scholarly journals Passive Immunization Reduces Murine Cytomegalovirus-Induced Brain Pathology in Newborn Mice

2008 ◽  
Vol 82 (24) ◽  
pp. 12172-12180 ◽  
Author(s):  
Đurđica Cekinović ◽  
Mijo Golemac ◽  
Ester Pernjak Pugel ◽  
Jelena Tomac ◽  
Luka Čičin-Šain ◽  
...  
Keyword(s):  
Virus Titer ◽  
Passive Immunization ◽  
Immune Serum ◽  
Murine Cytomegalovirus ◽  
Cns Infection ◽  
Newborn Mice ◽  
Specific Antibodies ◽  
Control Serum ◽  
The Brain ◽  
Infected Newborn

ABSTRACT Human cytomegalovirus (HCMV) is the most frequent cause of congenital viral infections in humans and frequently leads to long-term central nervous system (CNS) abnormalities that include learning disabilities, microcephaly, and hearing loss. The pathogenesis of the CNS infection has not been fully elucidated and may arise as a result of direct damage of CMV-infected neurons or indirectly secondary to inflammatory response to infection. We used a recently established model of mouse CMV (MCMV) infection in newborn mice to analyze the contribution of humoral immunity to virus clearance from the brain. In brains of MCMV-infected newborn mice treated with immune serum, the titer of infectious virus was reduced below detection limit, whereas in the brains of mice receiving control (nonimmune) serum significant amounts of virus were recovered. Moreover, histopathological and immunohistological analyses revealed significantly less CNS inflammation in mice treated with immune serum. Treatment with MCMV-specific monoclonal antibodies also resulted in the reduction of virus titer in the brain. Recipients of control serum or irrelevant antibodies had more viral foci, marked mononuclear cell infiltrates, and prominent glial nodules in their brains than mice treated with immune serum or MCMV-specific antibodies. In conclusion, our data indicate that virus-specific antibodies have a protective role in the development of CNS pathology in MCMV-infected newborn mice, suggesting that antiviral antibodies may be an important component of protective immunological responses during CMV infection of the developing CNS.

scholarly journals Acquisition of Maternal Antibodies both from the Placenta and by Lactation Protects Mouse Offspring from Yersinia pestis Challenge

2012 ◽  
Vol 19 (11) ◽  
pp. 1746-1750 ◽  
Author(s):  
Zhizhen Qi ◽  
Haihong Zhao ◽  
Qingwen Zhang ◽  
Yujing Bi ◽  
Lingling Ren ◽  
...  
Keyword(s):  
Yersinia Pestis ◽  
Subunit Vaccine ◽  
Protective Efficacy ◽  
Passive Immunization ◽  
Maternal Antibodies ◽  
Newborn Mice ◽  
Content Type ◽  
Specific Antibodies ◽  
Transmission Modes ◽  
Passive Antibodies

ABSTRACTArtificially passive immunization has been demonstrated to be effective againstYersinia pestisinfection in animals. However, maternal antibodies' protective efficacy against plague has not yet been demonstrated. Here, we evaluated the kinetics, protective efficacy, and transmission modes of maternal antibodies, using mice immunized with plague subunit vaccine SV1 (20 μg of F1 and 10 μg of rV270). The results showed that the rV270- and F1-specific antibodies could be detected in the sera of newborn mice (NM) until 10 and 14 weeks of age, respectively. There was no antibody titer difference between the parturient mice immunized with SV1 (PM-S) and the caesarean-section newborns (CSN) from the PM-S or between the lactating mice immunized by SV1 (LM-S) and the cross-fostered mice (CFM) during 3 weeks of lactation. The NM had a 72% protection against 4,800 CFUY. pestisstrain 141 challenge at 6 weeks of age, whereas at 14 weeks of age, NM all succumbed to 5,700 CFU ofY. pestischallenge. After 7 weeks of age, CFM had an 84% protection against 5,000 CFU ofY. pestischallenge. These results indicated that maternal antibodies induced by the plague subunit vaccine in mother mice can be transferred to NM by both placenta and lactation. Passive antibodies from the immunized mothers could persist for 3 months and provide early protection for NM. The degree of early protection is dependent on levels of the passively acquired antibody. The results indicate that passive immunization should be an effective countermeasure against plague during its epidemics.

scholarly journals CD4 T cells are required for maintenance of CD8 TRM cells and virus control in the brain of MCMV-infected newborn mice

2019 ◽  
Vol 208 (3-4) ◽  
pp. 487-494 ◽  
Author(s):  
Ilija Brizić ◽  
Lea Hiršl ◽  
Marko Šustić ◽  
Mijo Golemac ◽  
William J. Britt ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Newborn Mice ◽  
Virus Control ◽  
The Brain ◽  
Infected Newborn

scholarly journals NK/ILC1 cells mediate neuroinflammation and brain pathology following congenital CMV infection

