virus (Δ68H) replicated equivalently to its marker-rescued counterpart (Δ68HR) at early times but was cleared more rapidly than Δ68HR from all tissues at late times following corneal infection. In addition, the infection of the cornea with Δ68H induced less ocular disease than Δ68HR. These results suggested that Δ68H was attenuated due to its failure to control adaptive rather than innate immunity. In support of this idea, Δ68H stimulated a significantly stronger CD4+ T-cell-mediated delayed-type hypersensitivity response and resulted in significantly more production of gamma interferon and interleukin-2 from HSV-specific CD4+ T cells than Δ68HR. Taken together...

‣ The Cotton Rat Model of Respiratory Viral Infections Pathogenesis and Immunity

Boukhvalova, Marina S.; Prince, Gregory A.; Blanco, Jorge C.G.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Development of successful vaccines against human infectious diseases depends on using appropriate animal models for testing vaccine efficacy and safety. For some viral infections the task is further complicated by the frequently changing genetic make-up of the virus, as in the case of influenza, or by the existence of the little-understood phenomenon of vaccine-enhanced disease, as in the case of respiratory syncytial virus (RSV). The cotton rat S.hispidus has been used for years as an excellent small animal model of the RSV vaccine-enhanced disease. Recently, using cotton rats, we have demonstrated that vaccination against another paramyxovirus, human metapneumovirus (hMPV), can also lead to vaccine-enhanced disease. In addition to the study of paramyxoviruses, S.hispidus presents important advantages for the study of orthomyxoviruses such as influenza. The cotton rat is succeptible to infection with unadapted human influenza strains, and heterosubtypic immunity to influenza can be evoked in S.hispidus. The mechanisms of influenza, RSV, and hMPV pathogenesis and immunity can now be investigated in the cotton rat with the development of species-specific reagents for this animal model.

‣ Induction of Alternatively Activated Macrophages Enhances Pathogenesis during Severe Acute Respiratory Syndrome Coronavirus Infection

Page, Carly; Goicochea, Lindsay; Matthews, Krystal; Zhang, Yong; Klover, Peter; Holtzman, Michael J.; Hennighausen, Lothar; Frieman, Matthew
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /12/2012 Português
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Infection with severe acute respiratory syndrome coronavirus (SARS-CoV) causes acute lung injury (ALI) that often leads to severe lung disease. A mouse model of acute SARS-CoV infection has been helpful in understanding the host response to infection; however, there are still unanswered questions concerning SARS-CoV pathogenesis. We have shown that STAT1 plays an important role in the severity of SARS-CoV pathogenesis and that it is independent of the role of STAT1 in interferon signaling. Mice lacking STAT1 have greater weight loss, severe lung pathology with pre-pulmonary-fibrosis-like lesions, and an altered immune response following infection with SARS-CoV. We hypothesized that STAT1 plays a role in the polarization of the immune response, specifically in macrophages, resulting in a worsened outcome. To test this, we created bone marrow chimeras and cell-type-specific knockouts of STAT1 to identify which cell type(s) is critical to protection from severe lung disease after SARS-CoV infection. Bone marrow chimera experiments demonstrated that hematopoietic cells are responsible for the pathogenesis in STAT1−/− mice, and because of an induction of alternatively activated (AA) macrophages after infection, we hypothesized that the AA macrophages were critical for disease severity. Mice with STAT1 in either monocytes and macrophages (LysM/STAT1) or ciliated lung epithelial cells (FoxJ1/STAT1) deleted were created. Following infection...

‣ Daxx Upregulation within the Cytoplasm of Reovirus-Infected Cells Is Mediated by Interferon and Contributes to Apoptosis

Dionne, Kalen R.; Zhuang, Yonghua; Leser, J. Smith; Tyler, Kenneth L.; Clarke, Penny
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /03/2013 Português
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Reovirus infection is a well-characterized experimental system for the study of viral pathogenesis and antiviral immunity within the central nervous system (CNS). We have previously shown that c-Jun N-terminal kinase (JNK) and the Fas death receptor each play a role in neuronal apoptosis occurring in reovirus-infected brains. Death-associated protein 6 (Daxx) is a cellular protein that mechanistically links Fas signaling to JNK signaling in several models of apoptosis. In the present study, we demonstrate that Daxx is upregulated in reovirus-infected brain tissue through a type I interferon-mediated mechanism. Daxx upregulation is limited to brain regions that undergo reovirus-induced apoptosis and occurs in the cytoplasm and nucleus of neurons. Cytoplasmic Daxx is present in Fas-expressing cells during reovirus encephalitis, suggesting a role for Daxx in Fas-mediated apoptosis following reovirus infection. Further, in vitro expression of a dominant negative form of Daxx (DN-Daxx), which binds to Fas but which does not transmit downstream signaling, inhibits apoptosis of reovirus-infected cells. In contrast, in vitro depletion of Daxx results in increased expression of caspase 3 and apoptosis, suggesting that Daxx plays an antiapoptotic role in the nucleus. Overall...

‣ Recent molecular insights into rickettsial pathogenesis and immunity

Sahni, Sanjeev K; Narra, Hema P; Sahni, Abha; Walker, David H
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /10/2013 Português
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Human infections with arthropod-borne Rickettsia species remain a major global health issue, causing significant morbidity and mortality. Epidemic typhus due to Rickettsia prowazekii has an established reputation as the ‘scourge of armies’, and as a major determinant of significant ‘historical turning points’. No suitable vaccines for human use are currently available to prevent rickettsial diseases. The unique lifestyle features of rickettsiae include obligate intracellular parasitism, intracytoplasmic niche within the host cell, predilection for infection of microvascular endothelium in mammalian hosts, association with arthropods and the tendency for genomic reduction. The fundamental research in the field of Rickettsiology has witnessed significant recent progress in the areas of pathogen adhesion/invasion and host immune responses, as well as the genomics, proteomics, metabolomics, phylogenetics, motility and molecular manipulation of important rickettsial pathogens. The focus of this review article is to capture a snapshot of the latest developments pertaining to the mechanisms of rickettsial pathogenesis and immunity.