2021 ◽  
Vol 218 (5) ◽  
Author(s):  
Daria Kveštak ◽  
Vanda Juranić Lisnić ◽  
Berislav Lisnić ◽  
Jelena Tomac ◽  
Mijo Golemac ◽  
...  
Keyword(s):  
Virus Infection ◽  
Inflammatory Responses ◽  
Inflammatory Factors ◽  
Cns Infection ◽  
Dependent Manner ◽  
Mcmv Infection ◽  
Newborn Mice ◽  
Wide Range ◽  
Control Virus ◽  
The Brain

Congenital human cytomegalovirus (cHCMV) infection of the brain is associated with a wide range of neurocognitive sequelae. Using infection of newborn mice with mouse cytomegalovirus (MCMV) as a reliable model that recapitulates many aspects of cHCMV infection, including disseminated infection, CNS infection, altered neurodevelopment, and sensorineural hearing loss, we have previously shown that mitigation of inflammation prevented alterations in cerebellar development, suggesting that host inflammatory factors are key drivers of neurodevelopmental defects. Here, we show that MCMV infection causes a dramatic increase in the expression of the microglia-derived chemokines CXCL9/CXCL10, which recruit NK and ILC1 cells into the brain in a CXCR3-dependent manner. Surprisingly, brain-infiltrating innate immune cells not only were unable to control virus infection in the brain but also orchestrated pathological inflammatory responses, which lead to delays in cerebellar morphogenesis. Our results identify NK and ILC1 cells as the major mediators of immunopathology in response to virus infection in the developing CNS, which can be prevented by anti–IFN-γ antibodies.

scholarly journals Cytomegalovirus Infection and Inflammation in Developing Brain

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1078
Author(s):  
Fran Krstanović ◽  
William J. Britt ◽  
Stipan Jonjić ◽  
Ilija Brizić
Keyword(s):  
Cytomegalovirus Infection ◽  
Hcmv Infection ◽  
Severe Disease ◽  
Intraperitoneal Administration ◽  
Inflammatory Factors ◽  
Mcmv Infection ◽  
Newborn Mice ◽  
Organ Systems ◽  
Congenital Hcmv Infection ◽  
The Brain

Human cytomegalovirus (HCMV) is a highly prevalent herpesvirus that can cause severe disease in immunocompromised individuals and immunologically immature fetuses and newborns. Most infected newborns are able to resolve the infection without developing sequelae. However, in severe cases, congenital HCMV infection can result in life-threatening pathologies and permanent damage of organ systems that possess a low regenerative capacity. Despite the severity of the problem, HCMV infection of the central nervous system (CNS) remains inadequately characterized to date. Cytomegaloviruses (CMVs) show strict species specificity, limiting the use of HCMV in experimental animals. Infection following intraperitoneal administration of mouse cytomegalovirus (MCMV) into newborn mice efficiently recapitulates many aspects of congenital HCMV infection in CNS. Upon entering the CNS, CMV targets all resident brain cells, consequently leading to the development of widespread histopathology and inflammation. Effector functions from both resident cells and infiltrating immune cells efficiently resolve acute MCMV infection in the CNS. However, host-mediated inflammatory factors can also mediate the development of immunopathologies during CMV infection of the brain. Here, we provide an overview of the cytomegalovirus infection in the brain, local immune response to infection, and mechanisms leading to CNS sequelae.

scholarly journals Bystander Attenuation of Neuronal and Astrocyte Intercellular Communication by Murine Cytomegalovirus Infection of Glia

2007 ◽  
Vol 81 (13) ◽  
pp. 7286-7292 ◽  
Author(s):  
Winson S. C. Ho ◽  
Anthony N. van den Pol
Keyword(s):  
Intercellular Communication ◽  
Neuronal Development ◽  
Primary Cultures ◽  
Synaptic Activity ◽  
Murine Cytomegalovirus ◽  
Intercellular Signaling ◽  
Mcmv Infection ◽  
High Potassium ◽  
Infected Cells ◽  
The Brain

ABSTRACT Astrocytes are the first cells infected by murine cytomegalovirus (MCMV) in primary cultures of brain. These cells play key roles in intercellular signaling and neuronal development, and they modulate synaptic activity within the nervous system. Using ratiometric fura-2 digital calcium imaging of >8,000 neurons and glia, we found that MCMV-infected astrocytes showed an increase in intracellular basal calcium levels and an enhanced response to neuroactive substances, including glutamate and ATP, and to high potassium levels. Cultured neurons with no sign of MCMV infection showed attenuated synaptic signaling after infection of the underlying astrocyte substrate, and intercellular communication between astrocytes with no sign of infection was reduced by the presence of infected glia. These bystander effects would tend to cause further deterioration of cellular communication in the brain in addition to the problems caused by the loss of directly infected cells.

Protection against lethal enterovirus 71 infection in newborn mice by passive immunization with subunit VP1 vaccines and inactivated virus

Vaccine ◽  
2001 ◽  
Vol 20 (5-6) ◽  
pp. 895-904 ◽  
Author(s):  
Cheng-Nan Wu ◽  
Ya-Ching Lin ◽  
Cathy Fann ◽  
Nan-Shih Liao ◽  
Shin-Ru Shih ◽  
...  
Keyword(s):  
Passive Immunization ◽  
Enterovirus 71 ◽  
Newborn Mice ◽  
Enterovirus 71 Infection

scholarly journals Conserved Peptide with Therapeutic Potential to Overcome Nasopharyngeal Carcinoma

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Muhaimin R ◽  
Widyarti S ◽  
Widodo N
Keyword(s):  
B Cells ◽  
Nasopharyngeal Carcinoma ◽  
Epstein Barr Virus ◽  
Therapeutic Potential ◽  
Nasopharyngeal Cancer ◽  
Passive Immunization ◽  
Spleen Cells ◽  
Specific Antibodies ◽  
Barr Virus ◽  
Epstein Barr

Nasopharyngeal carcinoma (NPC) is a squamous-cell carcinoma that arises in the upper lining epithelium of the nasopharynx. In this study, conserved peptide (Ulin-1) of Epstein-Barr virus constructed by Biomodelling and Biocomputation was tested for its ability to stimulate B cells to produce specific antibodies. Spleen cells were isolated and cultured with anti-CD3 and lipopolysaccharide (LPS), and treated or not treated with Ulin-1. Cell culture was harvested six days after incubation and analyzed by flow cytometry. Here, we demonstrated the ability of Ulin-1 to stimulate B cells to produce specific antibodies. The results of this study illustrate the importance of Ulin-1 engineered by Biomodelling and Biocomputation as both active and passive immunization agents against nasopharyngeal cancer.

scholarly journals Adenylyl cyclase type 5 protein expression during cardiac development and stress

2009 ◽  
Vol 297 (5) ◽  
pp. H1776-H1782 ◽  
Author(s):  
Che-Lin Hu ◽  
Rachna Chandra ◽  
Hui Ge ◽  
Jayashree Pain ◽  
Lin Yan ◽  
...  
Keyword(s):  
Adenylyl Cyclase ◽  
Adrenergic Receptor ◽  
Ventricular Hypertrophy ◽  
Cardiac Development ◽  
Mammalian Species ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Receptor Stimulation ◽  
Specific Antibodies ◽  
The Brain

Adenylyl cyclase (AC) types 5 and 6 (AC5 and AC6) are the two major AC isoforms expressed in the mammalian heart that mediate signals from β-adrenergic receptor stimulation. Because of the unavailability of isoform-specific antibodies, it is difficult to ascertain the expression levels of AC5 protein in the heart. Here we demonstrated the successful generation of an AC5 isoform-specific mouse monoclonal antibody and studied the expression of AC5 protein during cardiac development in different mammalian species. The specificity of the antibody was confirmed using heart and brain tissues from AC5 knockout mice and from transgenic mice overexpressing AC5. In mice, the AC5 protein was highest in the brain but was also detectable in all organs studied, including the heart, brain, lung, liver, stomach, kidney, skeletal muscle, and vascular tissues. Western blot analysis showed that AC5 was most abundant in the neonatal heart and declined to basal levels in the adult heart. AC5 protein increased in the heart with pressure-overload left ventricular hypertrophy. Thus this new AC5 antibody demonstrated that this AC isoform behaves similarly to fetal type genes, such as atrial natriuretic peptide; i.e., it declines with development and increases with pressure-overload hypertrophy.

scholarly journals Reovirus Neurotropism and Virulence Are Dictated by Sequences in the Head Domain of the Viral Attachment Protein

2018 ◽  
Vol 92 (23) ◽  
Author(s):  
Danica M. Sutherland ◽  
Pavithra Aravamudhan ◽  
Melanie H. Dietrich ◽  
Thilo Stehle ◽  
Terence S. Dermody
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Ependymal Cells ◽  
Attachment Protein ◽  
Newborn Mice ◽  
Viral Attachment ◽  
Head Domain ◽  
Serotype 1 ◽  
The Central Nervous System ◽  
The Brain