‣ The Programmed Death-1 and Interleukin-10 Pathways Play a Down-Modulatory Role in LP-BM5 Retrovirus-Induced Murine Immunodeficiency Syndrome▿

Green, Kathy A.; Okazaki, Taku; Honjo, Tasuku; Cook, W. James; Green, William R.
Fonte: American Society for Microbiology (ASM) Publicador: American Society for Microbiology (ASM)
Tipo: Artigo de Revista Científica
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Pathology due to the immune system's response to viral infections often represents a delicate balance between inhibition of viral pathogenesis and regulation of protective immunity. In susceptible C57BL/6 (B6) mice, the murine retroviral isolate LP-BM5 induces splenomegaly, hypergammaglobulinemia, profound B- and T-cell immunodeficiency, and increased susceptibility to opportunistic pathogens and terminal B-cell lymphomas. Here, we report that B6.PD-1 (programmed death-1) and B6.IL-10 knockout mice are substantially more susceptible to LP-BM5-induced disease than wild-type B6 mice. LP-BM5-infected B6.PD-1−/− mice developed more severe splenomegaly, hypergammaglobulinemia, and immunodeficiency than infected B6 mice: PD-1−/− mice are more susceptible to lower doses of LP-BM5 and show more exaggerated disease early postinfection. LP-BM5-infected B6.IL-10−/− mice also develop exaggerated LP-BM5-induced disease, compared to B6 mice, without a significant change in the retroviral load. By reciprocal reconstitution experiments, comparing wild-type versus PD-1−/− sources of the requisite cells for LP-BM5 pathogenesis—CD4 T and B cells, PD-1+ B cells appear to be crucial in the normal limitation of LP-BM5-induced disease in B6 mice. Also...

‣ Pathogenesis and Immune Responses in Gnotobiotic Calves after Infection with the Genogroup II.4-HS66 Strain of Human Norovirus▿

Souza, M.; Azevedo, M. S. P.; Jung, K.; Cheetham, S.; Saif, L. J.
Fonte: American Society for Microbiology (ASM) Publicador: American Society for Microbiology (ASM)
Tipo: Artigo de Revista Científica
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We previously characterized the pathogenesis of two host-specific bovine enteric caliciviruses (BEC), the GIII.2 norovirus (NoV) strain CV186-OH and the phylogenetically unassigned NB strain, in gnotobiotic (Gn) calves. In this study we evaluated the Gn calf as an alternative animal model to study the pathogenesis and host immune responses to the human norovirus (HuNoV) strain GII.4-HS66. The HuNoV HS66 strain caused diarrhea (five/five calves) and intestinal lesions (one/two calves tested) in the proximal small intestine (duodenum and jejunum) of Gn calves, with lesions similar to, but less severe than, those described for the Newbury agent 2 (NA-2) and NB BEC. Viral capsid antigen was also detected in the jejunum of the proximal small intestine of one of two calves tested by immunohistochemistry. All inoculated calves shed virus in feces (five/five calves), and one/five had viremia. Antibodies and cytokine (proinflammatory, tumor necrosis factor alpha [TNF-α]; Th1, interleukin-12 [IL-12] and gamma interferon [IFN-γ]; Th2, IL-4; Th2/T-regulatory, IL-10) profiles were determined in serum, feces, and intestinal contents (IC) of the HuNoV-HS66-inoculated calves (n = 5) and controls (n = 4) by enzyme-linked immunosorbent assay in the acute (postinoculation day 3 [PID 3]) and convalescent (PID 28) stages of infection. The HuNoV-HS66-specific antibody and cytokine-secreting cells (CSCs) were quantitated by ELISPOT in mononuclear cells of local and systemic tissues at PID 28. Sixty-seven percent of the HuNoV-HS66-inoculated calves seroconverted...

‣ Virulence and Immunity Orchestrated by the Global Gene Regulator sigL in Mycobacterium avium subsp. paratuberculosis

Ghosh, Pallab; Steinberg, Howard; Talaat, Adel M.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /07/2014 Português
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Mycobacterium avium subsp. paratuberculosis causes Johne's disease in ruminants, a chronic enteric disease responsible for severe economic losses in the dairy industry. Global gene regulators, including sigma factors are important in regulating mycobacterial virulence. However, the biological significance of such regulators in M. avium subsp. paratuberculosis rremains elusive. To better decipher the role of sigma factors in M. avium subsp. paratuberculosis pathogenesis, we targeted a key sigma factor gene, sigL, activated in mycobacterium-infected macrophages. We interrogated an M. avium subsp. paratuberculosis ΔsigL mutant against a selected list of stressors that mimic the host microenvironments. Our data showed that sigL was important in maintaining bacterial survival under such stress conditions. Survival levels further reflected the inability of the ΔsigL mutant to persist inside the macrophage microenvironments. Additionally, mouse infection studies suggested a substantial role for sigL in M. avium subsp. paratuberculosis virulence, as indicated by the significant attenuation of the ΔsigL-deficient mutant compared to the parental strain. More importantly, when the sigL mutant was tested for its vaccine potential, protective immunity was generated in a vaccine/challenge model of murine paratuberculosis. Overall...