ABSTRACTViral capsid components that bind cellular receptors mediate critical functions in viral tropism and disease pathogenesis. Mammalian orthoreoviruses (reoviruses) spread systemically in newborn mice to cause serotype-specific disease in the central nervous system (CNS). Serotype 1 (T1) reovirus infects ependymal cells to cause nonlethal hydrocephalus, whereas serotype 3 (T3) reovirus infects neurons to cause fulminant and lethal encephalitis. This serotype-dependent difference in tropism and concomitant disease is attributed to the σ1 viral attachment protein, which is composed of head, body, and tail domains. To identify σ1 sequences that contribute to tropism for specific cell types in the CNS, we engineered a panel of viruses expressing chimeric σ1 proteins in which discrete σ1 domains have been reciprocally exchanged. Parental and chimeric σ1 viruses were compared for replication, tropism, and disease induction following intracranial inoculation of newborn mice. Viruses expressing T1 σ1 head sequences infect the ependyma, produce relatively lower titers in the brain, and do not cause significant disease. In contrast, viruses expressing T3 σ1 head sequences efficiently infect neurons, replicate to relatively higher titers in the brain, and cause a lethal encephalitis. Additionally, T3 σ1 head-expressing viruses display enhanced infectivity of cultured primary cortical neurons compared with T1 σ1 head-expressing viruses. These results indicate that T3 σ1 head domain sequences promote infection of neurons, likely by interaction with a neuron-specific receptor, and dictate tropism in the CNS and induction of encephalitis.IMPORTANCEViral encephalitis is a serious and often life-threatening inflammation of the brain. Mammalian orthoreoviruses are promising oncolytic therapeutics for humans but establish virulent, serotype-dependent disease in the central nervous system (CNS) of many young mammals. Serotype 1 reoviruses infect ependymal cells and produce hydrocephalus, whereas serotype 3 reoviruses infect neurons and cause encephalitis. Reovirus neurotropism is hypothesized to be dictated by the filamentous σ1 viral attachment protein. However, it is not apparent how this protein mediates disease. We discovered that sequences forming the most virion-distal domain of T1 and T3 σ1 coordinate infection of either ependyma or neurons, respectively, leading to mutually exclusive patterns of tropism and disease in the CNS. These studies contribute new knowledge about how reoviruses target cells for infection in the brain and inform the rational design of improved oncolytic therapies to mitigate difficult-to-treat tumors of the CNS.

Primary Peripheral Epstein-Barr Virus Infection Can Lead to CNS Infection and Neuroinflammation in a Rabbit Model: Implications for Multiple Sclerosis Pathogenesis

2021 ◽  
Author(s):  
Asma Hassani ◽  
Narendran Reguraman ◽  
Safa Shehab ◽  
Gulfaraz Khan
Keyword(s):  
Multiple Sclerosis ◽  
Epstein Barr Virus ◽  
Rabbit Model ◽  
Nerve Fibers ◽  
Cns Infection ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr ◽  
Cellular Aggregates ◽  
The Brain

Abstract Background: Epstein-Barr virus (EBV) is a common herpesvirus associated with malignant and non-malignant conditions. An accumulating body of evidence supports a role for EBV in the pathogenesis of multiple sclerosis (MS), a demyelinative disease of the CNS. However, little is known about the details of the link between EBV and MS. One obstacle which has hindered research in this area has been the lack of a suitable animal model recapitulating natural infection in humans. We have recently shown that healthy rabbits are susceptible to EBV infection, and viral persistence in these animals mimics latent infection in humans. Methods: We used the rabbit model to investigate if peripheral EBV infection can lead to infection of the CNS and its potential consequences. We injected EBV intravenously in one group of animals, and PBS in another, with and without immunosuppression. Histopathological changes and viral dynamics were examined in peripheral blood, spleen, brain, and spinal cord, using a range of molecular and histopathology techniques. Results: Our investigations uncovered important findings that could not be previously addressed. We showed that primary peripheral EBV infection can lead to the virus traversing the CNS. Cell associated, but not free virus in the plasma, correlated with CNS infection. The infected cells within the brain were found to be B-lymphocytes. Most notably, animals injected with EBV, but not PBS, developed inflammatory cellular aggregates in the CNS. The incidence of these aggregates increased in the immunosuppressed animals. The cellular aggregates contained compact clusters of macrophages surrounded by reactive astrocytes and dispersed B and T lymphocytes, but not myelinated nerve fibers. Moreover, studying EBV infection over a span of 28 days, revealed that the peak point for viral load in the periphery and CNS coincides with increased occurrence of cellular aggregates in the brain. Finally, peripheral EBV infection triggered temporal changes in the expression of latent viral transcripts and cytokines in the brain. Conclusion: The present study provides the first direct in vivo evidence for the role of peripheral EBV infection in CNS pathology, and highlights a unique model to dissect viral mechanisms contributing to the development of MS.

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